1. Genomics Proteomics Bioinformatics. 2015 Jun 17. pii: S1672-0229(15)00046-7. doi: 10.1016/j.gpb.2015.03.002. [Epub ahead of print] Primate torpor: Regulation of stress-activated protein kinases during daily torpor in the grey mouse lemur, Microcebus murinus. Biggar KK(1), Wu CW(2), Tessier SN(3), Zhang J(4), Pifferi F(5), Perret M(5), Storey KB(6). Author information: (1)Institute of Biochemistry and Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada; Biochemistry Department, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada. (2)Institute of Biochemistry and Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada; Department of Biology, Genetics Institute, University of Florida, Gainesville, FL 32611, USA. (3)Institute of Biochemistry and Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada; Department of Surgery & Center for Engineering in Medicine, Massachusetts General Hospital & Harvard Medical School, Charlestown, MA 02129, USA. (4)Institute of Biochemistry and Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada; Chemistry and Chemical Engineering Department, Royal Military College of Canada, Kingston, ON K7K 7B4, Canada. (5)UMR 7179 Centre National de la Recherche Scientifique, Muséum National d'Histoire Naturelle, 91800 Brunoy, France. (6)Institute of Biochemistry and Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada. Electronic address: kenneth_storey@carleton.ca. Very few selected species of primates are known to be capable of entering torpor. This exciting discovery means that the ability to enter a natural state of dormancy is an ancestral trait among primates and, in phylogenetic terms, is very close to the human lineage. To explore the regulatory mechanisms that underlie primate torpor, we analyzed signal transduction cascades to discover those involved in coordinating tissue responses during torpor. The responses of mitogen-activated protein kinase (MAPK) family members to primate torpor were compared in six organs of control (aroused) versus torpid grey mouse lemurs, Microcebus murinus. The proteins examined include extracellular signal-regulated kinases (ERKs), c-jun NH2-terminal kinases (JNKs), MAPK kinase (MEK), and p38, in addition to stress-related proteins p53 and heat shock protein 27 (HSP27). The activation of specific MAPK signal transduction pathways may provide a mechanism to regulate the expression of torpor-responsive genes or the regulation of selected downstream cellular processes. In response to torpor, each MAPK subfamily responded differently during torpor and each showed organ-specific patterns of response. For example, skeletal muscle displayed elevated relative phosphorylation of ERK1/2 during torpor. Interestingly, adipose tissues showed the highest degree of MAPK activation. Brown adipose tissue displayed an activation of ERK1/2 and p38, whereas white adipose tissue showed activation of ERK1/2, p38, MEK, and JNK during torpor. Importantly, both adipose tissues possess specialized functions that are critical for torpor, with brown adipose required for non-shivering thermogenesis and white adipose utilized as the primary source of lipid fuel for torpor. Overall, these data indicate crucial roles of MAPKs in the regulation of primate organs during torpor. Copyright © 2015. Production and hosting by Elsevier Ltd. PMID: 26093282 [PubMed - as supplied by publisher] 2. Am J Physiol Regul Integr Comp Physiol. 2015 Jun 3:ajpregu.00031.2015. doi: 10.1152/ajpregu.00031.2015. [Epub ahead of print] Regular Post-Exercise Cooling Enhances Mitochondrial Biogenesis through AMPK and p38 MAPK in Human Skeletal Muscle. Ihsan M(1), Markworth JF(2), Watson G(3), Choo HC(4), Govus A(5), Pham T(6), Hickey AJ(6), Cameron-Smith D(2), Abbiss CR(5). Author information: (1)Singapore Sports Institute Ihsan_Abdullah@sport.gov.sg. (2)The University of Auckland. (3)University of Tasmania. (4)National Institute of Education. (5)Edith Cowan University. (6)University of Auckland. This study investigated the effect of regular post-exercise cold water immersion (CWI) on muscle aerobic adaptations to endurance training. Eight males performed 3 sessions∙wk-1 of endurance training for 4 weeks. Following each session, subjects immersed one leg in a cold water bath (10°C; COLD) for 15 min while the contra-lateral leg served as control (CON). Muscle biopsies were obtained from vastus lateralis of both CON and COLD legs prior to training and 48 h following the last training session. Samples were analysed for signalling kinases; p38 mitogen activated protein kinase (p38 MAPK) and adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), enzyme activities indicative of mitochondrial biogenesis and protein subunits representative of respiratory chain complexes I-V. Following training, subjects' peak oxygen uptake and running velocity were improved by 5.9% and 6.2%, respectively (p < 0.05). Repeated CWI resulted in higher total AMPK, phosphorylated AMPK, phosphorylated acetyl-CoA carboxylase, β-3-hydroxyacyl-CoA-dehydrogenase and the protein subunits representative of complex-I and III (p < 0.05). Moreover, large effect sizes (Cohen's d > 0.8) were noted with changes in protein content of p38 (d = 1.02, p = 0.064), PGC-1α (d = 0.99, p = 0.079) and peroxisome proliferator-activated receptor α (d = 0.93, p = 0.010) in COLD compared with CON. No differences between conditions were observed in the representative protein subunits of respiratory complexes-II, IV, V and in the activities of several mitochondrial enzymes (p > 0.05). These findings indicate that regular CWI enhances p38, AMPK and possibly mitochondrial biogenesis. Copyright © 2015, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology. PMID: 26041108 [PubMed - as supplied by publisher] 3. J Nutr Sci Vitaminol (Tokyo). 2015;61(1):79-83. doi: 10.3177/jnsv.61.79. Kaempferia parviflora Extract Increases Whole-Body Energy Expenditure in Humans: Roles of Brown Adipose Tissue. Matsushita M(1), Yoneshiro T, Aita S, Kamiya T, Kusaba N, Yamaguchi K, Takagaki K, Kameya T, Sugie H, Saito M. Author information: (1)Department of Nutrition, School of Nursing and Nutrition, Tenshi College. Kaempferia parviflora extract (KP) has been reported to have a preventive effect on obesity in mice, probably by increasing energy expenditure (EE). The aims of the current study were to examine the acute effects of KP ingestion on whole-body EE in humans and to analyze its relation to the activity of brown adipose tissue (BAT), a site of non-shivering thermogenesis. After an oral ingestion of an ethanol extract of KP, EE increased significantly, showing a maximal increase of 229±69 kJ/d at 60 min, while it did not change after placebo ingestion. To evaluate BAT activity, the subjects underwent fluorodeoxyglucose-positron emission tomography, and divided into two groups with high- and low-BAT activities. A similar and greater response of EE to KP ingestion was observed in the high-BAT group (351±50 kJ/d at 60 min), but not in the low activity group. Placebo ingestion did not cause any significant EE change in either group. These results indicate that a single oral ingestion of the KP extract can potentially increase whole-body EE probably through the activation of BAT in healthy men, and may be useful as an anti-obesity regimen. PMID: 25994142 [PubMed - in process] 4. J Comp Physiol B. 2015 May 13. [Epub ahead of print] Brown adipose tissue: physiological function and evolutionary significance. Oelkrug R(1), Polymeropoulos ET, Jastroch M. Author information: (1)Department of Animal Physiology, Faculty of Biology, Philipps-Universität Marburg, Karl-von-Frisch Straße 8, 35043, Marburg, Germany, rebecca.oelkrug@uni-bonn.de. In modern eutherian (placental) mammals, brown adipose tissue (BAT) evolved as a specialized thermogenic organ that is responsible for adaptive non-shivering thermogenesis (NST). For NST, energy metabolism of BAT mitochondria is increased by activation of uncoupling protein 1 (UCP1), which dissipates the proton motive force as heat. Despite the presence of UCP1 orthologues prior to the divergence of teleost fish and mammalian lineages, UCP1's significance for thermogenic adipose tissue emerged at later evolutionary stages. Recent studies on the presence of BAT in metatherians (marsupials) and eutherians of the afrotherian clade provide novel insights into the evolution of adaptive NST in mammals. In particular studies on the 'protoendothermic' lesser hedgehog tenrec (Afrotheria) suggest an evolutionary scenario linking BAT to the onset of eutherian endothermy. Here, we review the physiological function and distribution of BAT in an evolutionary context by focusing on the latest research on phylogenetically distinct species. PMID: 25966796 [PubMed - as supplied by publisher] 5. Handb Exp Pharmacol. 2015 Apr 23. [Epub ahead of print] cGMP and Brown Adipose Tissue. Hoffmann LS(1), Larson CJ, Pfeifer A. Author information: (1)Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127, Bonn, Germany. The second messenger cyclic guanosine monophosphate (cGMP) is a key mediator in physiological processes such as vascular tone, and its essential involvement in pathways regulating metabolism has been recognized in recent years. Here, we focus on the fundamental role of cGMP in brown adipose tissue (BAT) differentiation and function. In contrast to white adipose tissue (WAT), which stores energy in the form of lipids, BAT consumes energy stored in lipids to generate heat. This so-called non-shivering thermogenesis takes place in BAT mitochondria, which express the specific uncoupling protein 1 (UCP1). The energy combusting properties of BAT render it a promising target in antiobesity strategies in which BAT could burn the surplus energy that has accumulated in obese and overweight individuals. cGMP is generated by guanylyl cyclases upon activation by nitric oxide or natriuretic peptides. It affects several downstream molecules including cGMP-receptor proteins such as cGMP-dependent protein kinase and is degraded by phosphodiesterases. The cGMP pathway contains several signaling molecules that can increase cGMP signaling, resulting in activation and recruitment of brown adipocytes, and hence can enhance the energy combusting features of BAT. In this review we highlight recent results showing the physiological significance of cGMP signaling in BAT, as well as pharmacological options targeting cGMP signaling that bear a high potential to become BAT-centered therapies for the treatment of obesity. PMID: 25903412 [PubMed - as supplied by publisher] 6. J Physiol Anthropol. 2015 Mar 13;34(1):11. doi: 10.1186/s40101-015-0051-9. Seasonal variation of non-shivering thermogenesis (NST) during mild cold exposure. Nishimura T, Motoi M, Egashira Y, Choi D, Aoyagi K, Watanuki S. BACKGROUND: The physiological function of non-shivering thermogenesis (NST) has been investigated in recent years, and some studies have discussed the importance of NST with respect to human cold adaptation. The present study aimed to clarify individual and seasonal variations in NST that occurred as a result of mild cold exposure. METHODS: Seventeen male university students participated in the present study during summer and winter. The climate chamber used was programmed so that ambient temperature dropped from 28°C to 16°C over an 80-min period. Physiological parameters of test subjects were recorded during the experiments. RESULTS: Increases in oxygen intake (VO2) during cold exposure were significantly greater without shivering in winter than they were in summer. Respiratory exchange ratio (RER) was significantly lower during thermoneutral baseline and cold exposure in winter than it was during the same periods in summer. In addition, there was a significant negative correlation between ΔVO2 and ΔRER. CONCLUSIONS: Increase of VO2 without shivering indicated increase of NST, and decrease of RER depends on the metabolization of fat in winter. These results suggested that NST activity was activated by seasonal acclimatization, and individual variation of NST depends on individual variation of fat metabolism. PMCID: PMC4364327 PMID: 25858699 [PubMed - in process] 7. PLoS One. 2015 Apr 8;10(4):e0120442. doi: 10.1371/journal.pone.0120442. eCollection 2015. Solar radiation during rewarming from torpor in elephant shrews: supplementation or substitution of endogenous heat production? Thompson ML(1), Mzilikazi N(1), Bennett NC(2), McKechnie AE(1). Author information: (1)Mammal Research Institute, Department of Zoology and Entomology, University of Pretoria, Private Bag X20, Hatfield 0028, South Africa. (2)South African Research Chair for Mammal Behavioural Ecology and Physiology, Department of Zoology and Entomology, University of Pretoria, Private Bag X20, Hatfield 0028, South Africa. Many small mammals bask in the sun during rewarming from heterothermy, but the implications of this behaviour for their energy balance remain little understood. Specifically, it remains unclear whether solar radiation supplements endogenous metabolic thermogenesis (i.e., rewarming occurs through the additive effects of internally-produced and external heat), or whether solar radiation reduces the energy required to rewarm by substituting (i.e, replacing) metabolic heat production. To address this question, we examined patterns of torpor and rewarming rates in eastern rock elephant shrews (Elephantulus myurus) housed in outdoor cages with access to either natural levels of solar radiation or levels that were experimentally reduced by means of shade cloth. We also tested whether acclimation to solar radiation availability was manifested via phenotypic flexibility in basal metabolic rate (BMR), non-shivering thermogenesis (NST) capacity and/or summit metabolism (Msum). Rewarming rates varied significantly among treatments, with elephant shrews experiencing natural solar radiation levels rewarming faster than conspecifics experiencing solar radiation levels equivalent to approximately 20% or 40% of natural levels. BMR differed significantly between individuals experiencing natural levels of solar radiation and conspecifics experiencing approximately 20% of natural levels, but no between-treatment difference was evident for NST capacity or Msum. The positive relationship between solar radiation availability and rewarming rate, together with the absence of acclimation in maximum non-shivering and total heat production capacities, suggests that under the conditions of this study solar radiation supplemented rather than substituted metabolic thermogenesis as a source of heat during rewarming from heterothermy. PMCID: PMC4390352 PMID: 25853244 [PubMed - in process] 8. Neuroscience. 2015 Jun 4;295:209-20. doi: 10.1016/j.neuroscience.2015.03.028. Epub 2015 Mar 23. Comparison of noradrenaline, dopamine and serotonin in mediating the tachycardic and thermogenic effects of methamphetamine in the ventral medial prefrontal cortex. Hassan SF(1), Zumut S(1), Burke PG(1), McMullan S(1), Cornish JL(2), Goodchild AK(3). Author information: (1)The Australian School of Advanced Medicine, Macquarie University, NSW 2109, Australia. (2)Neuropharmacology Laboratory, Department of Psychology, Macquarie University, NSW 2109, Australia. (3)The Australian School of Advanced Medicine, Macquarie University, NSW 2109, Australia. Electronic address: ann.goodchild@mq.edu.au. Methamphetamine (METH) is a psychostimulant that disrupts monoaminergic neurotransmission to evoke profound behavioral and physiological effects. Rapidly distributing to forebrain regions to increase synaptic concentrations of three monoamines (dopamine (DA), serotonin (5-HT) and noradrenaline (NA)), the medial prefrontal cortex (mPFC) is important in METH-altered behavioral and psychological profiles. Activation of the ventral mPFC can modify physiological variables, however, METH-evoked autonomic changes from this region are unknown. Therefore, the aim of this study was to characterize the respiratory, metabolic and cardiovascular effects of microinjection of METH, DA, 5-HT and NA into the ventral mPFC in urethane-anesthetized Sprague-Dawley rats. METH and NA microinjection evoked dose-related increases in heart rate, interscapular brown adipose tissue temperature and expired CO2, a pattern of response characteristic of non-shivering thermogenesis. NA and 5-HT microinjection elicited pressor and depressor responses, respectively, with matching baroreflex adjustments in sympathetic nerve activity while METH and DA evoked no change in vasomotor outflow. Low doses of METH and DA may evoke respiratory depression. These data suggest that METH's actions in the ventral mPFC, likely via adrenergic receptors, evoke non-shivering thermogenesis which may contribute to the increased body temperature and tachycardia seen in those that abuse METH. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved. PMID: 25813709 [PubMed - in process] 9. Biochem Cell Biol. 2015 Jun;93(3):251-61. doi: 10.1139/bcb-2014-0139. Epub 2015 Feb 5. Chronic activation of pattern recognition receptors suppresses brown adipogenesis of multipotent mesodermal stem cells and brown pre-adipocytes. Bae J(1), Chen J, Zhao L. Author information: (1)Department of Nutrition, The University of Tennessee, 1215 W. Cumberland Avenue, Knoxville, TN 37996-1920, USA. Brown adipose tissue (BAT) holds promise to combat obesity through energy-spending, non-shivering thermogenesis. Understanding of regulation of BAT development can lead to novel strategies to increase BAT mass and function for obesity treatment and prevention. Here, we report the effects of chronic activation of PRR on brown adipogenesis of multipotent mesodermal stem C3H10T1/2 cells and immortalized brown pre-adipocytes from the classical interscapular BAT of mice. Activation of NOD1, TLR4, or TLR2 by their respective synthetic ligand suppressed brown marker gene expression and lipid accumulation during differentiation of brown-like adipocytes of C3H10T1/2. Activation of the PRR only during the commitment was sufficient to suppress the differentiation. PRR activation suppressed PGC-1α mRNA, but induced PRDM16 mRNA at the commitment. Consistently, PRR activation suppressed the differentiation of immortalized brown pre-adipocytes. Activation of PRR induced NF-κB activation in both cells, which correlated with their abilities to suppress PPARγ transactivation, a critical event for brown adipogenesis. Taken together, our results demonstrate that chronic PRR activation suppressed brown adipogenesis of multipotent mesodermal stem cells and brown pre-adipocytes, possibly through suppression of PPARγ transactivation. The results suggest that anti- inflammatory therapies targeting PRRs may be beneficial for the BAT development. PMID: 25741603 [PubMed - in process] 10. Biochim Biophys Acta. 2015 May;1853(5):918-28. doi: 10.1016/j.bbamcr.2015.01.020. Epub 2015 Feb 2. Lipid droplet remodeling and interaction with mitochondria in mouse brown adipose tissue during cold treatment. Yu J(1), Zhang S(2), Cui L(3), Wang W(4), Na H(1), Zhu X(1), Li L(5), Xu G(4), Yang F(2), Christian M(6), Liu P(7). Author information: (1)National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. (2)National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. (3)National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China. (4)Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China. (5)Department of Anesthesiology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China. (6)Division of Translational and Systems Medicine, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK. (7)National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: pliu@ibp.ac.cn. Brown adipose tissue (BAT) maintains animal body temperature by non-shivering thermogenesis, which is through uncoupling protein 1 (UCP1) that uncouples oxidative phosphorylation and utilizes β-oxidation of fatty acids released from triacylglycerol (TAG) in lipid droplets (LDs). Increasing BAT activity and "browning" other tissues such as white adipose tissue (WAT) can enhance the expenditure of excess stored energy, and in turn reduce prevalence of metabolic diseases. Although many studies have characterized the biology of BAT and brown adipocytes, BAT LDs especially their activation induced by cold exposure remain to be explored. We have isolated LDs from mouse interscapular BAT and characterized the full proteome using mass spectrometry. Both morphological and biochemical experiments showed that the LDs could tightly associate with mitochondria. Under cold treatment mouse BAT started expressing LD structure protein PLIN-2/ADRP and increased expression of PLIN1. Both hormone sensitive lipase (HSL) and adipose TAG lipase (ATGL) were increased in LDs. In addition, isolated BAT LDs showed increased levels of the mitochondrial protein UCP1, and prolonged cold exposure could stimulate BAT mitochondrial cristae biogenesis. These changes were in agreement with the data from transcriptional analysis. Our results provide the BAT LD proteome for the first time and show that BAT LDs facilitate heat production by coupling increasing TAG hydrolysis through recruitment of ATGL and HSL to the organelle and expression of another LD resident protein PLIN2/ADRP, as well as by tightly associating with activated mitochondria. These findings will benefit the study of BAT activation and the interaction between LDs and mitochondria. Copyright © 2015 Elsevier B.V. All rights reserved. PMID: 25655664 [PubMed - in process] 11. Elife. 2015 Jan 27;4. doi: 10.7554/eLife.04517. Enhanced stability and polyadenylation of select mRNAs support rapid thermogenesis in the brown fat of a hibernator. Grabek KR(1), Diniz Behn C(2), Barsh GS(3), Hesselberth JR(1), Martin SL(1). Author information: (1)Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, United States. (2)Department of Applied Math and Statistics, Colorado School of Mines, Golden, United States. (3)Department of Research, HudsonAlpha Institute for Biotechnology, Huntsville, United States. During hibernation, animals cycle between torpor and arousal. These cycles involve dramatic but poorly understood mechanisms of dynamic physiological regulation at the level of gene expression. Each cycle, Brown Adipose Tissue (BAT) drives periodic arousal from torpor by generating essential heat. We applied digital transcriptome analysis to precisely timed samples to identify molecular pathways that underlie the intense activity cycles of hibernator BAT. A cohort of transcripts increased during torpor, paradoxical because transcription effectively ceases at these low temperatures. We show that this increase occurs not by elevated transcription but rather by enhanced stabilization associated with maintenance and/or extension of long poly(A) tails. Mathematical modeling further supports a temperature-sensitive mechanism to protect a subset of transcripts from ongoing bulk degradation instead of increased transcription. This subset was enriched in a C-rich motif and genes required for BAT activation, suggesting a model and mechanism to prioritize translation of key proteins for thermogenesis. PMCID: PMC4383249 PMID: 25626169 [PubMed - in process] 12. Postepy Hig Med Dosw (Online). 2015 Jan 16;69:69-79. doi: 10.5604/17322693.1136382. [Hypothermia--mechanism of action and pathophysiological changes in the human body]. [Article in Polish] Sosnowski P(1), Mikrut K(1), Krauss H(1). Author information: (1)Katedra i Zakład Fizjologii, Uniwersytet Medyczny im. K. Marcinkowskiego w Poznaniu. This review focuses on the physiological responses and pathophysiological changes induced by hypothermia. Normal body function depends on its ability to maintain thermal homeostasis. The human body can be divided arbitrarily into two thermal compartments: a core compartment (trunk and head), with precisely regulated temperature around 37°C, and a peripheral compartment (skin and extremities) with less strictly controlled temperature, and lower than the core temperature. Thermoregulatory processes occur in three phases: afferent thermal sensing, central regulation, mainly by the preoptic area of the anterior hypothalamus, and efferent response. Exposure to cold induces thermoregulatory responses including cutaneous vasoconstriction, shivering and non-shivering thermogenesis, and behavioral changes. Alterations of body temperature associated with impaired thermoregulation, decreased heat production or increased heat loss can lead to hypothermia. Hypothermia is defined as a core body temperature below 35ºC, and may be classified according to the origin as accidental (e.g. caused by exposure to a cold environment, drugs, or illness) or intentional (i.e. therapeutic), or by the degree of hypothermia as mild, moderate or severe. Classification by temperature is not universal. Lowering of body temperature disrupts the physiological processes at the molecular, cellular and system level, but hypothermia induced prior to cardiosurgical or neurosurgical procedures, by the decrease in tissue oxygen demand, can reduce the risk of cerebral or cardiac ischemic damage. Therapeutic hypothermia has been recommended as a clinical procedure in situations characterized by ischemia, such as cardiac arrest, stroke and brain injuries. PMID: 25614675 [PubMed - in process] 13. J Physiol Anthropol. 2014 Dec 22;33:38. doi: 10.1186/1880-6805-33-38. Seasonal effects of the UCP3 and the RPTOR gene polymorphisms on obesity traits in Japanese adults. Nakayama K(1), Miyashita H, Iwamoto S. Author information: (1)Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke-shi, Tochigi 329-0498, Japan. nakayama@jichi.ac.jp. BACKGROUND: Non-shivering thermogenesis (NST) involves a substantial amount of energy expenditure in humans and, thus, contributes to reducing the risk for obesity. Molecular evolutionary studies have reported that SNPs in/near the uncoupling protein 3 gene (UCP3) and the regulatory associated protein of mTOR complex 1 gene (RPTOR) might influence NST and confer adaptive advantages for modern human dispersal into cold environments. In the present study, the impact of these SNPs on obesity-related traits was investigated. METHODS: Study subjects consisted of 2,834 Japanese adults (percentage of female: 46%, mean age: 51.5). Associations of the UCP3-55C/T and the RPTOR-26934C/T - the 2 potential genetic variations involved in cold adaptation and thermogenic mechanisms in mammals, with quantitative obesity-related traits including body mass index (BMI), waist circumference, visceral fat area (VFA), VFA adjusted for BMI, and selected blood parameters - were tested using multiple linear regression models. Sliding windowsampling analysis was applied to depict seasonal effects of the SNPs on the obesity-related phenotypes. RESULTS: UCP3-55C/T and the RPTOR-26934C/T did not show any association with obesity traits and blood chemical parameters in multiple linear regression models consisting of the whole subjects. Moreover, sliding window sampling-based association analyses involving seasonality also failed to find associations between these two SNPs and obesity-related traits. CONCLUSIONS: UCP3-55C/T and the RPTOR-26934C/T may only have subtle effects on the development of obesity-related traits in the present humans. These two SNPs might be irrelevant to inter-individual variations in energy metabolism and efficiency of NST. PMCID: PMC4347541 PMID: 25533680 [PubMed - indexed for MEDLINE] 14. J Pediatr Endocrinol Metab. 2015 Jan;28(1-2):53-7. doi: 10.1515/jpem-2014-0337. Effects of T3 treatment on brown adipose tissue and energy expenditure in a patient with craniopharyngioma and hypothalamic obesity. van Santen HM, Schouten-Meeteren AY, Serlie M, Meijneke RW, van Trotsenburg AS, Verberne H, Holleman F, Fliers E. OBJECTIVE: Patients treated for childhood craniopharyngioma often develop hypothalamic obesity (HO), which has a huge impact on the physical condition and quality of life of these patients. Treatment for HO thus far has been disappointing, and although several different strategies have been attempted, all interventions had only transient effects. Since thyroid hormones increase energy expenditure metabolism (thyroid hormone induced thermogenesis), it was speculated that treatment with tri-iodothyronine (T3) may be beneficial. In 2002, a case report was published on reduction of body weight after T3 treatment for HO. No studies have been reported since. Recent experimental studies in rodents showed that T3 increases brown adipose tissue (BAT) activity via (pre)sympathetic pathways between the hypothalamus and BAT. Our aim was to investigate whether T3 treatment increases BAT activity in a patient with HO resulting from (treatment of) childhood craniopharyngioma. METHODS: Thyroxine treatment for central hypothyroidism was switched to T3 monotherapy. Serum T3 and free thyroxine (FT4) concentrations were measured twice weekly for 2 months. ¹²³I-MIBG and ¹⁸F-FDG-PET after induction of non-shivering thermogenesis for the assessment of sympathetic and metabolic activity of BAT as well as indirect calorimetry for assessment of resting energy expenditure were performed before and during T3 treatment. RESULTS: No change in sympathetic and metabolic BAT activity, energy expenditure, or BMI was seen during T3 treatment despite the expected changes in thyroid hormone plasma concentrations. CONCLUSION: We conclude that T3 monotherapy does not seem to be effective in decreasing HO in childhood craniopharyngioma. PMID: 25514327 [PubMed - in process] 15. Comp Biochem Physiol A Mol Integr Physiol. 2015 Feb;180:51-6. doi: 10.1016/j.cbpa.2014.11.003. Epub 2014 Nov 8. Selection for high activity-related aerobic metabolism does not alter the capacity of non-shivering thermogenesis in bank voles. Stawski C(1), Koteja P(2), Sadowska ET(2), Jefimow M(3), Wojciechowski MS(3). Author information: (1)Institute of Environmental Sciences, Jagiellonian University, ul. Gronostajowa 7, 30-387 Kraków, Poland. Electronic address: clare.stawski@gmail.com. (2)Institute of Environmental Sciences, Jagiellonian University, ul. Gronostajowa 7, 30-387 Kraków, Poland. (3)Department of Animal Physiology, Nicolaus Copernicus University, ul. Lwowska 1, 87-100 Toruń, Poland. An intriguing question is how the capacity of non-shivering thermogenesis (NST)-a special mechanism supporting endothermic thermoregulation in mammals-is affected by selection for high exercise metabolism. It has been proposed that high NST could be a mechanism to compensate for a low basal production of heat. On the other hand, high basal or activity metabolism is associated with physiological characteristics such as high performance of the circulatory system, which are also required for achieving a high NST. Here we tested whether selection for high aerobic exercise performance, which correlates with an increased basal metabolic rate, led to a correlated evolution of maximum and facultative NST. Therefore, we measured the NST of bank voles, Myodes (= Clethrionomys) glareolus, from lines selected for 13-14 generations (n=46) for high aerobic metabolism achieved during swimming and from unselected, control lines (n=46). Open-flow respirometry was used to measure the rate of oxygen consumption (V(·)O2) in anesthetized bank voles injected with noradrenaline (NA). After adjusting for body mass, maximum NST (maximum V(·)O2 recorded after injection of NA) did not differ between the selected (2.38±0.08 mLO2min(-1)) and control lines (2.36±0.08 mLO2min(-1); P=0.891). Facultative NST (= maximum NST minus resting metabolic rate of anesthetized animals) did not differ between the selected (1.49±0.07 mLO2min(-1)) and control lines (1.50±0.07 mLO2min(-1); P=0.985), either. Therefore, our results suggest that NST capacity is not strongly linked to maximum activity-related aerobic metabolic rate. Copyright © 2014 Elsevier Inc. All rights reserved. PMID: 25446149 [PubMed - in process] 16. J Hum Evol. 2014 Dec;77:167-78. doi: 10.1016/j.jhevol.2014.09.003. Epub 2014 Oct 18. Neandertal growth: what are the costs? Mateos A(1), Goikoetxea I(2), Leonard WR(3), Martín-González JÁ(4), Rodríguez-Gómez G(2), Rodríguez J(2). Author information: (1)Centro Nacional de Investigación sobre la Evolución Humana (CENIEH), Paseo Sierra de Atapuerca 3, 09002 Burgos, Spain. Electronic address: ana.mateos@cenieh.es. (2)Centro Nacional de Investigación sobre la Evolución Humana (CENIEH), Paseo Sierra de Atapuerca 3, 09002 Burgos, Spain. (3)Laboratory for Human Biology Research, Department of Anthropology, Northwestern University, Evanston, IL, USA. (4)Departamento Matemáticas y Computación, Universidad de Burgos, Burgos, Spain (1). Energetic approaches have been increasingly used to address key issues in Neandertal palaeoecology and palaeobiology. Previous research has focused exclusively on the energy requirements of adults and highlights the high energy demands of these individuals compared with modern humans. Less attention has been paid to the energy requirements of sub-adult Neandertals, even though this age group could provide clues for a better understanding of Neandertal life history. Accordingly, herein, we estimate the energy costs of maintenance and growth in Neandertal infants and children from one to six years of age and compare these costs with values for modern humans. Statural growth models for two modern human populations (Beasain and Evenki) and an average Neandertal model population are used to establish weight growth models. In turn, these models of body weight growth are used to estimate key components of energetic variables (basal metabolic rate, total energy expenditure, energy of growth and daily energy requirements). Between three and six years of age, Neandertal children have slightly lower basal and growth energy costs than do modern humans of the same age, due primarily to their smaller body mass and slower growth rates. The reduction in energy allocated to growth is likely the result of metabolic adaptations to other somatic factors and thermal stress. Data from contemporary human infants and children suggest that even mild cold stress increases non-shivering thermogenesis, thus elevating metabolic needs by 50% or more. These results suggest that thermal stress likely played a strong role in shaping the delayed developmental patterns and lower energy allocated to growth during early life in Neandertals relative to Homo sapiens. Copyright © 2014 Elsevier Ltd. All rights reserved. PMID: 25439708 [PubMed - in process] 17. J Therm Biol. 2014 Oct;45:1-8. doi: 10.1016/j.jtherbio.2014.07.003. Epub 2014 Jul 16. Thermoregulatory capacities and torpor in the South American marsupial, Dromiciops gliroides. Cortés PA(1), Franco M(2), Moreno-Gómez FN(3), Barrientos K(4), Nespolo RF(5). Author information: (1)Instituto de Ciencias Ambientales y Evolutivas, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja, Valdivia, Chile. Electronic address: pablocortesgarcia@gmail.com. (2)Facultad de Ciencias Naturales y Matemáticas, Universidad de Ibagué, Carrera 22 Calle 67 Barrio Ambalá, Ibagué-Tolima, Colombia. (3)Instituto de Ciencias Ambientales y Evolutivas, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja, Valdivia, Chile. (4)Facultad de Ciencias Agrarias; Instituto de Produccion y Sanidad Vegetal, Universidad Austral de Chile, Campus Isla Teja, Valdivia, Chile. (5)Instituto de Ciencias Ambientales y Evolutivas, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja, Valdivia, Chile. Electronic address: robertonespolorossi@gmail.com. During periods of adverse conditions small endotherms depend on a continuous supply of food and energy to maintain body temperature. Thus, rapid and reversible phenotypic modifications at different organizational levels are key for an efficient use of resources and survival. In this study, we provide a quantitative description of thermoregulatory capacities and energy-saving strategies in the Chilean marsupial Dromiciops gliroides. In particular, we evaluated the effect of thermal acclimation on basal metabolic rate (BMR), thermal conductance (C) and torpor patterns, as well as the presence of non-shivering thermogenesis (NST) as a rewarming mechanism in this marsupial. Non-significant effects of thermal acclimation were observed in BMR, C and body mass, but cold-acclimated individuals exhibited significantly longer torpor bouts. Also, minimum body temperature during torpor, inter-bout body temperature and arousal rewarming rate were lower in cold-acclimated animals. Furthermore, we found that D. gliroides did not display NST in response to Norepinephrine. Hence, despite the high regulation of torpor of other species, D. gliroides shows low flexibility in the ability to adjust energy expenditure and insulation properties, and (as in other marsupials) NST do not seems to be important as thermoregulatory mechanism. Copyright © 2014 Elsevier Ltd. All rights reserved. PMID: 25436944 [PubMed - in process] 18. Biol Rev Camb Philos Soc. 2014 Nov 25. doi: 10.1111/brv.12157. [Epub ahead of print] The role of skeletal-muscle-based thermogenic mechanisms in vertebrate endothermy. Rowland LA(1), Bal NC, Periasamy M. Author information: (1)Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH 43210, U.S.A. Thermogenesis is one of the most important homeostatic mechanisms that evolved during vertebrate evolution. Despite its importance for the survival of the organism, the mechanistic details behind various thermogenic processes remain incompletely understood. Although heat production from muscle has long been recognized as a thermogenic mechanism, whether muscle can produce heat independently of contraction remains controversial. Studies in birds and mammals suggest that skeletal muscle can be an important site of non-shivering thermogenesis (NST) and can be recruited during cold adaptation, although unequivocal evidence is lacking. Much research on thermogenesis during the last two decades has been focused on brown adipose tissue (BAT). These studies clearly implicate BAT as an important site of NST in mammals, in particular in newborns and rodents. However, BAT is either absent, as in birds and pigs, or is only a minor component, as in adult large mammals including humans, bringing into question the BAT-centric view of thermogenesis. This review focuses on the evolution and emergence of various thermogenic mechanisms in vertebrates from fish to man. A careful analysis of the existing data reveals that muscle was the earliest facultative thermogenic organ to emerge in vertebrates, long before the appearance of BAT in eutherian mammals. Additionally, these studies suggest that muscle-based thermogenesis is the dominant mechanism of heat production in many species including birds, marsupials, and certain mammals where BAT-mediated thermogenesis is absent or limited. We discuss the relevance of our recent findings showing that uncoupling of sarco(endo)plasmic reticulum Ca(2+) -ATPase (SERCA) by sarcolipin (SLN), resulting in futile cycling and increased heat production, could be the basis for NST in skeletal muscle. The overall goal of this review is to highlight the role of skeletal muscle as a thermogenic organ and provide a balanced view of thermogenesis in vertebrates. © 2014 Cambridge Philosophical Society. PMID: 25424279 [PubMed - as supplied by publisher] 19. Comput Struct Biotechnol J. 2014 Sep 18;11(19):101-5. doi: 10.1016/j.csbj.2014.09.005. eCollection 2014. MicroRNA Functions in Brite/Brown Fat - Novel Perspectives towards Anti-Obesity Strategies. Karbiener M(1), Scheideler M(1). Author information: (1)RNA Biology Group, Institute of Molecular Biotechnology, Graz University of Technology, Petersgasse 14, 8010 Graz, Austria. Current anti-obesity strategies are aiming at restricting energy uptake, but still, obesity treatment is far from being satisfactory. The discovery of active brown adipose tissue (BAT) in adult humans currently opens new avenues to combat obesity and follow-up complications as it tackles the other site of the energy balance: energy expenditure via non-shivering thermogenesis. This process of energy dissipation in the adipose tissue is tightly controlled, and the elucidation of its regulatory network is a key plank for therapeutic applications. MicroRNAs (miRNAs) belong to a novel class of regulatory determinants which are small non-coding RNAs with vital roles in regulating gene expression that also play a role in many human diseases. In this review we summarize miRNAs which have been shown to govern thermogenic, i.e. brite or brown, adipocyte recruitment and physiology. Notably, most miRNAs in this context have so far been characterized solely in mice, revealing a great demand for more human studies. As in the context of other diseases, RNA-based therapeutics have meanwhile entered clinical trials, further exploring the functions of miRNAs in brown and white adipose tissues could result in novel therapeutic approaches to treat obesity and its follow-up complications. PMCID: PMC4232565 PMID: 25408843 [PubMed] 20. Exp Physiol. 2014 Dec 1;99(12):1663-78. doi: 10.1113/expphysiol.2014.081596. Epub 2014 Oct 16. Enhanced pan-peroxisome proliferator-activated receptor gene and protein expression in adipose tissue of diet-induced obese mice treated with telmisartan. Penna-de-Carvalho A(1), Graus-Nunes F(1), Rabelo-Andrade J(1), Mandarim-de-Lacerda CA(1), Souza-Mello V(2). Author information: (1)Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil. (2)Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil souzamello.uerj@gmail.com. Telmisartan has previously been used to target obesity, showing peroxisome proliferator-activated receptor (PPAR) β/δ-related effects in white adipose tissue (WAT). We sought to evaluate whether telmisartan enhances gene and protein expression of all PPAR isoforms in WAT and brown adipose tissue (BAT), as well as their downstream effects upon insulin resistance, adipokine profile and adaptive thermogenesis. Male C57BL/6 mice were fed standard chow (SC; 10% lipids) or high-fat diet (HF; 50% lipids) for 10 weeks. Animals were then randomly allocated into the following four groups: SC, SC-T, HF and HF-T. Telmisartan [10 mg (kg diet)(-1)] was administered for 4 weeks in the diet. Animals in the HF group were overweight and exhibited hypertension, insulin resistance, decreased energy expenditure, a pro-inflammatory adipokine profile and abnormal fat pad mass distribution. Animals in the HF group showed decreased expression of PPARα, β/δ and γ in WAT and BAT, resulting in impaired glucose uptake and insufficient thermogenesis. Due to the improvement in the adipokine profile and enhanced insulin sensitivity with adequate insulin-stimulated glucose uptake after treatment with telmisartan, the activation of all PPAR isoforms in WAT was beneficial. In BAT, telmisartan induced sustained sympathetic activation, because the β3-adrenergic receptor was induced by PPARβ/δ, while uncoupling protein 1 was induced by PPARα to promote thermogenesis. Telmisartan exerted anti-obesity effects through higher pan-PPAR gene and protein expression. Upon PPARα, β/δ and γ (pan-PPAR) agonism in adipose tissue of obese mice, telmisartan ameliorates inflammation and insulin resistance, as well as inducing non-shivering thermogenesis. Our results point to new therapeutic targets for the control of obesity and comorbidities through pan-PPAR-related effects. © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society. PMID: 25326526 [PubMed - in process] 21. Eur J Nutr. 2014 Oct 9. [Epub ahead of print] 1,25-Dihydroxyvitamin D3/vitamin D receptor suppresses brown adipocyte differentiation and mitochondrial respiration. Ricciardi CJ(1), Bae J, Esposito D, Komarnytsky S, Hu P, Chen J, Zhao L. Author information: (1)Department of Nutrition, University of Tennessee, 1215 W. Cumberland Ave, Knoxville, TN, 37996, USA. PURPOSE: The vitamin D system plays a role in metabolism regulation. 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) suppressed 3T3-L1 white adipocyte differentiation. Vitamin D receptor (VDR) knockout mice showed increased energy expenditure, whereas mice with adipose-specific VDR over-expression showed decreased energy expenditure. Brown adipose tissue (BAT), now known to be present in adult humans, functions in non-shivering thermogenesis by uncoupling ATP synthesis from respiration and plays an important role in energy expenditure. However, the effects of 1,25(OH)2D3/VDR on brown adipocyte differentiation and mitochondrial respiration have not been reported. METHODS: mRNA expression of VDR and the metabolizing enzymes 1α-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24A1) were examined in BAT of mice models of obesity and during brown adipocyte differentiation. The effects of 1,25(OH)2D3 and VDR over-expression on brown adipocyte differentiation and functional outcomes were evaluated. RESULTS: No significant changes in mRNA of VDR and CYP27B1 were noted in both diet-induced obese (DIO) and ob/ob mice, whereas uncoupling protein 1 mRNA was downregulated in BAT of ob/ob, but not DIO mice when compared to the controls. In contrast, mRNA of VDR, CYP24A1, and CYP27B1 were downregulated during brown adipocyte differentiation in vitro. 1,25(OH)2D3 dose-dependently suppressed brown adipocyte differentiation, accompanied by suppressed isoproterenol-stimulated oxygen consumption rates (OCR), maximal OCR and OCR from proton leak. Consistently, over-expression of VDR also suppressed brown adipocyte differentiation. Further, both 1,25(OH)2D3 and VDR over-expression suppressed PPARγ transactivation in brown preadipocytes. CONCLUSION: Our results demonstrate the suppressive effects of 1,25(OH)2D3/VDR signaling on brown adipocyte differentiation and mitochondrial respiration. The role of 1,25(OH)2D3/VDR system in regulating BAT development and function in obesity warrant further investigation. PMID: 25296887 [PubMed - as supplied by publisher] 22. Biochim Biophys Acta. 2014 Dec;1841(12):1691-9. Contrasting effects of cold acclimation versus obesogenic diets on chemerin gene expression in brown and brite adipose tissues. Hansen IR, Jansson KM, Cannon B, Nedergaard J. Based on results from a signal sequence trap, we investigated chemerin gene expression in brown adipose tissue. Male NMRI mice were exposed to 30, 22 or 4 °C for 3 weeks, or were fed control (chow) diet, cafeteria diet or high-fat diet at thermoneutrality for the same time. In brown adipose tissue, cold acclimation strongly diminished chemerin gene expression, whereas obesogenic diets augmented expression. Qualitatively, changes in expression were paralleled in brite/beige adipose tissues (e.g. inguinal), whereas white adipose tissue (epididymal) and muscle did not react to these cues. Changes in tissue expression were not directly paralleled by alterations in plasma levels. Both these intact animal studies and brown adipocyte cell culture studies indicated that the gene expression regulation was not congruent with a sympathetic/adrenergic control. The data are discussed in relation to suggested endocrine, paracrine and autocrine effects of chemerin. PMID: 25224322 [PubMed - indexed for MEDLINE] 23. Cryobiology. 2014 Oct;69(2):333-8. doi: 10.1016/j.cryobiol.2014.08.008. Epub 2014 Sep 3. Global DNA modifications suppress transcription in brown adipose tissue during hibernation. Biggar Y(1), Storey KB(2). Author information: (1)Institute of Biochemistry and Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada. (2)Institute of Biochemistry and Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada. Electronic address: kenneth_storey@carleton.ca. Hibernation is crucial to winter survival for many small mammals and is characterized by prolonged periods of torpor during which strong global controls are applied to suppress energy-expensive cellular processes. We hypothesized that one strategy of energy conservation is a global reduction in gene transcription imparted by reversible modifications to DNA and to proteins involved in chromatin packing. Transcriptional regulation during hibernation was examined over euthermic control groups and five stages of the torpor/arousal cycle in brown adipose tissue of thirteen-lined ground squirrels (Ictidomys tridecemlineatus). Brown adipose is crucial to hibernation success because it is responsible for the non-shivering thermogenesis that rewarms animals during arousal. A direct modification of DNA during torpor was revealed by a 1.7-fold increase in global DNA methylation during long term torpor as compared with euthermic controls. Acetylation of histone H3 (on Lys23) was reduced by about 50% when squirrels entered torpor, which would result in increased chromatin packing (and transcriptional repression). This was accompanied by strong increases in histone deacetylase protein levels during torpor; e.g. HDAC1 and HDAC4 levels rose by 1.5- and 6-fold, respectively. Protein levels of two co-repressors of transcription, MBD1 and HP1, also increased by 1.9- and 1.5-fold, respectively, in long-term torpor and remained high during early arousal. MBD1, HP1 and HDACs all returned to near control values during interbout indicating a reversal of their inhibitory actions. Overall, the data presents strong evidence for a global suppression of transcription during torpor via the action of epigenetic regulatory mechanisms in brown adipose tissue of hibernating thirteen-lined ground squirrels. Copyright © 2014 Elsevier Inc. All rights reserved. PMID: 25192827 [PubMed - indexed for MEDLINE] 24. J Physiol Anthropol. 2014 Sep 3;33:27. doi: 10.1186/1880-6805-33-27. Relationship between mitochondrial haplogroup and seasonal changes of physiological responses to cold. Nishimura T(1), Watanuki S. Author information: (1)Department of Public Health, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. takayuki-n@nagasaki-u.ac.jp. BACKGROUND: Physiological responses to cold exhibit individual variation that can be affected by various factors, such as morphological characteristics, seasonal changes, and lifestyle; however, the genetic factors associated with this variation remain unclear. Recent studies have identified mtDNA as a potential genetic factor affecting cold adaptation. In addition, non-shivering thermogenesis (NST), a process closely related to mitochondrial dynamics, has also been suggested as an important factor affecting human response to cold. The present study aimed to clarify the relationship between mitochondrial haplogroup and NST during periods of mild cold exposure. METHODS: Seventeen healthy university students (D: n = 8, non-D: n = 9) participated in the present study during summer and winter. A climate chamber was programmed so that ambient temperature inside dropped from 28°C to 16°C over the course of an 80-minute period. Physiological parameters were recorded throughout the course of the experiments. RESULTS: Increases in VO2 were significantly greater during periods of cold exposure in winter than they were during periods of cold exposure in summer, and individuals from the D group exhibited greater winter values of ΔVO2 than individuals from the non-D group.Tre was significantly lower during periods of rest and cold exposure in winter; however, no significant difference was observed between Tre values of individuals in the D and non-D groups. In addition, although T¯dist was significantly lower during periods of rest in winter than it was during those same periods in summer, no significant seasonal differences in values of T¯dist were observed during periods of cold exposure. CONCLUSIONS: Results of the present study indicated that NST was greater in winter, and that the D group exhibited greater NST than the non-D group during winter. Despite the differences between groups in NST, no significant differences in rectal and skin temperatures were found between groups in either season. Therefore, it was supposed that mitochondrial DNA haplogroups had a greater effect on variation in energy expenditure involving NST than they had on insulative responses. Future studies are necessary in order to investigate more multiple candidate genes related to human cold adaptation and to elucidate the relationship between gene polymorphism and physiological polytypism. PMCID: PMC4169230 PMID: 25183371 [PubMed - indexed for MEDLINE] 25. J Comp Physiol B. 2014 Dec;184(8):1021-9. doi: 10.1007/s00360-014-0856-6. Epub 2014 Sep 3. Chronic mitochondrial uncoupling treatment prevents acute cold-induced oxidative stress in birds. Stier A(1), Massemin S, Criscuolo F. Author information: (1)GECCO (groupe écologie et conservation des vertébrés), University of Angers, Angers, France, antoine.stier@gmail.com. Endotherms have evolved two major types of thermogenesis that allow them to actively produce heat in response to cold exposure, either through muscular activity (i.e. shivering thermogenesis) or through futile electro-chemical cycles (i.e. non-shivering thermogenesis). Amongst the latter, mitochondrial uncoupling is of key importance because it is suggested to drive heat production at a low cost in terms of oxidative stress. While this has been experimentally shown in mammals, the oxidative stress consequences of cold exposure and mitochondrial uncoupling are clearly less understood in the other class of endotherms, the birds. We compared metabolic and oxidative stress responses of zebra finches chronically treated with or without a chemical mitochondrial uncoupler (2,4-dinitrophenol: DNP), undergoing an acute (24 h) and a chronic (4 weeks) cold exposure (12 °C). We predicted that control birds should present at least a transient elevation of oxidative stress levels in response to cold exposure. This oxidative stress cost should be more pronounced in control birds than in DNP-treated birds, due to their lower basal uncoupling state. Despite similar increase in metabolism, control birds presented elevated levels of DNA oxidative damage in response to acute (but not chronic) cold exposure, while DNP-treated birds did not. Plasma antioxidant capacity decreased overall in response to chronic cold exposure. These results show that acute cold exposure increases oxidative stress in birds. However, uncoupling mitochondrial functioning appears as a putative compensatory mechanism preventing cold-induced oxidative stress. This result confirms previous observations in mice and underlines non-shivering thermogenesis as a putative key mechanism for endotherms in mounting a response to cold at a low oxidative cost. PMID: 25183199 [PubMed - in process] 26. Diabetol Metab Syndr. 2014 Aug 12;6(1):83. doi: 10.1186/1758-5996-6-83. eCollection 2014. CNX-013-B2, a unique pan tissue acting rexinoid, modulates several nuclear receptors and controls multiple risk factors of the metabolic syndrome without risk of hypertriglyceridemia, hepatomegaly and body weight gain in animal models. Sadasivuni MK(1), Reddy BM(1), Singh J(1), Anup MO(1), Sunil V(1), Lakshmi MN(1), Yogeshwari S(1), Chacko SK(1), Pooja TL(1), Dandu A(1), Harish C(1), Gopala AS(1), Pratibha S(1), Naveenkumar BS(1), Pallavi PM(1), Verma MK(1), Moolemath Y(1), Somesh BP(1), Venkataranganna MV(1), Jagannath MR(1). Author information: (1)Connexios Life Sciences Pvt Ltd, Bangalore, India. BACKGROUND: In addition to their role in growth, cellular differentiation and homeostasis Retinoid X Receptors (RXR) regulate multiple physiological and metabolic pathways in various organs that have beneficial glucose and lipid (cholesterol) lowering, insulin sensitizing and anti-obesity effects. Rexinoids, compounds that specifically binds and activate RXR, are therefore considered as potential therapeutics for treating metabolic syndrome. Apparently many of the rexinoids developed in the past increased triglycerides, caused hepatomegaly and also suppressed the thyroid hormone axis. The aim of this study is to evaluate CNX-013-B2, a potent and highly selective rexinoid, for its potential to treat multiple risk factors of the metabolic syndrome. METHODS: CNX-013-B2 was selected in a screening system designed to identify compounds that selectively activated only a chosen sub-set of heterodimer partners of RXR of importance to treat insulin resistance. Male C57BL/6j mice (n = 10) on high fat diet (HFD) and 16 week old ob/ob mice (n = 8) were treated orally with CNX-013-B2 (10 mg/kg twice daily) or vehicle for 10 weeks and 4 weeks respectively. Measurement of plasma glucose, triglyceride, cholesterol including LDL-C, glycerol, free fatty acids, feed intake, body weight, oral glucose tolerance and non-shivering thermogenesis were performed at selected time points. After study termination such measurements as organ weight, triglyceride content, mRNA levels, protein phosphorylation along with histological analysis were performed. RESULTS: CNX-013-B2 selectively activates PPARs- α, β/δ and γ and modulates activity of LXR, THR and FXR. In ob/ob mice a significant reduction of 25% in fed glucose (p < 0.001 ), a 14% (p < 0.05) reduction in serum total cholesterol and 18% decrease (p < 0.01) in LDL-C and in DIO mice a reduction of 12% (p < 0.01 ) in fasting glucose, 20% in fed triglyceride (p < 0.01) and total cholesterol (p < 0.001) levels, coupled with enhanced insulin sensitivity, cold induced thermogenesis and 7% reduction in body weight were observed. CONCLUSION: CNX-013-B2 is an orally bio available selective rexinoid that can be used as a novel therapeutic agent for management of multiple risk factors of the metabolic syndrome without the risk of side effects reported to be associated with rexinoids. PMCID: PMC4138375 PMID: 25143786 [PubMed] 27. J Endocrinol. 2014 Oct;223(1):M31-8. doi: 10.1530/JOE-14-0155. Epub 2014 Aug 13. UCP1 is present in porcine adipose tissue and is responsive to postnatal leptin. Mostyn A(1), Attig L(1), Larcher T(1), Dou S(1), Chavatte-Palmer P(1), Boukthir M(1), Gertler A(1), Djiane J(1), E Symonds M(1), Abdennebi-Najar L(2). Author information: (1)UP 2012.10.101 EGEALInstitut Polytechnique LaSalle, Beauvais, FranceSchool of Veterinary Medicine and ScienceUniversity of Nottingham, Sutton Bonington Campus, LE12 5RD Nottingham, UKINRA UMR 703Ecole Nationale Vétérinaire, Nantes, FranceINRAUMR1198 BDR Biologie du Développement et Reproduction, Jouy-en-Josas, FranceUnité de Recherche 04UR08/03Faculté de Médecine, Tunis, TunisiaThe Hebrew University of JerusalemPO Box 12, Rehovot 76100, IsraelUnité NOPAINRA, Centre de recherche Jouy en Josas, Jouy-en-Josas, FranceEarly Life Research UnitAcademic Child Health, School of Medicine, University Hospital, The University of Nottingham, Nottingham NG7 2UH, UK. (2)UP 2012.10.101 EGEALInstitut Polytechnique LaSalle, Beauvais, FranceSchool of Veterinary Medicine and ScienceUniversity of Nottingham, Sutton Bonington Campus, LE12 5RD Nottingham, UKINRA UMR 703Ecole Nationale Vétérinaire, Nantes, FranceINRAUMR1198 BDR Biologie du Développement et Reproduction, Jouy-en-Josas, FranceUnité de Recherche 04UR08/03Faculté de Médecine, Tunis, TunisiaThe Hebrew University of JerusalemPO Box 12, Rehovot 76100, IsraelUnité NOPAINRA, Centre de recherche Jouy en Josas, Jouy-en-Josas, FranceEarly Life Research UnitAcademic Child Health, School of Medicine, University Hospital, The University of Nottingham, Nottingham NG7 2UH, UK latifa.najar@lasalle-beauvais.fr. Intrauterine growth restriction (IUGR) may be accompanied by inadequate thermoregulation, especially in piglets that are not considered to possess any brown adipose tissue (BAT) and are thus entirely dependent on shivering thermogenesis in order to maintain body temperature after birth. Leptin can stimulate heat production by promoting non-shivering thermogenesis in BAT, but whether this response occurs in piglets is unknown. Newborn female piglets that were characterised as showing IUGR (mean birth weight of approximately 0.98 kg) were therefore administered injections of either saline or leptin once a day for the first 5 days of neonatal life. The dose of leptin was 0.5 mg/kg, which is sufficient to increase plasma leptin by approximately tenfold and on the day of birth induced a rapid increase in body temperature to values similar to those of normal-sized 'control' piglets (mean birth weight of ∼1.47 kg). Perirenal adipose tissue was then sampled from all offspring at 21 days of age and the presence of the BAT-specific uncoupling protein 1 (UCP1) was determined by immunohistochemistry and immunoblotting. UCP1 was clearly detectable in all samples analysed and its abundance was significantly reduced in the IUGR piglets that had received saline compared with controls, but was raised to the same amount as in controls in those IUGR females given leptin. There were no differences in gene expression between primary markers of brown and white adipose tissues between groups. In conclusion, piglets possess BAT that when stimulated exogenously by leptin can promote increased body temperature. © 2014 Society for Endocrinology. PMID: 25122002 [PubMed - indexed for MEDLINE] 28. Metabolism. 2014 Oct;63(10):1280-6. doi: 10.1016/j.metabol.2014.06.017. Epub 2014 Jun 30. (18)F-fluorodeoxyglucose uptake in brown adipose tissue during insulin-induced hypoglycemia and mild cold exposure in non-diabetic adults. Schopman JE(1), Admiraal WM(2), Soeters MR(3), Ackermans MT(4), Bisschop PL(3), Frier BM(5), Hoekstra JB(2), Romijn JA(2), Verberne HJ(6), Holleman F(2). Author information: (1)Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: j.e.schopman@gmail.com. (2)Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands. (3)Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands. (4)Department of Clinical Chemistry, Laboratory of Endocrinology and Radiochemistry, Academic Medical Center, Amsterdam, The Netherlands. (5)Department of Diabetes, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom. (6)Department of Nuclear Medicine, Academic Medical Center, Amsterdam, The Netherlands. OBJECTIVE: Hypoglycemia is associated with increased heat production and, despite of this, hypothermia. Heat production is likely to be mediated by sympathetic innervation. Brown adipose tissue is activated by cold exposure and stimulated by the sympathetic nervous system. We therefore examined the effect of hypoglycemia on uptake of the labeled glucose analogue (18)F-fluorodeoxyglucose in brown adipose tissue using positron emission tomography and computer tomography. METHODS: In nine healthy adults (18)F-fluorodeoxyglucose uptake as measure of brown adipose tissue activity was assessed in a cold environment (17 °C) during euglycemia (blood glucose 4.5 mmol/L) and hypoglycemia (2.5 mmol/L) using a hyperinsulinemic glucose clamp. RESULTS: Brown adipose tissue activity was observed in all participants. No difference was observed in the median (range) maximal standardized uptake values of (18)F-fluorodeoxyglucose in brown adipose tissue between euglycemia and hypoglycemia: 4.2 (1.0-7.7) versus 3.1 (2.2-12.5) g/mL (p=0.7). Similarly there were no differences in mean standardized (18)F-fluorodeoxyglucose uptake values or total brown adipose tissue volume between euglycemia and hypoglycemia. Body temperature dropped by 0.6 °C from baseline during the hypoglycemic condition and remained unchanged during the euglycemic condition. There was no correlation between the maximal standardized uptake values of (18)F-fluorodeoxyglucose in brown adipose tissue and levels of counterregulatory hormones. CONCLUSIONS: This study shows that there is a similar amount of (18)F-fluorodeoxyglucose uptake in brown adipose tissue during hypoglycemia when compared to euglycemia, which makes a role for systemic catecholamines in brown adipose tissue activation and a role for brown adipose tissue thermogenesis in hypoglycemia associated hypothermia unlikely. Future studies in humans should determine whether hypoglycemia indeed increases energy expenditure, and if so which alternative source can explain this increase. Copyright © 2014 Elsevier Inc. All rights reserved. PMID: 25115550 [PubMed - indexed for MEDLINE] 29. Metabolism. 2014 Oct;63(10):1238-49. doi: 10.1016/j.metabol.2014.07.002. Epub 2014 Jul 7. Thermogenic adipocytes: from cells to physiology and medicine. Diaz MB(1), Herzig S(2), Vegiopoulos A(3). Author information: (1)Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120 Heidelberg, Germany. (2)Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120 Heidelberg, Germany. Electronic address: s.herzig@dkfz.de. (3)Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120 Heidelberg, Germany; DKFZ Junior Group Metabolism and Stem Cell Plasticity, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120 Heidelberg, Germany. The identification of active brown fat in humans has evoked widespread interest in the biology of non-shivering thermogenesis among basic and clinical researchers. As a consequence we have experienced a plethora of contributions related to cellular and molecular processes in thermogenic adipocytes as well as their function in the organismal context and their relevance to human physiology. In this review we focus on the cellular basis of non-shivering thermogenesis, particularly in relation to human health and metabolic disease. We provide an overview of the cellular function and distribution of thermogenic adipocytes in mouse and humans, and how this can be affected by environmental factors, such as prolonged cold exposure. We elaborate on recent evidence and open questions on the distinction of classical brown versus beige/brite adipocytes. Further, the origin of thermogenic adipocytes as well as current models for the recruitment of beige/brite adipocytes is discussed with an emphasis on the role of progenitor cells. Focusing on humans, we describe the expanding evidence for the activity, function and physiological relevance of thermogenic adipocytes. Finally, as the potential of thermogenic adipocyte activation as a therapeutic approach for the treatment of obesity and associated metabolic diseases becomes evident, we highlight goals and challenges for current research on the road to clinical translation. Copyright © 2014 Elsevier Inc. All rights reserved. PMID: 25107565 [PubMed - indexed for MEDLINE] 30. Comp Biochem Physiol A Mol Integr Physiol. 2014 Sep;175:82-9. doi: 10.1016/j.cbpa.2014.05.012. Epub 2014 May 23. Ontogeny of non-shivering thermogenesis in Muscovy ducklings (Cairina moschata). Teulier L(1), Rouanet JL(2), Rey B(3), Roussel D(2). Author information: (1)Laboratoire d'Ecologie des Hydrosystèmes Naturels et Anthropisés, UMR 5023, CNRS, Université Lyon 1, 43 Bvd 11 Novembre 1918, F-69622 Villeurbanne Cedex, France. Electronic address: lteulier@gmail.com. (2)Laboratoire d'Ecologie des Hydrosystèmes Naturels et Anthropisés, UMR 5023, CNRS, Université Lyon 1, 43 Bvd 11 Novembre 1918, F-69622 Villeurbanne Cedex, France. (3)Laboratoire de Biométrie et Biologie Évolutive, UMR 5558, CNRS, Université Lyon 1, 43 Bvd 11 Novembre 1918, F-69622 Villeurbanne Cedex, France; Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa. In precocial birds, developing the capacity for early regulatory thermogenesis appears as a fundamental prerequisite for survival and growth in cold environments. However, the exact nature of these processes has not been thoroughly investigated. Several bird species, such as Muscovy ducks (Cairina moschata), develop muscular non-shivering thermogenesis when chronically exposed to cold. The aim of this study was to investigate the age-dependent development of non-shivering thermogenesis in ducklings reared either at thermoneutrality (25°C) or in the cold (4°C). Non-shivering thermogenesis was assessed weekly by simultaneously measuring whole body metabolic heat production and electromyographic activity during shivering at different temperatures ranging from 29°C to 0°C. We found that ducklings reared at thermoneutrality displayed a capacity for non-shivering thermogenesis during the first month of post-hatching life. This thermogenic mechanism increased further in ducklings chronically exposed to a cold environment, but it decreased over time when birds were kept in a thermoneutral environment. Copyright © 2014 Elsevier Inc. All rights reserved. PMID: 24862961 [PubMed - indexed for MEDLINE] 31. Mol Cell Biochem. 2014 Aug;393(1-2):271-82. doi: 10.1007/s11010-014-2070-y. Epub 2014 Apr 29. Characterization of adipocyte stress response pathways during hibernation in thirteen-lined ground squirrels. Rouble AN(1), Tessier SN, Storey KB. Author information: (1)Institute of Biochemistry & Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada. To avoid the harsh conditions of winter climates, hibernating mammals undergo a systematic depression of physiological function by reducing their metabolic rate. During this process, hibernators are exposed to significant stresses (e.g., low body temperature, ischemia-reperfusion) that must be dealt with appropriately to avoid irreversible tissue damage. Consequently, we investigated the contribution of stress-responsive antioxidant enzymes, heat shock proteins, signal transduction pathways (e.g., mitogen-activated protein kinases, MAPK), and transcription factors for their role in conferring tolerance to stress in the hibernating thirteen-lined ground squirrel (Ictidomys tridecemlineatus). Using a combination of multiplex protein panels and traditional immunoblotting procedures, we have focused on these stress factors in brown adipose tissue (BAT) and white adipose tissue (WAT) over cycles of torpor-arousal since they provide the means for heat production as a result of non-shivering thermogenesis and the mobilization of critical energy reserves, respectively. We show the differential and tissue-specific regulation of stress factors including a unified upregulation of the antioxidant enzyme Thioredoxin 1 in both tissues, an upregulation of superoxide dismutase (SOD1 and SOD2) in WAT, and an increase in heat shock proteins during the transitory periods of the torpor-arousal cycle (HSP90α in BAT and HSP60 in WAT). Additionally, an upregulation of the active form of ERK1/2 and p38 in BAT and select transcription factors (e.g., CREB-1 and ELK-1) in both tissues were identified. These data provide us with greater insight into the molecular mechanisms responsible for this animal's natural stress tolerance and outline molecular signatures which define stress resistance. PMID: 24777704 [PubMed - indexed for MEDLINE] 32. PLoS One. 2014 Apr 10;9(4):e94698. doi: 10.1371/journal.pone.0094698. eCollection 2014. Time course of physiological and psychological responses in humans during a 20-day severe-cold-acclimation programme. Brazaitis M(1), Eimantas N(1), Daniuseviciute L(2), Baranauskiene N(1), Skrodeniene E(3), Skurvydas A(1). Author information: (1)Sports Science and Innovation Institute, Lithuanian Sports University, Kaunas, Lithuania. (2)Department of Educational Studies, Kaunas University of Technology, Kaunas, Lithuania. (3)Department of Laboratory Medicines, Medical Academy, Lithuanian University of Health Science, Kaunas, Lithuania. The time course of physiological and psychological markers during cold acclimation (CA) was explored. The experiment included 17 controlled (i.e., until the rectal temperature reached 35.5°C or 170 min had elapsed; for the CA-17 session, the subjects (n = 14) were immersed in water for the same amount of time as that used in the CA-1 session) head-out water immersions at a temperature of 14°C over 20 days. The data obtained in this study suggest that the subjects exhibited a thermoregulatory shift from peripheral-to-central to solely central input thermoregulation, as well as from shivering to non-shivering thermogenesis throughout the CA. In the first six CA sessions, a hypothermic type of acclimation was found; further CA (CA-7 to CA-16) led to a transitional shift to a hypothermic-insulative type of acclimation. Interestingly, when the subjects were immersed in water for the same time as that used in the CA-1 session (CA-17), the CA led to a hypothermic type of acclimation. The presence of a metabolic type of thermogenesis was evident only under thermoneutral conditions. Cold-water immersion decreased the concentration of cold-stress markers, reduced the activity of the innate immune system, suppressed specific immunity to a lesser degree and yielded less discomfort and cold sensation. We found a negative correlation between body mass index and Δ metabolic heat production before and after CA. PMCID: PMC3983237 PMID: 24722189 [PubMed - indexed for MEDLINE] 33. Biol Rev Camb Philos Soc. 2015 Feb;90(1):77-88. doi: 10.1111/brv.12099. Epub 2014 Apr 7. Molecular pathways linking non-shivering thermogenesis and obesity: focusing on brown adipose tissue development. Valente A(1), Jamurtas AZ, Koutedakis Y, Flouris AD. Author information: (1)FAME Laboratory, Centre for Research and Technology Hellas, Karies, Trikala, 42100, Greece; School of Physical Education and Exercise Sciences, University of Thessaly, Trikala, 42100, Greece. An increase in energy intake and/or a decrease in energy expenditure lead to fat storage, causing overweight and obesity phenotypes. The objective of this review was to analyse, for the first time using a systematic approach, all published evidence from the past 8 years regarding the molecular pathways linking non-shivering thermogenesis and obesity in mammals, focusing on mechanisms involved in brown adipose tissue development. Two major databases were scanned from 2006 to 2013 using 'brown adipose tissue' AND 'uncoupling protein-1' AND 'mammalian thermoregulation' AND 'obesity' as key words. A total of 61 articles were retrieved using the search criteria. The available research used knockout methodologies, various substances, molecules and agonist treatments, or different temperature and diet conditions, to assess the molecular pathways linking non-shivering thermogenesis and obesity. By integrating the results of the evaluated animal and human studies, our analysis identified specific molecules that enhance non-shivering thermogenesis and metabolism by: (i) stimulating 'brite' (brown-like) cell development in white adipose tissue; (ii) increasing uncoupling protein-1 expression in brite adipocytes; and (iii) augmenting brown and/or brite adipose tissue mass. The latter can be also increased through low temperature, hibernation and/or molecules involved in brown adipocyte differentiation. Cold stimuli and/or certain molecules activate uncoupling protein-1 in the existing brown adipocytes, thus increasing total energy expenditure by a magnitude proportional to the number of available brown adipocytes. Future research should address the interplay between body mass, brown adipose tissue mass, as well as the main molecules involved in brite cell development. © 2014 The Authors. Biological Reviews © 2014 Cambridge Philosophical Society. PMID: 24708171 [PubMed - in process] 34. Int J Obes (Lond). 2015 Feb;39(2):339-45. doi: 10.1038/ijo.2014.56. Epub 2014 Apr 3. Moderate calorie restriction during gestation programs offspring for lower BAT thermogenic capacity driven by thyroid and sympathetic signaling. Palou M(1), Priego T(1), Romero M(2), Szostaczuk N(1), Konieczna J(1), Cabrer C(1), Remesar X(2), Palou A(1), Pico C(1). Author information: (1)Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics), University of the Balearic Islands and CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Palma de Mallorca, Spain. (2)Department of Nutrition and Food Sciences, Faculty of Biology, University of Barcelona and CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Barcelona, Spain. BACKGROUND: Maternal calorie restriction during pregnancy programs offspring for later overweight and metabolic disturbances. Brown adipose tissue (BAT) is responsible for non-shivering thermogenesis and has recently emerged as a very likely target for human obesity therapy. OBJECTIVE: Here we aimed to assess whether the detrimental effects of undernutrition during gestation could be related to impaired thermogenic capacity in BAT and to investigate the potential mechanisms involved. METHODS: Offspring of control and 20% calorie-restricted rats (days 1-12 of pregnancy) (CR) were studied at the age of 25 days. Protein levels of uncoupling protein 1 (UCP1) and tyrosine hydroxylase (TyrOH); mRNA levels of lipoprotein lipase (LPL), carnitine palmitoyltransferase 1 (CPT1) and deiodinase iodothyronine type II (DIO2) in BAT; and blood parameters including thyroid hormones, were determined. The response to 24-h cold exposure was also studied by measuring body temperature changes over time, and final BAT UCP1 levels. RESULTS: Compared with controls, CR animals displayed in BAT lower UCP1 and TyrOH protein levels and lower LPL and CPT1 mRNA levels; they also showed lower triiodothyronine (T3) plasma levels. CR males, but not females, revealed lower DIO2 mRNA levels than controls. When exposed to cold, CR rats experienced a transient decline in body temperature, but the values were reestablished after 24 h, despite having lower UCP1 levels than controls. CONCLUSIONS: These results suggest that BAT thermogenic capacity is diminished in CR animals, involving impaired BAT sympathetic innervation and thyroid hormone signaling. These alterations make animals more sensitive to cold and may contribute to long-term outcomes of gestational calorie restriction in promoting obesity and related metabolic alterations. PMID: 24694665 [PubMed - in process] 35. Heredity (Edinb). 2014 Sep;113(3):259-67. doi: 10.1038/hdy.2014.24. Epub 2014 Mar 26. Searching for signatures of cold adaptations in modern and archaic humans: hints from the brown adipose tissue genes. Sazzini M(1), Schiavo G(2), De Fanti S(1), Martelli PL(3), Casadio R(3), Luiselli D(1). Author information: (1)1] Laboratory of Molecular Anthropology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy [2] Centre for Genome Biology, University of Bologna, Bologna, Italy. (2)Department of Agro-Food Technologies, University of Bologna, Bologna, Italy. (3)1] Centre for Genome Biology, University of Bologna, Bologna, Italy [2] Biocomputing Group, Department of Biological, Geological and Environmental Sciences, University of Bologna, University of Bologna, Bologna, Italy. Adaptation to low temperatures has been reasonably developed in the human species during the colonization of the Eurasian landmass subsequent to Out of Africa migrations of anatomically modern humans. In addition to morphological and cultural changes, also metabolic ones are supposed to have favored human isolation from cold and body heat production and this can be hypothesized also for most Neandertal and at least for some Denisovan populations, which lived in geographical areas that strongly experienced the last glacial period. Modulation of non-shivering thermogenesis, for which adipocytes belonging to the brown adipose tissue are the most specialized cells, might have driven these metabolic adaptations. To perform an exploratory analysis aimed at looking into this hypothesis, variation at 28 genes involved in such functional pathway was investigated in modern populations from different climate zones, as well as in Neandertal and Denisovan genomes. Patterns of variation at the LEPR gene, strongly related to increased heat dissipation by mitochondria, appeared to have been shaped by positive selection in modern East Asians, but not in Europeans. Moreover, a single potentially cold-adapted LEPR allele, different from the supposed adaptive one identified in Homo sapiens, was found also in Neandertal and Denisovan genomes. These findings suggest that independent mechanisms for cold adaptations might have been developed in different non-African human groups, as well as that the evolution of possible enhanced thermal efficiency in Neandertals and in some Denisovan populations has plausibly entailed significant changes also in other functional pathways than in the examined one. PMID: 24667833 [PubMed - indexed for MEDLINE] 36. Lancet Diabetes Endocrinol. 2014 Mar;2(3):210-7. doi: 10.1016/S2213-8587(13)70156-6. Epub 2013 Nov 12. Brown adipose tissue volume in healthy lean south Asian adults compared with white Caucasians: a prospective, case-controlled observational study. Bakker LE(1), Boon MR(2), van der Linden RA(1), Arias-Bouda LP(3), van Klinken JB(4), Smit F(3), Verberne HJ(5), Jukema JW(6), Tamsma JT(1), Havekes LM(7), van Marken Lichtenbelt WD(8), Jazet IM(1), Rensen PC(9). Author information: (1)Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Netherlands. (2)Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands. Electronic address: m.r.boon@lumc.nl. (3)Department of Nuclear Medicine, Rijnland Hospital, Leiderdorp, Netherlands. (4)Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands. (5)Department of Nuclear Medicine, Academic Medical Center, Amsterdam, Netherlands. (6)Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands. (7)Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands; TNO-Biosciences, Leiden, Netherlands. (8)Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, Netherlands. (9)Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands. Comment in Lancet Diabetes Endocrinol. 2014 Mar;2(3):185-6. BACKGROUND: Individuals of south Asian origin have a very high risk of developing type 2 diabetes compared with white Caucasians. We aimed to assess volume and activity of brown adipose tissue (BAT), which is thought to have a role in energy metabolism by combusting fatty acids and glucose to produce heat and might contribute to the difference in incidence of type 2 diabetes between ethnic groups. METHODS: We enrolled Dutch nationals with south Asian ancestry and matched Caucasian participants at The Rijnland Hospital (Leiderdorp, Netherlands). Eligible participants were healthy lean men aged 18-28 years, and we matched groups for BMI. We measured BAT volume and activity with cold-induced (18)F-fluorodeoxyglucose ((18)F-FDG) PET CT scans, and assessed resting energy expenditure, non-shivering thermogenesis, and serum parameters. This study is registered with the Netherlands Trial Register, number 2473. FINDINGS: Between March 1, 2013, and June 1, 2013, we enrolled 12 participants in each group; one Caucasian participant developed hyperventilation after (18)F-FDG administration, and was excluded from all cold-induced and BAT measurements. Compared with Caucasian participants, south Asian participants did not differ in age (mean 23.6 years [SD 2.8] for south Asians vs 24.6 years [2.8] for Caucasians) or BMI (21.5 kg/m(2) [2.0] vs 22.0 kg/m(2) [1.6]), but were shorter (1.74 m [0.06] vs 1.85 m [0.04]) and lighter (65.0 kg [8.5] vs 75.1 kg [7.2]). Thermoneutral resting energy expenditure was 1297 kcal per day (SD 123) in south Asian participants compared with 1689 kcal per day (193) in white Caucasian participants (difference -32%, p=0.0008). On cold exposure, shiver temperature of south Asians was 2.0°C higher than Caucasians (p=0.0067) and non-shivering thermogenesis was increased by 20% in white Caucasians (p<0.0001) but was not increased in south Asians. Although the maximum and mean standardised uptake values of (18)F-FDG in BAT did not differ between groups, total BAT volume was lower in south Asians (188 mL [SD 81]) than it was in Caucasians (287 mL [169]; difference -34%, p=0.04). Overall, BAT volume correlated positively with basal resting energy expenditure in all assessable individuals (β=0.44, p=0.04). INTERPRETATION: Lower resting energy expenditure, non-shivering thermogenesis, and BAT volumes in south Asian populations might underlie their high susceptibility to metabolic disturbances, such as obesity and type 2 diabetes. Development of strategies to increase BAT volume and activity might help prevent and treat such disorders, particularly in south Asian individuals. FUNDING: Dutch Heart Foundation (2009T038) and Dutch Diabetes Research Foundation (2012.11.1500). Copyright © 2014 Elsevier Ltd. All rights reserved. PMID: 24622751 [PubMed - indexed for MEDLINE] 37. Adipocyte. 2014 Jan 1;3(1):4-9. doi: 10.4161/adip.26232. Epub 2013 Aug 28. The origin and definition of brite versus white and classical brown adipocytes. Rosenwald M(1), Wolfrum C(1). Author information: (1)Institute of Food Nutrition and Health; ETH Zürich; Schwerzenbach, Switzerland. White adipose tissue stores energy while brown adipose tissue contributes to body temperature maintenance through non-shivering thermogenesis. In addition, brite (brown-in-white) adipocytes resembling classical brown adipocytes within predominantly white adipose tissue can be found in response to cold adaptation or other stimuli. Even though our understanding of brite adipocyte formation has increased substantially in the last few years, it is still unclear how brite and classical brown adipocytes are formed in vivo. In this review, we outline and discuss the current understanding of brite adipocyte nomenclature, developmental origin and possible mechanisms of their recruitment. We reason that future work in the field will bridge in vivo tracing studies and primary cell characterization with molecular mechanistic data from in vitro approaches to devise new means to increase energy expenditure. PMCID: PMC3917931 PMID: 24575363 [PubMed] 38. Ann Med. 2015 Mar;47(2):123-32. doi: 10.3109/07853890.2013.874663. Epub 2014 Feb 13. Endogenous ways to stimulate brown adipose tissue in humans. Broeders E(1), Bouvy ND, van Marken Lichtenbelt WD. Author information: (1)Department of Human Biology, NUTRIM - School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre , Maastricht , the Netherlands. Obesity is the result of disequilibrium between energy intake and energy expenditure (EE). Successful long-term weight loss is difficult to achieve with current strategies for the correction of this caloric imbalance. Non-shivering thermogenesis (NST) in brown adipose tissue (BAT) is a possible therapeutic target for the prevention and treatment of obesity and associated metabolic diseases. In recent years, more knowledge about the function and stimulation of bat has been obtained. The sympathetic nervous system (SNS) is currently seen as the main effector for brown fat function. Also, interplay between the thyroid axis and SNS plays an important role in BAT thermogenesis. Almost daily new pathways for the induction of BAT thermogenesis and 'browning' of white adipose tissue (WAT) are identified. Especially the activation of BAT via endogenous pathways has received strong scientific attention. Here we will discuss the relevance of several pathways in activating BAT and their implications for the treatment of obesity. In this review we will focus on the discussion of the most promising endocrine and paracrine pathways to stimulate BAT, by factors and pathways that naturally occur in the human body. PMID: 24521443 [PubMed - in process] 39. PLoS One. 2014 Feb 3;9(2):e87793. doi: 10.1371/journal.pone.0087793. eCollection 2014. The direct cooling of the preoptic-hypothalamic area elicits the release of thyroid stimulating hormone during wakefulness but not during REM sleep. Martelli D(1), Luppi M(2), Cerri M(2), Tupone D(3), Mastrotto M(4), Perez E(2), Zamboni G(2), Amici R(2). Author information: (1)Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy ; Systems Neurophysiology Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia. (2)Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy. (3)Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy ; Department of Neurological Surgery, Oregon Health and Science University, Portland, Oregon, United States of America. (4)Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy ; Department of Cellular and Molecular Physiology and Center for Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut, United States of America. Thermoregulatory responses to temperature changes are not operant during REM sleep (REMS), but fully operant in non-REM sleep and wakefulness. The specificity of the relationship between REMS and the impairment of thermoregulation was tested by eliciting the reflex release of Thyrotropin Releasing Hormone (TRH), which is integrated at hypothalamic level. By inducing the sequential secretion of Thyroid Stimulating Hormone (TSH) and Thyroid Hormone, TRH intervenes in the regulation of obligatory and non-shivering thermogenesis. Experiments were performed on male albino rats implanted with epidural electrodes for EEG recording and 2 silver-copper wire thermodes, bilaterally placed in the preoptic-hypothalamic area (POA) and connected to small thermoelectric heat pumps driven by a low-voltage high current DC power supply. In preliminary experiments, a thermistor was added in order to measure hypothalamic temperature. The activation of TRH hypophysiotropic neurons by the thermode cooling of POA was indirectly assessed, in conditions in which thermoregulation was either fully operant (wakefulness) or not operant (REMS), by a radioimmunoassay determination of plasmatic levels of TSH. Different POA cooling were performed for 120 s or 40 s at current intensities of 80 mA and 125 mA, respectively. At both current intensities, POA cooling elicited, with respect to control values (no cooling current), a significant increase in plasmatic TSH levels in wakefulness, but not during REMS. These results confirm the inactivation of POA thermal sensitivity during REMS and show, for the first time, that this inactivation concerns also the fundamental endocrine control of non-shivering thermogenesis. PMCID: PMC3911997 PMID: 24498374 [PubMed - indexed for MEDLINE] 40. Nat Commun. 2014;5:3224. doi: 10.1038/ncomms4224. Critical roles of nardilysin in the maintenance of body temperature homoeostasis. Hiraoka Y(1), Matsuoka T(2), Ohno M(3), Nakamura K(4), Saijo S(3), Matsumura S(5), Nishi K(3), Sakamoto J(3), Chen PM(3), Inoue K(5), Fushiki T(5), Kita T(6), Kimura T(3), Nishi E(3). Author information: (1)1] Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan [2] [3]. (2)1] Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan [2]. (3)Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. (4)Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. (5)Laboratory of Nutrition Chemistry, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kitashirakawa-Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan. (6)Kobe City Medical Center General Hospital, 4-6 Minatojima-nakamachi, Chuo-ku, Kobe 650-0046, Japan. Body temperature homoeostasis in mammals is governed centrally through the regulation of shivering and non-shivering thermogenesis and cutaneous vasomotion. Non-shivering thermogenesis in brown adipose tissue (BAT) is mediated by sympathetic activation, followed by PGC-1α induction, which drives UCP1. Here we identify nardilysin (Nrd1 and NRDc) as a critical regulator of body temperature homoeostasis. Nrd1(-/-) mice show increased energy expenditure owing to enhanced BAT thermogenesis and hyperactivity. Despite these findings, Nrd1(-/-) mice show hypothermia and cold intolerance that are attributed to the lowered set point of body temperature, poor insulation and impaired cold-induced thermogenesis. Induction of β3-adrenergic receptor, PGC-1α and UCP1 in response to cold is severely impaired in the absence of NRDc. At the molecular level, NRDc and PGC-1α interact and co-localize at the UCP1 enhancer, where NRDc represses PGC-1α activity. These findings reveal a novel nuclear function of NRDc and provide important insights into the mechanism of thermoregulation. PMCID: PMC3926010 PMID: 24492630 [PubMed - in process] 41. PLoS One. 2013 Dec 30;8(12):e85157. doi: 10.1371/journal.pone.0085157. eCollection 2013. Transcriptomic analysis of brown adipose tissue across the physiological extremes of natural hibernation. Hampton M(1), Melvin RG(2), Andrews MT(2). Author information: (1)Department of Mathematics and Statistics, University of Minnesota Duluth, Duluth, Minnesota, United States of America. (2)Department of Biology, University of Minnesota Duluth, Duluth, Minnesota, United States of America. We used RNAseq to generate a comprehensive transcriptome of Brown Adipose Tissue (BAT) over the course of a year in the naturally hibernating thirteen-lined ground squirrel, Ictidomys tridecemlineatus. During hibernation ground squirrels do not feed and use fat stored in White Adipose Tissue (WAT) as their primary source of fuel. Stored lipid is consumed at high rates by BAT to generate heat at specific points during the hibernation season. The highest rate of BAT activity occurs during periodic arousals from hypothermic torpor bouts, referred to as Interbout Arousals (IBAs). IBAs are characterized by whole body re-warming (from 5 to 37 °C) in 2-3 hours, and provide a unique opportunity to determine the genes responsible for the highly efficient lipid oxidation and heat generation that drives the arousal process. Illumina HighSeq sequencing identified 14,573 distinct BAT mRNAs and quantified their levels at four points: active ground squirrels in April and October, and hibernating animals during both torpor and IBA. Based on significant changes in mRNA levels across the four collection points, 2,083 genes were shown to be differentially expressed. In addition to providing detail on the expression of nuclear genes encoding mitochondrial proteins, and genes involved in beta-adrenergic and lipolytic pathways, we identified differentially expressed genes encoding various transcription factors and other regulatory proteins which may play critical roles in high efficiency fat catabolism, non-shivering thermogenesis, and transitions into and out of the torpid state. PMCID: PMC3875542 PMID: 24386461 [PubMed - indexed for MEDLINE] 42. Int J Obes (Lond). 2014 Aug;38(8):1027-34. doi: 10.1038/ijo.2013.230. Epub 2013 Dec 6. Enhancement of brown fat thermogenesis using chenodeoxycholic acid in mice. Teodoro JS(1), Zouhar P(2), Flachs P(2), Bardova K(2), Janovska P(2), Gomes AP(1), Duarte FV(1), Varela AT(1), Rolo AP(3), Palmeira CM(1), Kopecký J(2). Author information: (1)1] Center for Neuroscience and Cell Biology, Faculty of Science and Technology, University of Coimbra, Coimbra, Portugal [2] Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, Coimbra, Portugal. (2)Department of Adipose Tissue Biology, Institute of Physiology Academy of Sciences of the Czech Republic v.v.i., Prague, Czech Republic. (3)1] Center for Neuroscience and Cell Biology, Faculty of Science and Technology, University of Coimbra, Coimbra, Portugal [2] Department of Biology, University of Aveiro, Aveiro, Portugal. OBJECTIVE: Besides their role in lipid absorption, bile acids (BAs) can act as signalling molecules. Cholic acid was shown to counteract obesity and associated metabolic disorders in high-fat-diet (cHF)-fed mice while enhancing energy expenditure through induction of mitochondrial uncoupling protein 1 (UCP1) and activation of non-shivering thermogenesis in brown adipose tissue (BAT). In this study, the effects of another natural BA, chenodeoxycholic acid (CDCA), on dietary obesity, UCP1 in both interscapular BAT and in white adipose tissue (brite cells in WAT), were characterized in dietary-obese mice. RESEARCH DESIGN: To induce obesity and associated metabolic disorders, male 2-month-old C57BL/6J mice were fed cHF (35% lipid wt wt(-1), mainly corn oil) for 4 months. Mice were then fed either (i) for 8 weeks with cHF or with cHF with two different doses (0.5%, 1%; wt wt(-1)) of CDCA (8-week reversion); or (ii) for 3 weeks with cHF or with cHF with 1% CDCA, or pair-fed (PF) to match calorie intake of the CDCA mice fed ad libitum; mice on standard chow diet were also used (3-week reversion). RESULTS: In the 8-week reversion, the CDCA intervention resulted in a dose-dependent reduction of obesity, dyslipidaemia and glucose intolerance, which could be largely explained by a transient decrease in food intake. The 3-week reversion revealed mild CDCA-dependent and food intake-independent induction of UCP1-mediated thermogenesis in interscapular BAT, negligible increase of UCP1 in subcutaneous WAT and a shift from carbohydrate to lipid oxidation. CONCLUSIONS: CDCA could reverse obesity in cHF-fed mice, mainly in response to the reduction in food intake, an effect probably occuring but neglected in previous studies using cholic acid. Nevertheless, CDCA-dependent and food intake-independent induction of UCP1 in BAT (but not in WAT) could contribute to the reduction in adiposity and to the stabilization of the lean phenotype. PMID: 24310401 [PubMed - indexed for MEDLINE] 43. Magn Reson Imaging. 2014 Feb;32(2):107-17. doi: 10.1016/j.mri.2013.10.003. Epub 2013 Oct 15. MRI detection of brown adipose tissue with low fat content in newborns with hypothermia. Hu HH(1), Wu TW(2), Yin L(3), Kim MS(3), Chia JM(4), Perkins TG(4), Gilsanz V(5). Author information: (1)Radiology, Children's Hospital Los Angeles, Los Angeles, CA, USA. Electronic address: hhu@chla.usc.edu. (2)Neonatology, Children's Hospital Los Angeles, Los Angeles, CA, USA. (3)Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA. (4)Philips Healthcare, Cleveland, OH, USA. (5)Radiology, Children's Hospital Los Angeles, Los Angeles, CA, USA; Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA. PURPOSE: To report the observation of brown adipose tissue (BAT) with low fat content in neonates with hypoxic-ischemic encephalopathy (HIE) after they have undergone hypothermia therapy. MATERIALS AND METHODS: The local ethics committee approved the imaging study. Ten HIE neonates (3 males, 7 females, age range: 2-3days) were studied on a 3-T MRI system using a low-flip-angle (3°) six-echo proton-density-weighted chemical-shift-encoded water-fat pulse sequence. Fat-signal fraction (FF) measurements of supraclavicular and interscapular (nape) BAT and adjacent subcutaneous white adipose tissues (WAT) were compared to those from five non-HIE neonates, two recruited for the present investigation and three from a previous study. RESULTS: In HIE neonates, the FF range for the supraclavicular, interscapular, and subcutaneous regions was 10.3%-29.9%, 28.0%-57.9%, and 62.6%-88.0%, respectively. In non-HIE neonates, the values were 23.7%-42.2% (p=0.01), 45.4%-59.5% (p=0.06), and 67.8%-86.3% (p=0.38), respectively. On an individual basis, supraclavicular BAT FF was consistently the lowest, interscapular BAT values were higher, and subcutaneous WAT values were the highest (p<0.01). CONCLUSION: We speculate that hypothermia therapy in HIE neonates likely promotes BAT-mediated non-shivering thermogenesis, which subsequently leads to a depletion of the tissue's intracellular fat stores. We believe that this is consequently reflected in lower FF values, particularly in the supraclavicular BAT depot, in contrast to non-HIE neonates. © 2013. PMCID: PMC3947181 PMID: 24239336 [PubMed - indexed for MEDLINE] 44. Diabetes Obes Metab. 2013 Sep;15 Suppl 3:34-8. doi: 10.1111/dom.12154. The immune cells in adipose tissue. Ferrante AW Jr(1). Author information: (1)Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA. awf7@columbia.edu Although the pathological role of the immune system in several metabolic disorders, including type 1 diabetes mellitus (T1DM) and Addison's disease, has long been recognized and studied, only in the last decade has it become apparent that the immune system plays a broad and more subtle role in local and systemic metabolism. It is now apparent that the immune system monitors and responds to specific metabolic cues in both pathologic and non-pathologic settings through a set of processes dubbed immunometabolism. Expansion of adipose tissue mass, activation of lipolysis, eating a high fat diet and even non-shivering thermogenesis all lead to the recruitment and activation of immune cells in key metabolic tissues. The responses are complex and not completely defined, and indeed, as is typical of rapidly evolving research areas, there are some conflicting reports, especially related to the metabolic consequences of manipulation of immune function. However, what is clear is the consensus that metabolic processes, especially obesity and obesity-related complications, activate both the innate and adaptive arms of the immune system. Canonical immune processes consist of discrete steps: surveillance, recognition, effector action and resolution. Over the last decade evidence for each part of the immune response has been found at the intersection of the immune system with metabolism. Although evidence for immune surveillance and modulation of metabolism has been found in the liver, muscle, hypothalamus and pancreas, immune cell function has been most intensively studied and best understood in adipose tissue where studies continue to provide insights into the intersection of the metabolic and immune systems. Here we review the modulation of immune cell populations in adipose tissue and discuss regulatory processes implicated in controlling the interface between metabolism and immunologic function. © 2013 John Wiley & Sons Ltd. PMCID: PMC3777665 PMID: 24003919 [PubMed - indexed for MEDLINE] 45. PLoS One. 2013 Sep 6;8(9):e74154. doi: 10.1371/journal.pone.0074154. eCollection 2013. Growth prior to thermogenesis for a quick fledging of Adélie penguin chicks (Pygoscelis adeliae). Dégletagne C(1), Roussel D, Rouanet JL, Baudimont F, Moureaux EM, Harvey S, Duchamp C, Le Maho Y, Raccurt M. Author information: (1)Laboratoire d'Ecologie des Hydrosystèmes Naturels et Anthropisés, UMR5023, Université Lyon 1, Villeurbanne, France. The evolutionary trade-off between tissue growth and mature function restricts the post natal development of polar birds. The present study uses an original integrative approach as it includes gene expression, plus biochemical and physiological analysis to investigate how Adélie penguin chicks achieve a rapid growth despite the energetic constraints linked to the cold and the very short breeding season in Antarctica. In pectoralis muscle, the main thermogenic tissue in birds, our data show that the transition from ectothermy to endothermy on Day 15 post- hatching is associated with substantial and coordinated changes in the transcription of key genes. While the early activation of genes controlling cell growth and differentiation (avGHR, avIGF-1R, T3Rβ) is rapidly down-regulated after hatching, the global increase in the relative expression of genes involved in thermoregulation (avUCP, avANT, avLPL) and transcriptional regulation (avPGC1α, avT3Rβ) underlie the muscular acquisition of oxidative metabolism. Adélie chicks only become real endotherms at 15 days of age with the development of an oxidative muscle phenotype and the ability to shiver efficiently. The persistent muscular expression of IGF-1 throughout growth probably acts as a local mediator to adjust muscle size and its oxidative capacity to anticipate the new physiological demands of future Dives in cold water. The up-regulation of T3Rβ mRNA levels suggests that circulating T3 may play an important role in the late maturation of skeletal muscle by reinforcing, at least in part, the paracrine action of IGF-1. From day 30, the metabolic shift from mixed substrate to lipid metabolism, with the markedly increased mRNA levels of muscle avLPL, avANT and avUCP, suggests the late development of a fatty acid-enhanced muscle non-shivering thermogenesis mechanism. This molecular control is the key to this finely-tuned strategy by which the Adélie penguin chick successfully heads for the sea on schedule. PMCID: PMC3765356 PMID: 24040194 [PubMed - indexed for MEDLINE] 46. Indian J Physiol Pharmacol. 2012 Oct-Dec;56(4):301-13. Hypothalamic temperature: a key regulator in homeostatic restoration of sleep during chronic cold exposure in rats. Kaushik MK(1), Kumar VM, Mallick HN. Author information: (1)Sleep Research Laboratory, Department of Physiology, All India Institute of Medical Sciences, New Delhi--110 029, India. Exposure to cold ambient temperature (Ta) affects sleep-wake (S-W) state. The vigilance states on the other hand influence thermal status of the animals. Simultaneous recording of body temperature (Tb) with S-W is crucial to understand the homeostatic relationship between the two. In the present study we recorded both Tb and hypothalamic temperature (Thy) along with S-W, during acute and chronic exposure to mild cold (Ta). Electrooculogram (EOG), electroencephalogram (EEG) and electromyogram (EMG) electrodes were chronically implanted in rats to assess S-W. A thermocouple, near the preoptic area, and radio transmitter in the peritoneum, were implanted, to record Thy and Tb respectively. After three days of baseline recordings of S-W, Thy and Tb at Ta of 26 dergrees C, the rats were exposed to mild cold Ta (18 degrees C) for 28 days. All the parameters were recorded during cold exposure and also for five days after the termination of cold exposure. On the first day of cold exposure there was a decrease in slow wave sleep and paradoxical sleep, but they were restored by the 21st day of continued exposure. The Thy remained decreased throughout the cold exposure. Though the Tb showed a slight decrease on the first day of cold exposure, there was no appreciable change during the subsequent days. The Thy came back to near pre exposure level on termination of cod exposure. The decrease in Thy during mild cold exposure would have triggered cold defense mechanisms. Increase in wakefulness during acute cold exposure and non-shivering thermogenesis during chronic cold exposure are probably responsible for the maintenance of Tb. Decrease in Thy is probably the key trigger for initiating thermoregulatory measures to maintain Tb and homeostatic restoration of sleep. PMID: 23781649 [PubMed - indexed for MEDLINE] 47. Front Endocrinol (Lausanne). 2013 Jun 12;4:71. doi: 10.3389/fendo.2013.00071. eCollection 2013. Adipokines mediate inflammation and insulin resistance. Kwon H(1), Pessin JE. Author information: (1)Department of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine , Bronx, NY , USA. For many years, adipose tissue was considered as an inert energy storage organ that accumulates and stores triacylglycerols during energy excess and releases fatty acids in times of systemic energy need. However, over the last two decades adipose tissue depots have been established as highly active endocrine and metabolically important organs that modulate energy expenditure and glucose homeostasis. In rodents, brown adipose tissue plays an essential role in non-shivering thermogenesis and in energy dissipation that can serve to protect against diet-induced obesity. White adipose tissue collectively referred too as either subcutaneous or visceral adipose tissue is responsible for the secretion of an array of signaling molecules, termed adipokines. These adipokines function as classic circulating hormones to communicate with other organs including brain, liver, muscle, the immune system, and adipose tissue itself. The dysregulation of adipokines has been implicated in obesity, type 2 diabetes, and cardiovascular disease. Recently, inflammatory responses in adipose tissue have been shown as a major mechanism to induce peripheral tissue insulin resistance. Although leptin and adiponectin regulate feeding behavior and energy expenditure, these adipokines are also involved in the regulation of inflammatory responses. Adipose tissue secretes various pro- and anti-inflammatory adipokines to modulate inflammation and insulin resistance. In obese humans and rodent models, the expression of pro-inflammatory adipokines is enhanced to induce insulin resistance. Collectively, these findings have suggested that obesity-induced insulin resistance may result, at least in part, from an imbalance in the expression of pro- and anti-inflammatory adipokines. Thus we will review the recent progress regarding the physiological and molecular functions of adipokines in the obesity-induced inflammation and insulin resistance with perspectives on future directions. PMCID: PMC3679475 PMID: 23781214 [PubMed] 48. Biochim Biophys Acta. 2014 Mar;1842(3):340-51. doi: 10.1016/j.bbadis.2013.05.027. Epub 2013 Jun 4. Adipocyte lineages: tracing back the origins of fat. Sanchez-Gurmaches J(1), Guertin DA(2). Author information: (1)Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. (2)Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: david.guertin@umassmed.edu. The obesity epidemic has intensified efforts to understand the mechanisms controlling adipose tissue development. Adipose tissue is generally classified as white adipose tissue (WAT), the major energy storing tissue, or brown adipose tissue (BAT), which mediates non-shivering thermogenesis. It is hypothesized that brite adipocytes (brown in white) may represent a third adipocyte class. The recent realization that brown fat exist in adult humans suggests increasing brown fat energy expenditure could be a therapeutic strategy to combat obesity. To understand adipose tissue development, several groups are tracing the origins of mature adipocytes back to their adult precursor and embryonic ancestors. From these studies emerged a model that brown adipocytes originate from a precursor shared with skeletal muscle that expresses Myf5-Cre, while all white adipocytes originate from a Myf5-negative precursors. While this provided a rational explanation to why BAT is more metabolically favorable than WAT, recent work indicates the situation is more complex because subsets of white adipocytes also arise from Myf5-Cre expressing precursors. Lineage tracing studies further suggest that the vasculature may provide a niche supporting both brown and white adipocyte progenitors; however, the identity of the adipocyte progenitor cell is under debate. Differences in origin between adipocytes could explain metabolic heterogeneity between depots and/or influence body fat patterning particularly in lipodystrophy disorders. Here, we discuss recent insights into adipose tissue origins highlighting lineage-tracing studies in mice, how variations in metabolism or signaling between lineages could affect body fat distribution, and the questions that remain unresolved. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. Copyright © 2013 Elsevier B.V. All rights reserved. PMCID: PMC3805734 PMID: 23747579 [PubMed - indexed for MEDLINE] 49. Methods Mol Biol. 2013;1020:175-92. doi: 10.1007/978-1-62703-459-3_11. Analysis of cGMP signaling in adipocytes. Jennissen K(1), Haas B, Mitschke MM, Siegel F, Pfeifer A. Author information: (1)Institute of Pharmacology and Toxicology, Universität Bonn, Bonn, Germany. Obesity has reached pandemic dimensions with more than half a billion adults affected worldwide. Detailed knowledge of adipose biology is required for the development of urgently needed novel therapies directed against obesity. Two types of adipose tissue can be distinguished in humans and mice: white adipose tissue (WAT), which primarily stores energy in the form of lipids and has endocrine functions. In contrast, brown adipose tissue (BAT) dissipates energy in the form of heat (thermogenesis). Recent studies in humans demonstrated that BAT not only plays a role for non-shivering thermogenesis in newborns but is also metabolically active in adults. Here, we describe protocols for the generation of cellular models for the analysis of adipogenesis as well as function of brown and white fat. These models are based on the in vitro differentiation of mesenchymal stem cells (MSCs) isolated from adipose tissues. Using specific differentiation protocols, the role of cGMP signaling in both brown as well as white adipocytes can be studied. PMID: 23709033 [PubMed - indexed for MEDLINE] 50. J Cell Biochem. 2013 Oct;114(10):2306-13. doi: 10.1002/jcb.24577. Concerted expression of the thermogenic and bioenergetic mitochondrial protein machinery in brown adipose tissue. Guillen C(1), Bartolome A, Vila-Bedmar R, García-Aguilar A, Gomez-Hernandez A, Benito M. Author information: (1)Faculty of Pharmacy, Department of Biochemistry and Molecular Biology II, Complutense University of Madrid, Madrid, Spain. Brown adipose tissue (BAT) is specialized in non-shivering thermogenesis through the expression of the mitochondrial uncoupling protein-1 (UCP1). In this paper, we describe the relationship between UCP1 and proteins involved in ATP synthesis. By the use of BATIRKO mice, which have enhanced UCP1 expression in BAT, an increase in ATP synthase as well as in ubiquinol cytochrome c reductase levels was observed. Alterations in mitochondrial mass or variations in ATP levels were not observed in BAT of these mice. In addition, using a protocol of brown adipocyte differentiation, the concerted expression of UCP1 with ATP synthase was found. These two scenarios revealed that increases in the uncoupling machinery of brown adypocites must be concomitantly followed by an enhancement of proteins involved in ATP synthesis. These concerted changes reflect the need to maintain ATP production in an essentially uncoupling cell type. Copyright © 2013 Wiley Periodicals, Inc. PMID: 23606415 [PubMed - indexed for MEDLINE] 51. Adipocyte. 2012 Apr 1;1(2):116-120. An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis. Morrison SF(1), Madden CJ, Tupone D. Author information: (1)Department of Neurological Surgery; Oregon Health & Science University; Portland, OR USA. Non-shivering thermogenesis in brown adipose tissue (BAT) plays an important role in thermoregulatory cold-defense and, through its metabolic consumption of energy reserves to produce heat, can affect the long-term regulation of adiposity. An orexinergic pathway from the perifornical lateral hypothalamus (PeF/LH) to the rostral raphe pallidus (rRPa) has been demonstrated to increase the gain of the excitatory drives to medullary sympathetic premotor neurons controlling BAT sympathetic outflow and BAT thermogenesis. With this background, we consider neural mechanisms that could underlie orexin's modulation of the excitability of BAT sympathetic premotor neurons in rRPa and the potential role of altered BAT thermogenesis in pathological conditions associated with the absence of the central orexin system. Overall, these new data enhance our understanding of the role of central orexin in regulating body temperature and energy homeostasis and provide further insight into the neurochemical regulation of BAT thermogenesis and metabolism. PMCID: PMC3607627 PMID: 23538704 [PubMed] 52. Biochim Biophys Acta. 2013 May;1831(5):986-1003. doi: 10.1016/j.bbalip.2013.02.003. Epub 2013 Feb 20. Stimulation of mitochondrial oxidative capacity in white fat independent of UCP1: a key to lean phenotype. Flachs P(1), Rossmeisl M, Kuda O, Kopecky J. Author information: (1)Department of Adipose Tissue Biology, Institute of Physiology Academy of Sciences of the Czech Republic, v.v.i., Prague, Czech Republic. We are facing a revival of the strategy to counteract obesity and associated metabolic disorders by inducing thermogenesis mediated by mitochondrial uncoupling protein-1 (UCP1). Thus, the main focus is on the adaptive non-shivering thermogenesis occurring both in the typical depots of brown adipose tissue (BAT) and in UCP1-containing cells that could be induced in white adipose tissue (WAT). Because contribution of WAT to resting metabolic rate is relatively small, the possibility to reduce adiposity by enhancing energy expenditure in classical white adipocytes is largely neglected. However, several pieces of evidence support a notion that induction of energy expenditure based on oxidation of fatty acids (FA) in WAT may be beneficial for health, namely: (i) studies in both humans and rodents document negative association between oxidative capacity of mitochondria in WAT and obesity; (ii) pharmacological activation of AMPK in rats as well as cold-acclimation of UCP1-ablated mice results in obesity resistance associated with increased oxidative capacity in WAT; and (iii) combined intervention using long-chain n-3 polyunsaturated FA (omega 3) and mild calorie restriction exerted synergism in the prevention of obesity in mice fed a high-fat diet; this was associated with strong hypolipidemic and insulin-sensitizing effects, as well as prevention of inflammation, and synergistic induction of mitochondrial oxidative phosphorylation (OXPHOS) and FA oxidation, specifically in epididymal WAT. Importantly, these changes occurred without induction of UCP1 and suggested the involvement of: (i) futile substrate cycle in white adipocytes, which is based on lipolysis of intracellular triacylglycerols and re-esterification of FA, in association with the induction of mitochondrial OXPHOS capacity, β-oxidation, and energy expenditure; (ii) endogenous lipid mediators (namely endocannabinoids, eicosanoids, prostanoids, resolvins, and protectins) and their cognate receptors; and (iii) AMP-activated protein kinase in WAT. Quantitatively, the strong induction of FA oxidation in WAT in response to the combined intervention is similar to that observed in the transgenic mice rendered resistant to obesity by ectopic expression of UCP1 in WAT. The induction of UCP1-independent FA oxidation and energy expenditure in WAT in response to the above physiological stimuli could underlie the amelioration of obesity and low-grade WAT inflammation, and it could reduce the release of FA from adipose tissue and counteract harmful consequences of lipid accumulation in other tissues. In this respect, new combination treatments may be designed using naturally occurring micronutrients (e.g. omega 3), reduced calorie intake or pharmaceuticals, exerting synergism in the induction of the mitochondrial OXPHOS capacity and stimulation of lipid catabolism in white adipocytes, and improving metabolic flexibility of WAT. The role of mutual interactions between adipocytes and immune cells contained in WAT in tissue metabolism should be better characterised. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease. Copyright © 2013 Elsevier B.V. All rights reserved. PMID: 23454373 [PubMed - indexed for MEDLINE] 53. Diabetes Metab J. 2013 Feb;37(1):22-9. doi: 10.4093/dmj.2013.37.1.22. Epub 2013 Feb 15. Brown adipose tissue as a regulator of energy expenditure and body fat in humans. Saito M(1). Author information: (1)Department of Nutrition, Tenshi College, Sapporo, Japan. Brown adipose tissue (BAT) is recognized as the major site of sympathetically activated nonshivering thermogenesis during cold exposure and after spontaneous hyperphagia, thereby controling whole-body energy expenditure and body fat. In adult humans, BAT has long been believed to be absent or negligible, but recent studies using fluorodeoxyglucose-positron emission tomography, in combination with computed tomography, demonstrated the existence of metabolically active BAT in healthy adult humans. Human BAT is activated by acute cold exposure, being positively correlated to cold-induced increases in energy expenditure. The metabolic activity of BAT differs among individuals, being lower in older and obese individuals. Thus, BAT is recognized as a regulator of whole-body energy expenditure and body fat in humans as in small rodents, and a hopeful target combating obesity and related disorders. In fact, there are some food ingredients such as capsaicin and capsinoids, which have potential to activate and recruit BAT via activity on the specific receptor, transient receptor potential channels, thereby increasing energy expenditure and decreasing body fat modestly and consistently. PMCID: PMC3579148 PMID: 23441053 [PubMed] 54. Gen Comp Endocrinol. 2013 Apr 1;184:87-92. doi: 10.1016/j.ygcen.2013.01.006. Epub 2013 Jan 29. Diet-induced changes in Ucp1 expression in bovine adipose tissues. Asano H(1), Yamada T, Hashimoto O, Umemoto T, Sato R, Ohwatari S, Kanamori Y, Terachi T, Funaba M, Matsui T. Author information: (1)Division of Applied Biosciences, Kyoto University Graduate School of Agriculture, Kyoto 606-8502, Japan. Brown adipocytes, which regulate non-shivering thermogenesis, have been believed to exist in a limited number of mammalian species, and only under limited physiological conditions. Recent discoveries indicate that adult humans possess a significant number of functional brown adipocytes. This study explores the regulatory emergence of brown adipocytes in white adipose tissue (WAT) depots of fattening cattle. RT-PCR analyses indicated significant expression of Ucp1, a brown adipocyte-specific gene, in the WAT of 31-month-old Japanese Black steers. Immunohistochemical analysis revealed that Ucp1-positive small adipocytes were dispersed in the subcutaneous WAT. Next, we examined expression level of Ucp1 and other brown adipocyte-selective genes such as Pgc1α, Cidea, Dio2, Cox1, Cox7a1 and Cox8b in WAT of 30-month-old steers fed either diet with low protein/energy content (roughage diet) or that with high protein/energy content (concentrate diet) for 20months. Ucp1 expression in the subcutaneous WAT was significantly higher in the concentrate diet group than in the roughage diet group. Furthermore, the higher Ucp1 expression levels were limited to the subcutaneous WAT, and no differences between groups were detected in the mesenteric, perirenal, intermuscular or intramuscular WAT. Expression of Dio2, Cox1 and Cox8b was higher in the subcutaneous WAT but not in the mesenteric WAT of the concentrate diet group. Furthermore, expression of Prdm16, a positive regulator of differentiation toward brown adipocyte-lineage cells, and expression of leptin, a molecule that enhances activity of brown adipocytes, were significantly higher in the subcutaneous WAT of the concentrate diet group. This study demonstrates the presence of brown adipocytes in WAT depots of fattening cattle, and suggests the diet-related modulation of expression of genes predominantly expressed in brown adipocytes. Copyright © 2013 Elsevier Inc. All rights reserved. PMID: 23370305 [PubMed - indexed for MEDLINE] 55. Acta Physiol (Oxf). 2014 Jan;210(1):20-30. doi: 10.1111/apha.12053. Epub 2013 Jan 28. The developmental transition of ovine adipose tissue through early life. Pope M(1), Budge H, Symonds ME. Author information: (1)Early Life Nutrition Research Unit, Academic Division of Child Health, School of Medicine, University Hospital, The University of Nottingham, Nottingham, UK. AIM: Hypothermia induced by cold exposure at birth is prevented in sheep by the rapid onset of non-shivering thermogenesis in brown adipose tissue (BAT). Changes in adipose tissue composition in early life are therefore essential for survival but also influence adiposity in later life and were thus examined in detail during early development. METHODS: Changes in adipose composition were investigated by immunohistochemistry and qRT-PCR between the period from the first appearance of adipose in the mid gestation foetus, through birth and up to 1 month of age. RESULTS: We identified four distinct phases of development, each associated with pronounced changes in tissue histology and in distribution of the BAT specific uncoupling protein (UCP)1. At mid gestation, perirenal adipose tissue exhibited a dense proliferative, structure marked by high expression of KI-67 but with no UCP1 or visible lipid droplets. By late gestation large quantities of UCP1 were present, lipid storage was evident and expression of BAT-related genes were abundant (e.g. prolactin and β3 receptors). Subsequently, within 12 h of birth, the depot was largely depleted of lipid and expression of genes such as UCP1, PGC1α, CIDEA peaked. By 30 days UCP1 was undetectable and the depot contained large lipid droplets; however, genes characteristic of BAT (e.g. PRDM16 and BMP7) and most characteristic of white adipose tissue (e.g. leptin and RIP140) were still abundant. CONCLUSION: Adipose tissue undergoes profound compositional changes in early life, of which an increased understanding could offer potential interventions to retain BAT in later life. © 2012 The Authors Acta Physiologica © 2012 Scandinavian Physiological Society. PMID: 23351024 [PubMed - indexed for MEDLINE] 56. Physiol Behav. 2013 Feb 17;110-111:87-95. doi: 10.1016/j.physbeh.2012.12.018. Epub 2013 Jan 8. Impact of nesting material on mouse body temperature and physiology. Gaskill BN(1), Gordon CJ, Pajor EA, Lucas JR, Davis JK, Garner JP. Author information: (1)Animal Behavior and Well-Being Group, Department of Animal Science, Purdue University, 915 W. State Street, West Lafayette, IN 47907, USA. brianna.gaskill@crl.com In laboratories, mice are housed at 20-24 °C, which is below their lower critical temperature (≈30 °C). Thus, mice are potentially cold stressed, which can alter metabolism, immune function, and reproduction. These physiological changes reflect impaired wellbeing, and affect scientific outcomes. We hypothesized that nesting material would allow mice to alleviate cold stress by controlling their thermal microenvironment, thus insulating them, reducing heat loss and thermogenic processes. Naïve C57BL/6, CD-1, and BALB/c mice (24 male and 24 female/strain in groups of 3) were housed in standard cages at 20 °C either with or without 8 g nesting material for 4 weeks. Core body temperature was followed using intraperitoneal radio telemetry. The thermal properties of the nests were assessed using a thermal imaging camera, and related to nest quality. Higher scoring nests were negatively correlated with the mean radiated temperature and were thus more insulating. No effects of nesting material on body temperature were found. CD-1 mice with nesting material had higher end body weights than controls. No effect was seen in the other two strains. Mice with the telemetry implant had larger spleens than controls, possibly indicating an immune response to the implant or low level infection from the surgery. BALB/c mice express less mRNA for the UCP1 protein than mice without nesting material. This indicates that BALB/c's with nesting material do not utilize their brown fat to create heat as readily as controls. Nests can alleviate thermal discomfort by decreasing the amount of radiated heat and reduce the need for non-shivering thermogenesis. However, different strains appear to use different behavioral (through different primary modes of behavioral thermoregulation) and physiological strategies (utilizing thermogenesis to different degrees) to maintain a constant body temperature under cool standard laboratory ambient temperatures. Copyright © 2013 Elsevier Inc. All rights reserved. PMID: 23313562 [PubMed - indexed for MEDLINE] 57. Biomol Concepts. 2012 Aug;3(4):381-386. Orexin modulates brown adipose tissue thermogenesis. Madden CJ(1), Tupone D, Morrison SF. Author information: (1)Department of Neurological Surgery Oregon Health & Science University Portland, OR 97239. Non-shivering thermogenesis in brown adipose tissue (BAT) plays an important role in thermoregulation. In addition, activations of BAT have important implications for energy homeostasis due to the metabolic consumption of energy reserves entailed in the production of heat in this tissue. In this conceptual overview we describe the role of orexins/hypocretins within the central nervous system in the modulation of thermogenesis in BAT under several physiological conditions. Within this framework, we consider potential neural mechanisms underlying the pathological conditions associated with the absence of the central orexinergic modulation of BAT thermogenesis and energy expenditure. Overall, the experimental basis for our understanding of the role of central orexin in regulating body temperature and energy homeostasis provides an illustrative example that highlights several general principles and caveats that should help to guide future investigations of the neurochemical regulation of thermogenesis and metabolism. PMCID: PMC3535439 PMID: 23293681 [PubMed] 58. Br J Nutr. 2013 Jul 28;110(2):282-8. doi: 10.1017/S0007114512005089. Epub 2012 Dec 14. Effects of green tea extracts on non-shivering thermogenesis during mild cold exposure in young men. Gosselin C(1), Haman F. Author information: (1)Unité de Recherche sur Nutrition et Métabolisme, Hôpital Montfort, 713, Chemin Montréal, Ottawa, ON, Canada K1K 0T2. The effects of epigallocatechin-3-gallate (EGCG) and caffeine on non-shivering thermogenesis (NST) during cold exposure is unknown. The purpose of the present study was to quantify the effects of co-ingesting EGCG and caffeine on the thermogenic responses of a 3 h cold exposure. A total of eight healthy males were exposed to mild cold, using a liquid-conditioned suit perfused with 158C water, on two occasions and consumed a placebo or an extract of 1600 mg of EGCG and 600 mg of caffeine (Green tea). Thermic, metabolic and electromyographic measurements were monitored at baseline and during the cold exposure. Results showed that the AUC of shivering intensity over the cold exposure period was reduced by approximately 20% in the Green tea (266 (SEM 6)% maximal voluntary contraction (MVC) x min) compared with the Placebo (332 (SEM 69)%MVC x min) (P=0·01) treatments. In contrast, the total AUC for energy expenditure (EE) was approximately 10% higher in the Green tea (23·5 (SEM 1·4) kJ/kg x 180 min) compared with the Placebo (327 (SEM 74) kJ/kg 180 min) (P=0·007) treatments. The decrease in shivering activity combined with an increase in EE, following the ingestion of EGCG and caffeine during the cold exposure, indicates that NST pathways can be significantly stimulated in adult human subjects. The present study provides an experimental approach for human investigations into the potential role of diet and bioactive food ingredients in modulating NST during cold exposure. Stimulating NST pathways in such a manner may also provide important targets in the search of targets for the management of obesity and diabetes. PMID: 23237788 [PubMed - indexed for MEDLINE] 59. J Vis Exp. 2012 Nov 23;(69). pii: 4060. doi: 10.3791/4060. Functional imaging of brown fat in mice with 18F-FDG micro-PET/CT. Wang X(1), Minze LJ, Shi ZZ. Author information: (1)Department of Translational Imaging, The Methodist Hospital Research Institute, Houston, TX, USA. Brown adipose tissue (BAT) differs from white adipose tissue (WAT) by its discrete location and a brown-red color due to rich vascularization and high density of mitochondria. BAT plays a major role in energy expenditure and non-shivering thermogenesis in newborn mammals as well as the adults (1). BAT-mediated thermogenesis is highly regulated by the sympathetic nervous system, predominantly via β adrenergic receptor (2, 3). Recent studies have shown that BAT activities in human adults are negatively correlated with body mass index (BMI) and other diabetic parameters (4-6). BAT has thus been proposed as a potential target for anti-obesity/anti-diabetes therapy focusing on modulation of energy balance (6-8). While several cold challenge-based positron emission tomography (PET) methods are established for detecting human BAT (9-13), there is essentially no standardized protocol for imaging and quantification of BAT in small animal models such as mice. Here we describe a robust PET/CT imaging method for functional assessment of BAT in mice. Briefly, adult C57BL/6J mice were cold treated under fasting conditions for a duration of 4 hours before they received one dose of (18)F-Fluorodeoxyglucose (FDG). The mice were remained in the cold for one additional hour post FDG injection, and then scanned with a small animal-dedicated micro-PET/CT system. The acquired PET images were co-registered with the CT images for anatomical references and analyzed for FDG uptake in the interscapular BAT area to present BAT activity. This standardized cold-treatment and imaging protocol has been validated through testing BAT activities during pharmacological interventions, for example, the suppressed BAT activation by the treatment of β-adrenoceptor antagonist propranolol (14, 15), or the enhanced BAT activation by β3 agonist BRL37344 (16). The method described here can be applied to screen for drugs/compounds that modulate BAT activity, or to identify genes/pathways that are involved in BAT development and regulation in various preclinical and basic studies. PMCID: PMC3537196 PMID: 23207798 [PubMed - indexed for MEDLINE] 60. Mol Genet Metab. 2012 Dec;107(4):735-47. doi: 10.1016/j.ymgme.2012.10.015. Epub 2012 Oct 22. Peroxisome deficient aP2-Pex5 knockout mice display impaired white adipocyte and muscle function concomitant with reduced adrenergic tone. Martens K(1), Bottelbergs A, Peeters A, Jacobs F, Espeel M, Carmeliet P, Van Veldhoven PP, Baes M. Author information: (1)Laboratory of Cell Metabolism, Department of Pharmaceutical Sciences, KU Leuven, Leuven, Belgium. Peroxisomes are essential for intermediary lipid metabolism, but the role of these organelles has been primarily studied in the liver. We recently generated aP2-Pex5 conditional knockout mice that due to the nonselectivity of the aP2 promoter, not only had dysfunctional peroxisomes in the adipose tissue but also in the central and peripheral nervous system, besides some other tissues. Peroxisomes were however intact in the liver, heart, pancreas and muscle. Surprisingly, these mice not only showed dysfunctional white adipose tissue with increased fat mass and reduced lipolysis but also the skeletal muscle was affected including impaired shivering thermogenesis, reduced motor performance and increased insulin resistance. Non-shivering thermogenesis by brown adipose tissue was not altered. Strongly reduced levels of plasma adrenaline and to a lesser extent noradrenaline, impaired expression of catecholamine synthesizing enzymes in the adrenal medulla and reversal of all pathologies after administration of the β-agonist isoproterenol indicated that β-adrenergic signaling was reduced. Based on normal white adipose and muscle function in Nestin-Pex5 and Wnt-Pex5 knockout mice respectively, it is unlikely that peroxisome absence from the central and peripheral nervous system caused the phenotype. We conclude that peroxisomal metabolism is necessary to maintain the adrenergic tone in mice, which in turn determines metabolic homeostasis. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 23141464 [PubMed - indexed for MEDLINE] 61. Prog Lipid Res. 2013 Jan;52(1):51-61. doi: 10.1016/j.plipres.2012.08.001. Epub 2012 Aug 30. Manipulating molecular switches in brown adipocytes and their precursors: a therapeutic potential. Birerdinc A(1), Jarrar M, Stotish T, Randhawa M, Baranova A. Author information: (1)Center for the Study of Chronic Metabolic Diseases, School of Systems Biology, College of Science, George Mason University, Fairfax, VA, USA. Brown adipocytes constitute a metabolically active tissue responsible for non-shivering thermogenesis and the depletion of excess calories. Differentiation of brown fat adipocytes de novo or stimulation of pre-existing brown adipocytes within white adipose depots could provide a novel method for reducing the obesity and alleviating the consequences of type II diabetes worldwide. In this review, we addressed several molecular mechanisms involved in the control of brown fat activity, namely, the β₃-adrenergic stimulation of thermogenesis during exposure to cold or by catecholamines; the augmentation of thyroid function; the modulation of peroxisome proliferator-activated receptor gamma (PPARγ), transcription factors of the C/EBP family, and the PPARγ co-activator PRDM16; the COX-2-driven expression of UCP1; the stimulation of the vanilloid subfamily receptor TRPV1 by capsaicin and monoacylglycerols; the effects of BMP7 or its analogs; the cannabinoid receptor antagonists and melanogenesis modulating agents. Manipulating one or more of these pathways may provide a solution to the problem of harnessing brown fat's thermogenic potential. However, a better understanding of their interplay and other homeostatic mechanisms is required for the development of novel therapies for millions of obese and/or diabetic individuals. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22960032 [PubMed - indexed for MEDLINE] 62. Hum Mol Genet. 2012 Nov 15;21(22):4836-44. doi: 10.1093/hmg/dds315. Epub 2012 Aug 6. Opa3, a novel regulator of mitochondrial function, controls thermogenesis and abdominal fat mass in a mouse model for Costeff syndrome. Wells T(1), Davies JR, Guschina IA, Ball DJ, Davies JS, Davies VJ, Evans BA, Votruba M. Author information: (1)School of Biosciences, Cardiff University, Museum Avenue, Cardiff, UK. wellst@cardiff.ac.uk The interrelationship between brown adipose tissue (BAT) and white adipose tissue (WAT) is emerging as an important factor in obesity, but the effect of impairing non-shivering thermogenesis in BAT on lipid storage in WAT remains unclear. To address this, we have characterized the metabolic phenotype of a mouse model for Costeff syndrome, in which a point mutation in the mitochondrial membrane protein Opa3 impairs mitochondrial activity. Opa3(L122P) mice displayed an 80% reduction in insulin-like growth factor 1, postnatal growth retardation and hepatic steatosis. A 90% reduction in uncoupling protein 1 (UCP1) expression in interscapular BAT was accompanied by a marked reduction in surface body temperature, with a 2.5-fold elevation in interscapular BAT mass and lipid storage. The sequestration of circulating lipid into BAT resulted in profound reductions in epididymal and retroperitoneal WAT mass, without affecting subcutaneous WAT. The histological appearance and intense mitochondrial staining in intra-abdominal WAT suggest significant 'browning', but with UCP1 expression in WAT of Opa3(L122P) mice only 62% of that in wild-type littermates, any precursor differentiation does not appear to result in thermogenically active beige adipocytes. Thus, we have identified Opa3 as a novel regulator of lipid metabolism, coupling lipid uptake with lipid processing in liver and with thermogenesis in BAT. These findings indicate that skeletal and metabolic impairment in Costeff syndrome may be more significant than previously thought and that uncoupling lipid uptake from lipid metabolism in BAT may represent a novel approach to controlling WAT mass in obesity. PMID: 22869679 [PubMed - indexed for MEDLINE] 63. Eur Biophys J. 2012 Aug;41(8):675-9. doi: 10.1007/s00249-012-0844-2. Epub 2012 Jul 31. Assaying the proton transport and regulation of UCP1 using solid supported membranes. Blesneac I(1), Ravaud S, Machillot P, Zoonens M, Masscheylen S, Miroux B, Vivaudou M, Pebay-Peyroula E. Author information: (1)Institut de Biologie Structurale, Université Grenoble 1, 38027 Grenoble Cedex 1, France. The uncoupling protein 1 (UCP1) is a mitochondrial protein that carries protons across the inner mitochondrial membrane. It has an important role in non-shivering thermogenesis, and recent evidence suggests its role in human adult metabolism. Using rapid solution exchange on solid supported membranes, we succeeded in measuring electrical currents generated by the transport activity of UCP1. The protein was purified from mouse brown adipose tissue, reconstituted in liposomes and absorbed on solid supported membranes. A fast pH jump activated the ion transport, and electrical signals could be recorded. The currents were characterized by a fast rise and a slow decay, were stable over time, inhibited by purine nucleotides and activated by fatty acids. This new assay permits direct observation of UCP1 activity in controlled cell-free conditions, and opens up new possibilities for UCP1 functional characterization and drug screening because of its robustness and its potential for automation. PMID: 22847775 [PubMed - indexed for MEDLINE] 64. Trends Endocrinol Metab. 2012 Sep;23(9):435-43. doi: 10.1016/j.tem.2012.06.004. Epub 2012 Jul 10. Mitochondrial dysfunction in white adipose tissue. Kusminski CM(1), Scherer PE. Author information: (1)Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA. Although mitochondria in brown adipose tissue and their role in non-shivering thermogenesis have been widely studied, we have only a limited understanding of the relevance of mitochondria in white adipose tissue (WAT) for cellular homeostasis of the adipocyte and their impact upon systemic energy homeostasis. A better understanding of the regulatory role that white adipocyte mitochondria play in the regulation of whole-body physiology becomes increasingly important. WAT mitochondrial biogenesis can effectively be induced pharmacologically using a number of agents, including PPARγ agonists. Through their ability to influence key biochemical processes central to the adipocyte, such as fatty acid (FA) esterification and lipogenesis, as well as their impact upon the production and release of key adipokines, mitochondria play a crucial role in determining systemic insulin sensitivity. Copyright © 2012 Elsevier Ltd. All rights reserved. PMCID: PMC3430798 PMID: 22784416 [PubMed - indexed for MEDLINE] 65. Proc Nutr Soc. 2012 Aug;71(3):363-70. doi: 10.1017/S0029665112000584. Epub 2012 Jun 18. Adipose tissue development during early life: novel insights into energy balance from small and large mammals. Symonds ME(1), Pope M, Budge H. Author information: (1)The Early Life Nutrition Research Unit, Academic Child Health, School of Clinical Sciences, University Hospital, Nottingham NG7 2UH, UK. michael.symonds@nottingham.ac.uk Since the rediscovery of brown adipose tissue (BAT) in adult human subjects in 2007, there has been a dramatic resurgence in research interest in its role in heat production and energy balance. This has coincided with a reassessment of the origins of BAT and the suggestion that brown preadipocytes could share a common lineage with skeletal myoblasts. In precocial newborns, such as sheep, the onset of non-shivering thermogenesis through activation of the BAT-specific uncoupling protein 1 (UCP1) is essential for effective adaptation to the cold exposure of the extra-uterine environment. This is mediated by a combination of endocrine adaptations which accompany normal parturition at birth and further endocrine stimulation from the mother's milk. Three distinct adipose depots have been identified in all species studied to date. These contain either primarily white, primarily brown or a mix of brown and white adipocytes. The latter tissue type is present, at least, in the fetus and, thereafter, appears to take on the characteristics of white adipose tissue during postnatal development. It is becoming apparent that a range of organ-specific mechanisms can promote UCP1 expression. They include the liver, heart and skeletal muscle, and involve unique endocrine systems that are stimulated by cold exposure and/or exercise. These multiple pathways that promote BAT function vary with age and between species that may determine the potential to be manipulated in early life. Such interventions could modify, or reverse, the normal ontogenic pathway by which BAT disappears after birth, thereby facilitating BAT thermogenesis through the life cycle. PMID: 22704581 [PubMed - indexed for MEDLINE] 66. Front Endocrinol (Lausanne). 2012 Feb 6;3:14. doi: 10.3389/fendo.2012.00014. eCollection 2012. Recruitment of brown adipose tissue as a therapy for obesity-associated diseases. Boss O(1), Farmer SR. Author information: (1)Energesis Pharmaceuticals, Inc. Cambridge, MA, USA. Brown adipose tissue (BAT) has been recognized for more than 20 years to play a key role in cold-induced non-shivering thermogenesis (CIT, NST), and body weight homeostasis in animals. BAT is a flexible tissue that can be recruited by stimuli (including small molecules in animals), and atrophies in the absence of a stimulus. In fact, the contribution of BAT (and UCP1) to resting metabolic rate and healthy body weight homeostasis in animals (rodents) is now well established. Many investigations have shown that resistance to obesity and associated disorders in various rodent models is due to increased BAT mass and the number of brown adipocytes or UCP1 expression in various depots. The recent discovery of active BAT in adult humans has rekindled the notion that BAT is a therapeutic target for combating obesity-related metabolic disorders. In this review, we highlight investigations performed in rodents that support the contention that activation of BAT formation and/or function in obese individuals is therapeutically powerful. We also propose that enhancement of brown adipocyte functions in white adipose tissue (WAT) will also regulate energy balance as well as reduce insulin resistance in obesity-associated inflammation in WAT. PMCID: PMC3356088 PMID: 22654854 [PubMed] 67. J Comp Physiol B. 2012 Oct;182(7):971-83. Epub 2012 May 22. Maximal thermogenic capacity and non-shivering thermogenesis in the South American subterranean rodent Ctenomys talarum. Luna F(1), Roca P, Oliver J, Antenucci CD. Author information: (1)Laboratorio de Ecología Fisiológica y del Comportamiento, Instituto de Investigaciones Marinas y Costeras (IIMyC), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Mar del Plata, Mar del Plata, Argentina. fluna@mdp.edu.ar Subterranean rodents inhabit closed tunnel systems that are hypoxic and hypercapnic and buffer aboveground ambient temperature. In contrast to other strictly subterranean rodents, Ctenomys talarum exhibits activity on the surface during foraging and dispersion and hence, is exposed also to the aboveground environment. In this context, this species is a valuable model to explore how the interplay between underground and aboveground use affects the relationship among basal metabolic rate (BMR), cold-induced maximum metabolic rate (MMR), shivering (ST), and non-shivering thermogenesis (NST). In this work, we provide the first evidence of the presence of NST, including the expression of uncoupling proteins in brown adipose tissue (BAT), and shivering thermogenesis in Ctenomys talarum, a species belonging to the most numerous subterranean genus, endemic to South America. Our results show no differences in BMR, cold-induced MMR, and NST between cold- (15 °C) and warm- (25 °C) acclimated individuals. Furthermore, thermal acclimation had no effect on the expression of mitochondrial uncoupling protein 1 (UCP1) in BAT. Only cytochrome c oxidase (COX) content and activity increased during cold acclimation. When interscapular BAT was removed, NST decreased more than 30%, whereas cold-induced MMR remained unchanged. All together, these data suggest that cold-induced MMR reaches a maximum in warm-acclimated individuals and so a probable ceiling in NST and UCP1 expression in BAT. Possible thermogenic mechanisms explaining the increase in the oxidative capacity, mediated by COX in BAT of cold-acclimated individuals and the role of ST in subterranean life habits are proposed. PMID: 22614630 [PubMed - indexed for MEDLINE] 68. FEBS Lett. 2012 Apr 5;586(7):1073-8. doi: 10.1016/j.febslet.2012.03.009. Epub 2012 Mar 13. Uncoupling proteins (UCP) in unicellular eukaryotes: true UCPs or UCP1-like acting proteins? Luévano-Martínez LA(1). Author information: (1)Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Cidade Universitária, Av Prof Lineu Prestes 748, 05508-000 São Paulo, Brazil. aluevano@iq.usp.br Uncoupling proteins belong to the superfamily of mitochondrial anion carriers. They are apparently present throughout the Eukarya domain in which only some members have an established physiological function, i.e. UCP1 from brown adipose tissue is involved in non-shivering thermogenesis. However, the proteins responsible for the phenotype observed in unicellular organisms have not been characterized. In this report we analyzed functional evidence concerning unicellular UCPs and found that true UCPs are restricted to some taxonomical groups while proteins conferring a UCP1-like phenotype to fungi and most protists are the result of a promiscuous activity exerted by other mitochondrial anion carriers. We describe a possible evolutionary route followed by these proteins by which they acquire this promiscuous mechanism. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. PMID: 22569266 [PubMed - indexed for MEDLINE] 69. PLoS One. 2012;7(3):e33553. doi: 10.1371/journal.pone.0033553. Epub 2012 Mar 16. Private heat for public warmth: how huddling shapes individual thermogenic responses of rabbit pups. Gilbert C(1), McCafferty DJ, Giroud S, Ancel A, Blanc S. Author information: (1)Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, UMR 7179, CNRS, MNHN, Maisons-Alfort, France. cgilbert@vet-alfort.fr BACKGROUND: Within their litter, young altricial mammals compete for energy (constraining growth and survival) but cooperate for warmth. The aim of this study was to examine the mechanisms by which huddling in altricial infants influences individual heat production and loss, while providing public warmth. Although considered as a textbook example, it is surprising to note that physiological mechanisms underlying huddling are still not fully characterised. METHODOLOGY/PRINCIPAL FINDINGS: The brown adipose tissue (BAT) contribution to energy output was assessed as a function of the ability of rabbit (Oryctolagus cuniculus) pups to huddle (placed in groups of 6 and 2, or isolated) and of their thermoregulatory capacities (non-insulated before 5 days old and insulated at ca. 10 days old). BAT contribution of pups exposed to cold was examined by combining techniques of infrared thermography (surface temperature), indirect calorimetry (total energy expenditure, TEE) and telemetry (body temperature). Through local heating, the huddle provided each pup whatever their age with an ambient "public warmth" in the cold, which particularly benefited non-insulated pups. Huddling allowed pups facing a progressive cold challenge to buffer the decreasing ambient temperature by delaying the activation of their thermogenic response, especially when fur-insulated. In this way, huddling permitted pups to effectively shift from a non-insulated to a pseudo-insulated thermal state while continuously allocating energy to growth. The high correlation between TEE and the difference in surface temperatures between BAT and back areas of the body reveals that energy loss for non-shivering thermogenesis is the major factor constraining the amount of energy allocated to growth in non-insulated altricial pups. CONCLUSIONS/SIGNIFICANCE: By providing public warmth with minimal individual costs at a stage of life when pups are the most vulnerable, huddling buffers cold challenges and ensures a constant allocation of energy to growth by reducing BAT activation. PMCID: PMC3306396 PMID: 22438947 [PubMed - indexed for MEDLINE] 70. J Perinatol. 2012 May;32(5):317-24. doi: 10.1038/jp.2012.11. Epub 2012 Mar 1. Thermal protection of the newborn in resource-limited environments. Lunze K(1), Hamer DH. Author information: (1)Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. karsten.lunze@post.harvard.edu Appropriate thermal protection of the newborn prevents hypothermia and its associated burden of morbidity and mortality. Yet, current global birth practices tend to not adequately address this challenge. Here, we discuss the pathophysiology of hypothermia in the newborn, its prevention and therapeutic options with particular attention to resource-limited environments. Newborns are equipped with sophisticated mechanisms of body temperature regulation. Neonatal thermoregulation is a critical function for newborn survival, regulated in the hypothalamus and mediated by endocrine pathways. Hypothermia activates cellular metabolism through shivering and non-shivering thermogenesis. In newborns, optimal temperature ranges are narrow and thermoregulatory mechanisms easily overwhelmed, particularly in premature and low-birth weight infants. Hyperthermia most commonly is associated with dehydration and potentially sepsis. The lack of thermal protection promptly leads to hypothermia, which is associated with detrimental metabolic and other pathophysiological processes. Simple thermal protection strategies are feasible at community and institutional levels in resource-limited environments. Appropriate interventions include skin-to-skin care, breastfeeding and protective clothing or devices. Due to poor provider training and limited awareness of the problem, appropriate thermal care of the newborn is often neglected in many settings. Education and appropriate devices might foster improved hypothermia management through mothers, birth attendants and health care workers. Integration of relatively simple thermal protection interventions into existing mother and child health programs can effectively prevent newborn hypothermia even in resource-limited environments. PMID: 22382859 [PubMed - indexed for MEDLINE] 71. Comp Biochem Physiol A Mol Integr Physiol. 2012 Apr;161(4):395-400. doi: 10.1016/j.cbpa.2011.12.012. Epub 2011 Dec 29. Chronic cold acclimation increases thermogenic capacity, non-shivering thermogenesis and muscle citrate synthase activity in both wild-type and brown adipose tissue deficient mice. Mineo PM(1), Cassell EA, Roberts ME, Schaeffer PJ. Author information: (1)Department of Zoology, Miami University, Oxford, OH 45056, USA. The purpose of this study was to determine whether chronic cold exposure would increase the aerobic capacity of skeletal muscle in UCP-dta mice, a transgenic line lacking brown adipose tissue (BAT). Wild type and UCP-dta mice were acclimated to either warm (23 °C), or cold (4 °C) conditions. Cold increased muscle oxidative capacity nearly equivalently in wild-type and UCP-dta mice, but did not affect the respiratory function of isolated mitochondria. Summit metabolism ( ̇V O2summit) and norepinephrine-induced thermogenesis ( ̇V O2NST) were significantly lower in UCP-dta mice relative to wild-type mice regardless of temperature treatment, but both were significantly higher in cold relative to warm acclimated mice. BAT mass was significantly higher in the cold relative to warm acclimated wild-type mice, but not in cold acclimated UCP-dta mice. BAT citrate synthase activity was lower in transgenic animals regardless of acclimation temperature and BAT citrate synthase activity per depot was significantly higher only in the cold acclimated wild-type mice. Muscle citrate synthase activity was increased in both genotypes. As defects in muscle oxidative function have been observed with obesity and type 2 diabetes, these results suggest that chronic cold exposure is a useful intervention to drive skeletal muscle oxidative capacity in mouse models of obesity. Copyright © 2011 Elsevier Inc. All rights reserved. PMCID: PMC3724519 PMID: 22233932 [PubMed - indexed for MEDLINE] 72. Eur J Endocrinol. 2012 Mar;166(3):433-40. doi: 10.1530/EJE-11-0888. Epub 2011 Dec 14. Thyroid hyperactivity with high thyroglobulin in serum despite sufficient iodine intake in chronic cold adaptation in an Arctic Inuit hunter population. Andersen S(1), Kleinschmidt K, Hvingel B, Laurberg P. Author information: (1)Arctic Health Research Centre, Aalborg University Hospital, Hobrovej 42D, 9000 Aalborg, Denmark. stiga@dadlnet.dk OBJECTIVE: Adult man hosts brown adipose tissue with the capacity to consume energy and dissipate heat. This is essential for non-shivering thermogenesis and its activation depends on sympathetic activity and thyroid hormones. This led us to evaluate the impact of chronic cold exposure on thyroid activity and thyroid hormones in serum in Arctic residents. DESIGN: Comparative, population-based study (n = 535) performed in Greenland. METHODS: Hunters were compared with other men, and Inuit in remote settlements in East Greenland with no modern housing facilities were compared with the residents of the capital city in West Greenland and residents of a major town in East Greenland in a cross-sectional study. We used interview-based questionnaires, measured TSH, free thyroxine, free triiodothyronine (fT(3)), thyroglobulin (TG) antibody and TG (a measure of thyroid activity) in serum, and iodine and creatinine in spot urine samples. RESULTS: Serum TG was the highest among hunters (P = 0.009) and settlement dwellers (P = 0.001), who were most markedly exposed to cold, even though they had the highest urinary iodine excretion (hunters, P < 0.001; settlement dwellers, P < 0.001). Hunters and settlement dwellers also had the lowest fT(3) (hunters, P < 0.001; settlement dwellers, P < 0.001) after adjusting for gender, age, smoking habits, alcohol intake and iodine excretion in multivariate linear regression models. TSH was not influenced by measures of cold exposure (hunter, P = 0.36; residence, P = 0.91). CONCLUSIONS: Cold exposure influenced thyroid hormones and TG in serum in Arctic populations consistent with consumption of thyroid hormone and higher thyroid hormone turnover. Findings emphasise that changes in thyroid activity are essential in cold adaptation in Arctic residents. PMID: 22170797 [PubMed - indexed for MEDLINE] 73. Eur J Neurosci. 2011 Nov;34(9):1442-52. doi: 10.1111/j.1460-9568.2011.07863.x. Epub 2011 Oct 6. Social defeat stress induces hyperthermia through activation of thermoregulatory sympathetic premotor neurons in the medullary raphe region. Lkhagvasuren B(1), Nakamura Y, Oka T, Sudo N, Nakamura K. Author information: (1)Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Psychological stress-induced hyperthermia is a fundamental autonomic response in mammals. However, the central circuitry underlying this stress response is poorly understood. Here, we sought to identify sympathetic premotor neurons that mediate a hyperthermic response to social defeat stress, a psychological stress model. Intruder rats that were defeated by a dominant resident conspecific exhibited a rapid increase in abdominal temperature by up to 2.0  °C. In these defeated rats, we found that expression of Fos, a marker of neuronal activation, was increased in the rostral medullary raphe region centered in the rostral raphe pallidus and adjacent raphe magnus nuclei. In this region, Fos expression was observed in a large population of neurons expressing vesicular glutamate transporter 3 (VGLUT3), which are known as sympathetic premotor neurons controlling non-shivering thermogenesis in brown adipose tissue (BAT) and thermoregulatory constriction of skin blood vessels, and also in a small population of tryptophan hydroxylase-positive serotonergic neurons. Intraperitoneal injection of diazepam, an anxiolytic agent, but not indomethacin, an antipyretic, significantly reduced both the stress-induced hyperthermia and Fos expression in these medullary raphe neuronal populations. Systemic blockade of β3 -adrenoreceptors, which are abundantly expressed in BAT, also attenuated the stress-induced hyperthermia. These results suggest that psychological stress signals activate VGLUT3-expressing medullary raphe sympathetic premotor neurons, which then drive hyperthermic effector responses including BAT thermogenesis through β(3) -adrenoreceptors. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd. PMID: 21978215 [PubMed - indexed for MEDLINE] 74. Clin Exp Pharmacol Physiol. 2011 Dec;38(12):879-87. doi: 10.1111/j.1440-1681.2011.05601.x. Human epicardial fat: what is new and what is missing? Sacks HS(1), Fain JN. Author information: (1)Endocrinology and Diabetes Division 111D, VA Greater Los Angeles Healthcare System, Los Angeles, California 90073, USA. hsacks@hotmail.com 1. Putative physiological functions of human epicardial adipose tissue (EAT) include: (i) lipid storage for the energy needs of the myocardium; (ii) thermoregulation, whereby brown fat components of EAT generate heat by non-shivering thermogenesis in response to core cooling; (iii) neuroprotection of the cardiac autonomic ganglia and nerves; and (iv) regulation of vasomotion and luminal size of the coronary arteries. Under pathophysiological circumstances, EAT may play an adverse paracrine role in cardiac arrhythmias and in lipotoxic cardiomyopathy, but of major current interest is its hypothetical role as an immunological organ contributing to inflammation around coronary artery disease (CAD). 2. The amount of EAT measured either by echocardiographic thickness over the free wall of the right ventricle or as volume by computed tomography expands in patients with obesity both without and with CAD. The mechanisms other than obesity governing the increase in EAT volume in CAD are unknown, but EAT around CAD is infiltrated by chronic inflammatory cells and overexpresses genes for adipokines that have pro- or anti-inflammatory actions and regulate oxidative stress plus angiogenesis. 3. Many cross-sectional studies have shown positive associations between increased EAT mass and stable CAD burden. One prospective population-based epidemiological study suggested that EAT volume at baseline is a predictor of acute myocardial infarction, but was without significant incremental predictive value after adjustment for established cardiovascular risk factors. However, strategies are needed to obtain robust epidemiological, interventional and experimental evidence to prove or disprove the hypothesis that EAT is a cardiovascular risk factor locally contributing to CAD. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd. PMID: 21895738 [PubMed - indexed for MEDLINE] 75. Acta Physiol (Oxf). 2011 Dec;203(4):419-27. doi: 10.1111/j.1748-1716.2011.02336.x. Epub 2011 Aug 12. Increased systolic blood pressure after mild cold and rewarming: relation to cold-induced thermogenesis and age. Kingma BR(1), Frijns AJ, Saris WH, van Steenhoven AA, Lichtenbelt WD. Author information: (1)Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism of Maastricht University Medical Center+, the Netherlands. b.kingma@maastrichtuniversity.nl AIM: Higher winter mortality in elderly has been associated with augmented systolic blood pressure (SBP) response and with impaired defense of core temperature. Here we investigated whether the augmented SBP upon mild cold exposure remains after a rewarming period, and whether SBP changes are linked to thermoregulation. Therefore, we tested the following hypotheses: cold-induced increase in SBP (1) remains augmented after rewarming in elderly compared to young adults (2) is related to non-shivering thermogenesis (NST) upon mild cold (3) is related to vasoconstriction upon mild cold. METHODS: Blood pressure, energy expenditure (EE), skin and core temperature, skin perfusion (abdomen, forearm, both sides of hand) and % body fat were measured in 12 young adults (Y) and 12 elderly (E). Supine subjects were exposed to a thermoneutral baseline 0.5 h (T(air) = 30.1°C), 1 h mild cold (T(air) = 20.7°C), 1 h rewarming (T(air) = 34.8°C) and 1 h baseline (T(air) = 30.5°C). RESULTS: Upon mild cold only the young adults showed significant NST (Y: +2.5 ± 0.6 W m(-2), P < 0.05). No significant age effects in vasoconstriction were observed. After rewarming per cent change in SBP (%ΔSBP) remained significantly increased in both age groups and was augmented in elderly (Y: +5.0% ± 1.2% vs. E: +14.7% ± 3.1%, P < 0.05). Regression analysis revealed that %ΔSBP significantly related to ΔEE upon mild cold (P < 0.01, r(2) = 0.35) and in elderly also to %body fat (P < 0.02, r(2) = 0.57). CONCLUSION: Individual changes in SBP after rewarming correlate negatively to NST. Elderly did not show NST, which explains the greater SBP increase in this group. In elderly a relatively large %body fat protected against the adverse effects of mild cold. © 2011 Maastricht University Acta Physiologica © 2011 Scandinavian Physiological Society. PMID: 21707931 [PubMed - indexed for MEDLINE] 76. PLoS One. 2011;6(6):e19833. doi: 10.1371/journal.pone.0019833. Epub 2011 Jun 16. Functional evolution of leptin of Ochotona curzoniae in adaptive thermogenesis driven by cold environmental stress. Yang J(1), Bromage TG, Zhao Q, Xu BH, Gao WL, Tian HF, Tang HJ, Liu DW, Zhao XQ. Author information: (1)Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China. BACKGROUND: Environmental stress can accelerate the directional selection and evolutionary rate of specific stress-response proteins to bring about new or altered functions, enhancing an organism's fitness to challenging environments. Plateau pika (Ochotona curzoniae), an endemic and keystone species on Qinghai-Tibetan Plateau, is a high hypoxia and low temperature tolerant mammal with high resting metabolic rate and non-shivering thermogenesis to cope in this harsh plateau environment. Leptin is a key hormone related to how these animals regulate energy homeostasis. Previous molecular evolutionary analysis helped to generate the hypothesis that adaptive evolution of plateau pika leptin may be driven by cold stress. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis, recombinant pika leptin was first purified. The thermogenic characteristics of C57BL/6J mice injected with pika leptin under warm (23±1°C) and cold (5±1°C) acclimation is investigated. Expression levels of genes regulating adaptive thermogenesis in brown adipose tissue and the hypothalamus are compared between pika leptin and human leptin treatment, suggesting that pika leptin has adaptively and functionally evolved. Our results show that pika leptin regulates energy homeostasis via reduced food intake and increased energy expenditure under both warm and cold conditions. Compared with human leptin, pika leptin demonstrates a superior induced capacity for adaptive thermogenesis, which is reflected in a more enhanced β-oxidation, mitochondrial biogenesis and heat production. Moreover, leptin treatment combined with cold stimulation has a significant synergistic effect on adaptive thermogenesis, more so than is observed with a single cold exposure or single leptin treatment. CONCLUSIONS/SIGNIFICANCE: These findings support the hypothesis that cold stress has driven the functional evolution of plateau pika leptin as an ecological adaptation to the Qinghai-Tibetan Plateau. PMCID: PMC3116822 PMID: 21698227 [PubMed - indexed for MEDLINE] 77. J Physiol. 2011 Jul 15;589(Pt 14):3641-58. doi: 10.1113/jphysiol.2011.210047. Epub 2011 May 24. Central efferent pathways for cold-defensive and febrile shivering. Nakamura K(1), Morrison SF. Author information: (1)Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. kazu@cp.kyoto-u.ac.jp Shivering is a remarkable somatomotor thermogenic response that is controlled by brain mechanisms. We recorded EMGs in anaesthetized rats to elucidate the central neural circuitry for shivering and identified several brain regions whose thermoregulatory neurons comprise the efferent pathway driving shivering responses to skin cooling and pyrogenic stimulation. We simultaneously monitored parameters from sympathetic effectors: brown adipose tissue (BAT) temperature for non-shivering thermogenesis and arterial pressure and heart rate for cardiovascular responses. Acute skin cooling consistently increased EMG, BAT temperature and heart rate and these responses were eliminated by inhibition of neurons in the median preoptic nucleus (MnPO) with nanoinjection of muscimol. Stimulation of the MnPO evoked shivering, BAT thermogenesis and tachycardia, which were all reversed by antagonizing GABA(A) receptors in the medial preoptic area (MPO). Inhibition of neurons in the dorsomedial hypothalamus (DMH) or rostral raphe pallidus nucleus (rRPa) with muscimol or activation of 5-HT1A receptors in the rRPa with 8-OH-DPAT eliminated the shivering, BAT thermogenic, tachycardic and pressor responses evoked by skin cooling or by nanoinjection of prostaglandin (PG) E2, a pyrogenic mediator, into the MPO. These data are summarized with a schematic model in which the shivering as well as the sympathetic responses for cold defence and fever are driven by descending excitatory signalling through the DMH and the rRPa, which is under a tonic inhibitory control from a local circuit in the preoptic area. These results provide the interesting notion that, under the demand for increasing levels of heat production, parallel central efferent pathways control the somatic and sympathetic motor systems to drive thermogenesis. PMCID: PMC3167123 PMID: 21610139 [PubMed - indexed for MEDLINE] 78. Ross Fiziol Zh Im I M Sechenova. 2011 Feb;97(2):218-26. [Effect of TRPM8 ion channel activation on thermoregulatory response to cooling]. [Article in Russian] Kozyreva TV, Kozaruk VP, Tkachenko EIa, Khramova GM. In rats, the effect of activation of the cold- and menthol-sensitive TRPM8 ion channel on different thermoregulatory parameters: total oxygen consumption, carbon dioxide release, respiration coefficient, constriction response of skin blood vessels, muscle activity, was studied. Activation of TRPM8 with menthol even in thermoneutral conditions produces an increase in oxygen consumption and a decrease in respiratory coefficient, which may suggest enhanced non-shivering thermogenesis and lipolysis. Rapid cooling against the background of TRPM8 activation is characterized by a decrease in the temperature thresholds of all thermoregulatory responses without associated changes in sequences of their initiation as well as in enhancement of metabolic component of emergency thermogenesis which leads to improved maintenance of core temperature in conditions when external cold acts on the organism. The obtained data on the effect of TRPM8 activation on metabolic parameters in thermoneutral conditions and under cooling suggest acontinuous involvement of this receptor in regulation of total metabolism and, possibly, in determination of the type of organism's metabolism as well as in determination of organism's response to external cooling. PMID: 21598682 [PubMed - indexed for MEDLINE] 79. Biosci Rep. 2012 Feb;32(1):53-9. doi: 10.1042/BSR20100144. Brown adipose tissue mitochondria: modulation by GDP and fatty acids depends on the respiratory substrates. De Meis L(1), Ketzer LA, Camacho-Pereira J, Galina A. Author information: (1)Instituto de Bioquímica Médica, Laboratório de Bioenergética, Programa de Bioquímica e Biofísica Celular, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Cidade Universitária, RJ, 21941-902, Brazil. demeis@bioqmed.ufrj.br The UCP1 [first UCP (uncoupling protein)] that is found in the mitochondria of brown adipocytes [BAT (brown adipose tissue)] regulates the heat production, a process linked to non-shivering thermogenesis. The activity of UCP1 is modulated by GDP and fatty acids. In this report, we demonstrate that respiration and heat released by BAT mitochondria vary depending on the respiratory substrate utilized and the coupling state of the mitochondria. It has already been established that, in the presence of pyruvate/malate, BAT mitochondria are coupled by faf-BSA (fatty-acid-free BSA) and GDP, leading to an increase in ATP synthesis and mitochondrial membrane potential along with simultaneous decreases in both the rates of respiration and heat production. Oleate restores the uncoupled state, inhibiting ATP synthesis and increasing the rates of both respiration and heat production. We now show that in the presence of succinate: (i) the rates of uncoupled mitochondria respiration and heat production are five times slower than in the presence of pyruvate/malate; (ii) faf-BSA and GDP accelerate heat and respiration as a result and, in coupled mitochondria, these two rates are accelerated compared with pyruvate/malate; (iii) in spite of the differences in respiration and heat production noted with the two substrates, the membrane potential and the ATP synthesized were the same; and (iv) oleate promoted a decrease in heat production and respiration in coupled mitochondria, an effect different from that observed using pyruvate/malate. These effects are not related to the production of ROS (reactive oxygen species). We suggest that succinate could stimulate a new route to heat production in BAT mitochondria. PMCID: PMC3198502 PMID: 21561434 [PubMed - indexed for MEDLINE] 80. J Ayub Med Coll Abbottabad. 2011 Apr-Jun;23(2):55-8. Effect of ascorbic acid on fatigue of skeletal muscle fibres in long-term cold exposed Sprague Dawley rats. Rashid A, Khan UA, Ayub M. BACKGROUND: On exposure to prolonged cold temperature, the body responds for effective heat production both by shivering and non-shivering thermogenesis. Cold exposure increases the production of reactive oxygen species which influence the sarcoplasmic reticulum Ca++ release from the skeletal muscles and affect their contractile properties. The role of ascorbic acid supplementation on force of contraction during fatigue of cold exposed skeletal muscles was evaluated in this study. METHOD: Ninety healthy, male Sprague Dawley rats were randomly divided into three groups of control (I), cold exposed (II), and cold exposed with ascorbic acid 500 mg/L supplementation mixed in drinking water (III). Group II and III were given cold exposure by keeping their cages in ice-filled tubs for 1 hr/day for one month. After one month, the extensor digitorum longus muscle was dissected out and force of contraction during fatigue in the skeletal muscle fibres was analysed on a computerised data acquisition system. RESULTS: The cold exposed group showed a significant delay in the force of contraction during fatigue of skeletal muscle fibres compared to control group. Group III showed easy fatigability and a better force of contraction than the cold exposed group. CONCLUSIONS: Ascorbic acid increases the force of contraction and decreases resistance to fatigue in the muscles exposed to chronic cold. PMID: 24800343 [PubMed - indexed for MEDLINE] 81. Horm Res Paediatr. 2011;75(4):231-9. doi: 10.1159/000324806. Epub 2011 Mar 2. Renaissance of brown adipose tissue. Tews D(1), Wabitsch M. Author information: (1)Division of Pediatric Endocrinology and Diabetes, Endocrine Research Laboratory, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany. The recent discovery of functional brown adipose tissue in human adults raised this tissue again into the focus of current investigations concerning human energy homeostasis. Brown fat is a key thermogenic tissue and is essential for non-shivering thermogenesis in the human newborn and hibernating mammals. This review highlights the biological and molecular aspects of brown adipose tissue development and function from the embryonic state to childhood and adolescence. Copyright © 2011 S. Karger AG, Basel. PMID: 21372557 [PubMed - indexed for MEDLINE] 82. Lab Invest. 2011 May;91(5):704-10. doi: 10.1038/labinvest.2011.6. Epub 2011 Feb 14. Carnitine is necessary to maintain the phenotype and function of brown adipose tissue. Ozaki K(1), Sano T, Tsuji N, Matsuura T, Narama I. Author information: (1)Department of Pathology, Faculty of Pharmaceutical Science, Setsunan University, Hirakata, Osaka, Japan. ozaki@pharm.setsunan.ac.jp The juvenile visceral steatosis (JVS) mouse is a mutant strain with an inherited systemic carnitine deficiency. Mice of this strain show clinical signs attributable to impaired heat production and disturbed energy production. Brown adipose tissue (BAT) is the primary site of non-shivering thermogenesis in the presence of uncoupling protein-1 (UCP-1) in rodents and humans, especially in infants. To investigate the possible cause of impaired heat production in BAT, we studied the morphological features, carnitine concentration, and UCP-1 production of BAT in JVS mice. The effect of carnitine administration on these parameters was also examined. JVS mice aged 5 or 10 days (60 each) and age-matched control mice were used in this study, along with 10-day-old JVS mice treated subcutaneously with L-carnitine once a day between postpartum days 5 and 10. JVS mice showed lower body temperatures and lower concentrations of carnitine in BAT. Morphologically, BAT cells in JVS mice contained large lipid vacuoles and small mitochondria, similar to those present in white adipose tissue cells. In addition, UCP-1 mRNA and protein expression levels were significantly reduced in JVS as compared with control mice. Carnitine treatment resulted in significant increases in body temperature and carnitine concentrations in BAT, together with the recovery of normal morphological features. UCP-1 mRNA and protein expression levels were also significantly increased. These findings strongly suggest that carnitine is essential for maintaining the function and morphology of BAT. PMID: 21321536 [PubMed - indexed for MEDLINE] 83. Front Endocrinol (Lausanne). 2011 Dec 21;2:84. doi: 10.3389/fendo.2011.00084. eCollection 2011. Control of Brown Adipose Tissue Glucose and Lipid Metabolism by PPARγ. Festuccia WT(1), Blanchard PG, Deshaies Y. Author information: (1)Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo São Paulo, Brazil. Brown adipose tissue (BAT) non-shivering thermogenesis impacts energy homeostasis in rodents and humans. Mitochondrial uncoupling protein 1 in brown fat cells produces heat by dissipating the energy generated by fatty acid and glucose oxidation. In addition to thermogenesis and despite its small relative size, sympathetically activated BAT constitutes an important glucose, fatty acid, and triacylglycerol-clearing organ, and such function could potentially be used to alleviate dyslipidemias, hyperglycemia, and insulin resistance. To date, chronic sympathetic innervation and peroxisome proliferator-activated receptor (PPAR) γ activation are the only recognized inducers of BAT recruitment. Here, we review the major differences between these two BAT inducers in the regulation of lipolysis, fatty acid oxidation, lipid uptake and triacylglycerol synthesis, glucose uptake, and de novo lipogenesis. Whereas BAT recruitment through sympathetic drive translates into functional thermogenic activity, PPARγ-mediated recruitment is associated with a reduction in sympathetic activity leading to increased lipid storage in brown adipocytes. The promising therapeutic role of BAT in the treatment of hypertriglyceridemic and hyperglycemic conditions is also discussed. PMCID: PMC3356105 PMID: 22654830 [PubMed] 84. Front Endocrinol (Lausanne). 2011 Oct 17;2:52. doi: 10.3389/fendo.2011.00052. eCollection 2011. Human brown fat and obesity: methodological aspects. van Marken Lichtenbelt W(1). Author information: (1)Department of Human Biology, School for Nutrition and Toxicology and Metabolism, Maastricht University Medical Center Maastricht, Netherlands. Much is known about brown adipose tissue (BAT) in rodents. Its function is to generate heat in response to low environmental temperatures and to diet or overfeeding. The knowledge about BAT in humans is still rather limited despite the recent rediscovery of its functionality in adults. This review highlights the information available on the contribution of BAT in increasing human energy expenditure in relation to obesity. Besides that methodological aspects will be discussed that need special attention in order to unravel the heat producing capacity of human BAT, the recruitment of the tissue, and its functionality. PMCID: PMC3356108 PMID: 22654813 [PubMed] 85. Regul Pept. 2011 Feb 25;167(1):91-6. doi: 10.1016/j.regpep.2010.12.001. Epub 2010 Dec 10. Alterations of glucose-dependent insulinotropic polypeptide (GIP) during cold acclimation. Irwin N(1), Francis JM, Flatt PR. Author information: (1)SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT521SA, UK. n.irwin@ulster.ac.uk Cold acclimation is initially associated with shivering thermogenesis in skeletal muscle followed by adaptive non-shivering thermogenesis, particularly in brown adipose tissue (BAT). In response, hyperphagia occurs to meet increased metabolic demand and thermoregulation. The present study investigates the effects of cold (4 ± 1 °C) acclimation and hyperphagia on circulating and intestinal levels of gastric inhibitory polypeptide (GIP) in rats. Pair fed animals were used as additional controls in some experiments. Cold acclimation for 42 days significantly (p<0.01) increased daily food intake. There was no corresponding change in body weight. However, body weights of pair fed cold exposed rats were significantly (p<0.01) reduced compared to controls and ad libitum fed cold exposed rats. By day 42, non-fasting plasma glucose was increased (p<0.05) by chronic cold exposure regardless of food intake. Corresponding plasma insulin concentrations were significantly (p<0.01) lower in pair fed cold exposed rats. Circulating GIP levels were elevated (p<0.05) in ad libitum fed cold acclimated rats on days 18 and 24, but returned to normal levels by the end of the study. The glycaemic response to oral glucose was improved (p<0.01) in all cold exposed rats, with significantly (p<0.05) elevated GIP responses in ad libitum fed rats and significantly (p<0.05) reduced insulin responses in pair fed rats. In keeping with this, insulin sensitivity was enhanced (p<0.05) in cold exposed rats compared to controls. By the end of the study, cold acclimated rats had significantly (p<0.01) increased BAT mass and intestinal concentrations of GIP and GLP-1 compared to controls, independent of food intake. These data indicate that changes in the secretion and actions of GIP may be involved in the metabolic adaptations to cold acclimation in rats. Copyright © 2010 Elsevier B.V. All rights reserved. PMID: 21146561 [PubMed - indexed for MEDLINE] 86. Bull Exp Biol Med. 2010 Jul;149(1):21-5. Mechanisms of modulation of thermoregulatory reactions during cooling in hypertensive rats by the sympathetic nervous system. [Article in English, Russian] Tkachenko EY(1), Kozyreva TV. Author information: (1)Laboratory of Thermophysiology, Institute of Physiology, Siberian Division of Russian Academy of Medical Sciences, Novosibirsk, Russia. Susceptibility of thermoregulatory responses to cold to blockage of α(1)- and β-adrenoreceptors differs in health and hypertension. α(1)-Adrenoceptor blockade reduces vessel reactivity during cooling and vessel reaction to cold becomes similar to that in intact normotensive rats. Changes in the structure of metabolic response to cold in favor of non-shivering thermogenesis typical of hypertensive animals becomes even more pronounced under conditions of α(1)-adrenoceptor blockade due to inhibition of cold shivering. Blockage of β-adrenoceptors does not affect parameters of vascular response to cooling. In hypertensive rats, in contrast to normotensive animals, β-adrenoceptor blockade during cooling increased temperature thresholds for total metabolic reaction and shivering. The maximum shivering intensity also increased, which partially compensated inhibition of non-shivering thermogenesis. In the whole organism, blockade of one type of adrenoceptors during cooling leads to intensification of compensatory mechanisms realized through adrenoceptors of the other type. In hypertensive rats, compensatory capacities of thermogenic processes controlled by α(1)- and β-adrenoceptors are impaired in comparison with normotensive animals under conditions of inhibition of both shivering and non-shivering thermogenesis. PMID: 21113449 [PubMed - indexed for MEDLINE] 87. Fiziol Cheloveka. 2010 Sep-Oct;36(5):121-39. [Homeostatic non-shivering thermogenesis in man: facts and speculations]. [Article in Russian] Son'kin VD, Kirdin AA, Andreev RS, Akimov EB. In this review it is considered up-to date researches of different forms of non-shivering thermogenesis that related to thermoregulatory and substrate homeostasis. Term "homeostatic non-shivering thermogenesis (HNST)" is proposed for explanation of facultative heat production stimulated by cold exposure, food intake and accumulation of lactate during intensive muscle load. There are common and different features of physiological activity displayed in three HNST types. Existence of these common points gets a probability to propose general physiological mechanisms of HNST realization. Between other candidates for HNST location brown adipose tissue (BAT) has real unquestionable advantage for this specific function. There is close relationship between thermogenic function in cold environment and diet-induced thermogenesis that allows to link two HNST types and BAT activity together. Here we present data indirectly confirming BAT functioning in processes of homeostatic normalization not due to cold acclimation or food intake. Also we give consideration to new data about BAT functional activity, its topographic body location, mechanisms of uncoupled respiration in different tissues in adult humans and methods of BAT diagnostics which include molecular marker using. We adduce a number of facts confirming our suggestion about BAT activity can be related to homeostatic normalization after physical load. At last, we bring forward experimental research program for examination of our hypothesis about BAT universal homeostatic function in humans. PMID: 21061677 [PubMed - indexed for MEDLINE] 88. J Physiol. 2010 Nov 1;588(Pt 21):4117-29. doi: 10.1113/jphysiol.2010.195099. Epub 2010 Aug 31. Orexin neurons are indispensable for stress-induced thermogenesis in mice. Zhang W(1), Sunanaga J, Takahashi Y, Mori T, Sakurai T, Kanmura Y, Kuwaki T. Author information: (1)Department of Molecular and Integrative Physiology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan. Comment in J Physiol. 2010 Nov 1;588(Pt 21):4067-8. Orexin neurons contribute to cardiovascular, respiratory and analgesic components of the fight-or-flight response against stressors. Here, we examined whether the same is true for stress-induced hyperthermia. We used prepro-orexin knockout mice (ORX-KO) and orexin neuron-ablated mice (ORX-AB) in which the latter lack not only orexin, but also other putative neurotransmitter/modulators contained in the orexin neurons. In response to repetitive insertion of a temperature probe into their rectum (handling stress), ORX-KO mice showed a normal temperature change as compared to that of wild-type littermates (WT) while ORX-AB showed an attenuated response. Stress-induced expression of uncoupling protein-1, a key molecule in non-shivering thermogenesis in the brown adipose tissue (BAT), was also blunted in ORX-AB but not in ORX-KO. When the BAT was directly activated by a β3 adrenergic agonist, there was no difference in the resultant BAT temperature among the groups, indicating that BAT per se was normal in ORX-AB. In WT and ORX-KO, handling stress activated orexin neurons (as revealed by increased expression of c-Fos) and the resultant hyperthermia was largely blunted by pre-treatment with a β3 antagonist. This observation further supports the notion that attenuated stress-induced hyperthermia in ORX-AB mice was caused by a loss of orexin neurons and abnormal BAT regulation. This study pointed out, for the first time, the possible importance of co-existent neurotransmitter/modulators in the orexin neurons for stress-induced hyperthermia and the importance of integrity of the orexin neurons for full expression of multiple facets of the fight-or-flight response. PMCID: PMC3002445 PMID: 20807795 [PubMed - indexed for MEDLINE] 89. Biochem Biophys Res Commun. 2010 Sep 24;400(3):318-22. doi: 10.1016/j.bbrc.2010.08.053. Epub 2010 Aug 19. Brown adipose tissue function in short-chain acyl-CoA dehydrogenase deficient mice. Skilling H(1), Coen PM, Fairfull L, Ferrell RE, Goodpaster BH, Vockley J, Goetzman ES. Author information: (1)Department of Pediatrics, The Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA. Brown adipose tissue is a highly specialized organ that uses mitochondrial fatty acid oxidation to fuel non-shivering thermogenesis. In mice, mutations in the acyl-CoA dehydrogenase family of fatty acid oxidation genes are associated with sensitivity to cold. Brown adipose tissue function has not previously been characterized in these knockout strains. Short-chain acyl-CoA dehydrogenase (SCAD) deficient mice were found to have increased brown adipose tissue mass as well as modest cardiac hypertrophy. Uncoupling protein-1 was reduced by 70% in brown adipose tissue and this was not due to a change in mitochondrial number, nor was it due to decreased signal transduction through protein kinase A which is known to be a major regulator of uncoupling protein-1 expression. PKA activity and in vitro lipolysis were normal in brown adipose tissue, although in white adipose tissue a modest increase in basal lipolysis was seen in SCAD-/- mice. Finally, an in vivo norepinephrine challenge of brown adipose tissue thermogenesis revealed normal heat production in SCAD-/- mice. These results suggest that reduced brown adipose tissue function is not the major factor causing cold sensitivity in acyl-CoA dehydrogenase knockout strains. We speculate that other mechanisms such as shivering capacity, cardiac function, and reduced hepatic glycogen stores are involved. Copyright © 2010 Elsevier Inc. All rights reserved. PMCID: PMC2946480 PMID: 20727852 [PubMed - indexed for MEDLINE] 90. J Comp Physiol B. 2011 Jan;181(1):137-45. doi: 10.1007/s00360-010-0503-9. Epub 2010 Aug 1. Torpor patterns, arousal rates, and temporal organization of torpor entry in wildtype and UCP1-ablated mice. Oelkrug R(1), Heldmaier G, Meyer CW. Author information: (1)Department of Animal Physiology, Faculty of Biology, Philipps-Universität, Karl-von-Frisch Strasse 8, 35043 Marburg, Germany. In eutherian mammals, uncoupling protein 1 (UCP1) mediated non-shivering thermogenesis from brown adipose tissue (BAT) provides a mechanism through which arousal from torpor and hibernation is facilitated. In order to directly assess the magnitude by which the presence or absence of UCP1 affects torpor patterns, rewarming and arousal rates within one species we compared fasting induced torpor in wildtype (UCP1(+/+)) and UCP1-ablated mice (UCP(-/-)). Torpor was induced by depriving mice of food for up to 48 h and by a reduction of ambient temperature (T (a)) from 30 to 18°C at four different time points after 18, 24, 30 and 36 h of food deprivation. In most cases, torpor bouts occurred within 20 min after the switch in ambient temperature (30-18°C). Torpor bouts expressed during the light phase lasted 3-6 h while significantly longer bouts (up to 16 h) were observed when mice entered torpor during the dark phase. The degree of hypometabolism (5-22 ml h(-1)) and hypothermia (19.5-26.7°C) was comparable in wildtype and UCP1-ablated mice, and both genotypes were able to regain normothermia. In contrast to wildtype mice, UCP1-ablated mice did not display multiple torpor bouts per day and their peak rewarming rates from torpor were reduced by 50% (UCP1(+/+): 0.24 ± 0.08°C min(-1); UCP1(-/-): 0.12 ± 0.04°C min(-1)). UCP1-ablated mice therefore took significantly longer to rewarm from 25 to 32°C (39 vs. 70 min) and required 60% more energy for this process. Our results demonstrate the energetic benefit of functional BAT for rapid arousal from torpor. They also suggest that torpor entry and maintenance may be dependent on endogenous rhythms. PMID: 20680295 [PubMed - indexed for MEDLINE] 91. Comp Biochem Physiol B Biochem Mol Biol. 2010 Nov;157(3):301-9. doi: 10.1016/j.cbpb.2010.07.004. Epub 2010 Jul 23. Thermogenesis in CD-1 mice after combined chronic hypoxia and cold acclimation. Beaudry JL(1), McClelland GB. Author information: (1)Department of Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada. jbeaudry@yorku.ca Many small mammals thermoregulate through shivering in muscle and/or non-shivering thermogenesis (NST) via brown adipose tissue (BAT) by the actions of mitochondrial uncoupling proteins (UCPs). An up-regulation of these mechanisms would be advantageous in a cold environment but not in conditions of low oxygen as it leads to needless increases in energy expenditure. We examined the chronic effect of 4 weeks of exposure to hypobaric hypoxia (H, 480 mm Hg), cold (C, 5 degrees C) and the combination of the two stressors (HC) compared to normoxic thermoneutral controls (N, 28 degrees C) in male CD-1 mice. We found that hypoxic/cold acclimated mice had significantly lower body temperatures (T(b)) after acclimation along with complete abolishment of diurnal T(b) fluctuations. Capacity for NST was assessed by changes in intrascapular BAT mass, mitochondrial content and UCP1 content per milligram mitochondria. Acclimation caused distinct remodeling of BAT that was reflected in differences in NE-induced increases in oxygen consumption (VO(2)) used to assess NST capacity. Reduction of T(b) in HC acclimated mice was not due to a decreased heat-generating capacity of BAT. VO(2) during an acute temperature challenge (32 to 4 degrees C) in normoxia was similar in all treatment groups compared to controls but thermal conductance was greater in C acclimated mice and T(b) higher in HC acclimated mice. We propose that an overriding inhibition by hypoxia on neural feedback pathways persists even after weeks of acclimation when combined with chronic cold. Copyright 2010 Elsevier Inc. All rights reserved. PMID: 20659581 [PubMed - indexed for MEDLINE] 92. J Exp Biol. 2010 Jul 15;213(Pt 14):2476-82. doi: 10.1242/jeb.043489. Cold-acclimation-induced non-shivering thermogenesis in birds is associated with upregulation of avian UCP but not with innate uncoupling or altered ATP efficiency. Teulier L(1), Rouanet JL, Letexier D, Romestaing C, Belouze M, Rey B, Duchamp C, Roussel D. Author information: (1)Université de Lyon, CNRS, UMR5123, Laboratoire de Physiologie Intégrative, Cellulaire et Moléculaire, F-69622 Villeurbanne, France. Despite their lack of brown adipose tissue, some bird species develop regulatory non-shivering thermogenesis (NST) of skeletal muscle origin in response to cold acclimation. Mechanisms involved in avian NST are still unclear but may involve reduced energetic coupling in skeletal muscle mitochondria through the expression of an avian homologue of mammalian uncoupling proteins. The aim of this work was to investigate whether the expression of avian uncoupling protein (avUCP) would correlate with the capacity for cold-induced muscle NST. Various levels of cold acclimation were obtained by rearing 1-week-old ducklings (Cairina moschata) for 4 weeks at three different ambient temperatures (25 degrees C, 11 degrees C or 4 degrees C). Muscle NST was measured by simultaneous recordings of metabolic rate and electromyographic activity (gastrocnemius muscle) at ambient temperatures (T(a)) ranging from 27 degrees C to -5 degrees C. The expression of avUCP gene and mitochondrial bioenergetics were also determined in gastrocnemius muscle. Results showed that muscle NST capacity depends on the T(a) at which ducklings were acclimated, i.e. the lower the rearing temperature, the higher the capacity for NST. This increased metabolic heat production occurred in parallel with an upregulation of avUCP, which was not associated with a change in mitochondrial membrane conductance. The intensity of mitochondrial oxidative phosphorylation also increased in proportion with the harshness of cold, while the efficiency of ATP generation was equally effective in all three acclimation temperatures. In the absence of mitochondrial uncoupling, these data indicate a clear link between avUCP expression and the capacity of ducklings to adjust their muscular aerobic activity to cold exposure. PMID: 20581277 [PubMed - indexed for MEDLINE] 93. PLoS One. 2010 Jun 4;5(6):e10962. doi: 10.1371/journal.pone.0010962. Deletion of inducible nitric-oxide synthase in leptin-deficient mice improves brown adipose tissue function. Becerril S(1), Rodríguez A, Catalán V, Sáinz N, Ramírez B, Collantes M, Peñuelas I, Gómez-Ambrosi J, Frühbeck G. Author information: (1)Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain. BACKGROUND: Leptin and nitric oxide (NO) on their own participate in the control of non-shivering thermogenesis. However, the functional interplay between both factors in this process has not been explored so far. Therefore, the aim of the present study was to analyze the impact of the absence of the inducible NO synthase (iNOS) gene in the regulation of energy balance in ob/ob mice. METHODS AND FINDINGS: Double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes were generated, and the expression of molecules involved in the control of brown fat cell function was analyzed by real-time PCR, western-blot and immunohistochemistry. Twelve week-old DBKO mice exhibited reduced body weight (p<0.05), decreased amounts of total fat pads (p<0.05), lower food efficiency rates (p<0.05) and higher rectal temperature (p<0.05) than ob/ob mice. Ablation of iNOS also improved the carbohydrate and lipid metabolism of ob/ob mice. DBKO showed a marked reduction in the size of brown adipocytes compared to ob/ob mutants. In this sense, in comparison to ob/ob mice, DBKO rodents showed an increase in the expression of PR domain containing 16 (Prdm16), a transcriptional regulator of brown adipogenesis. Moreover, iNOS deletion enhanced the expression of mitochondria-related proteins, such as peroxisome proliferator-activated receptor gamma coactivator-1 alpha (Pgc-1alpha), sirtuin-1 (Sirt-1) and sirtuin-3 (Sirt-3). Accordingly, mitochondrial uncoupling proteins 1 and 3 (Ucp-1 and Ucp-3) were upregulated in brown adipose tissue (BAT) of DBKO mice as compared to ob/ob rodents. CONCLUSION: Ablation of iNOS improved the energy balance of ob/ob mice by decreasing food efficiency through an increase in thermogenesis. These effects may be mediated, in part, through the recovery of the BAT phenotype and brown fat cell function improvement. PMCID: PMC2881035 PMID: 20532036 [PubMed - indexed for MEDLINE] 94. Brain Res. 2010 Jun 21;1339:49-59. doi: 10.1016/j.brainres.2010.04.021. Epub 2010 Apr 21. Estrogen in the medial preoptic nucleus of the hypothalamus modulates cold responses in female rats. Uchida Y(1), Tokizawa K, Nakamura M, Mori H, Nagashima K. Author information: (1)Faculty of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan. The present study examined the effect of the central administration of estrogen on responses to the cold. Estrogen or cholesterol was applied locally to the medial preoptic nucleus (MPO) or dorsomedial hypothalamic nucleus (DMH) of the hypothalamus in free-moving ovariectomized rats. Forty-eight hours after the application, rats had 2-h exposure at 10 or 25 degrees C. Body temperature (T(b)) and the tail surface temperature (T(tail)) were continuously measured by telemetry and thermography, respectively. The change of T(b) at 10 degrees C from the 25 degrees C baseline was higher in the estrogen application in the MPO than that in the cholesterol application; however, such difference was not observed in the DMH application. The uncoupling 1 protein mRNA level in the interscapular brown adipose tissue involved in non-shivering thermogenesis was not different between the estrogen and cholesterol applications in the MPO and DMH. T(tail) decreased in the cold, which was greater after the estrogen application in the MPO than after the cholesterol application. These results show that estrogen affects the MPO in female rats, changing T(b) in the cold. Moreover, suppression of heat loss from the tail may be involved in the mechanism. Copyright 2010 Elsevier B.V. All rights reserved. PMID: 20416284 [PubMed - indexed for MEDLINE] 95. Exp Gerontol. 2010 Jun;45(6):442-8. doi: 10.1016/j.exger.2010.03.013. Epub 2010 Mar 25. Non-shivering thermogenesis activation and maintenance in the aging gray mouse lemur (Microcebus murinus). Terrien J(1), Ambid L, Nibbelink M, Saint-Charles A, Aujard F. Author information: (1)UMR CNRS/MNHN, Brunoy, France. jeremy.terrien@hotmail.fr The cold-induced enhancement of non-shivering thermogenesis (NST), involving brown-adipose tissue (BAT) metabolism, could participate to impair energy balance in the aged gray mouse lemur (Microcebus murinus). We first investigated the age-related modulations of cold-stimulated BAT cell morphology and contents. Then, NST was pharmacologically stimulated to assess whether aging impaired NST activation in the mouse lemur. In reference conditions, the ability to activate NST was preserved during aging in the mouse lemur as BAT morphology and UCP-1 presence did not differ between adult and aged mouse lemurs. Also, the pharmacological activation of NST revealed similar increased levels of O(2) consumption in adult and aged animals, confirming that no age effect could be evidenced on NST activation at 25 degrees C. However, preliminary histological data revealed a lack of lipid resources in one aged individual during cold exposure. Surprisingly, the pharmacological activation of NST revealed an impaired evacuation of the excess body heat in aged animals, associated with increased energy expenditure. Thus, aging seems to be related to decreased capacities in the maintenance of NST rather than in its activation. Energy mobilization could be impaired in the aging mouse lemur but remains to be demonstrated. 2010 Elsevier Inc. All rights reserved. PMID: 20347030 [PubMed - indexed for MEDLINE] 96. Genes Nutr. 2010 Sep;5(3):225-35. doi: 10.1007/s12263-009-0162-1. Epub 2009 Dec 13. Antioxidative defense and mitochondrial thermogenic response in brown adipose tissue. Petrović V, Buzadžić B, Korać A, Korać B. Cold-exposure activates interscapular brown adipose tissue (IBAT) non-shivering thermogenesis that relies primarily on intensification of metabolic rate and uncoupling. During cold-acclimation, uncoupling in IBAT decreases superoxide (O(2) (·-)) production and as an adaptive response the activities of manganese and copper, zinc superoxide dismutase (Mn- and CuZn-SOD, respectively) are decreased, as well. However, molecular mechanisms governing this SODs adaptive response are still unsolved. Besides, knowing that NO reinforces IBAT uncoupling, we wondered whether nitric oxide (NO) is taking part in SODs regulation? Mn- and CuZn-SOD mRNA and protein expression, uncoupling protein 1 (UCP1), nitrotyrosine and nuclear factor-kappa B (NF-κB) immunolabeling, as well as total SOD (tSOD) activity in IBAT of rats subjected to cold (4 ± 1°C) for 1, 3, 7, 12, 21 and 45 days and treated by l-arginine or N(ω)-nitro-l-arginine-methyl ester (l-NAME) were examined. Cold increased UCP1 immunopositivity and decreased tSOD activity during entire cold-acclimation and transiently, (day 3), activated NF-κB and increased Mn and CuZn-SOD mRNA expression and nitrotyrosine labeling, suggesting NO involvement in this signaling. However, SODs mRNA expression was decreasing from day 12 till the end of cold-acclimation. l-arginine augmented and prolonged cold-induced UCP1 and nitrotyrosine immunopositivity, NF-κB activation and SODs mRNA expression increase, while l-NAME expressed an opposite effect. Related to cold, l-arginine decreased, while l-NAME increased Mn-SOD protein expression. In contrast, neither low temperature nor both treatments applied affected CuZn-SOD protein expression. The results showed that adaptive decrease in SODs activity on uncoupling-decreased O(2) (·-) production was achieved already at the level of gene transcription and that NO takes part in the regulation of IBAT SOD isoforms. PMCID: PMC2935534 PMID: 20012899 [PubMed] 97. Zoolog Sci. 2009 Apr;26(4):277-83. Increased mass of slow-type skeletal muscles and depressed myostatin gene expression in cold-tolerant chicks. Ijiri D(1), Miura M, Kanai Y, Hirabayashi M. Author information: (1)Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan. Temperature is maintained in birds by skeletal muscle shivering as well as by non-shivering thermogenesis in a cold environment because they lack brown adipose tissue, which is a mammalian thermogenic organ. Chicks acquire cold tolerance after their skeletal muscles mature. Here, we found that muscle fibers transformed to the slow-twitch type with increasing gene expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), and that the mass increased with decreasing myostatin gene expression, in the leg muscles of 7-day-old and younger chicks within 24 h of cold exposure. Muscle fibers did not transform and the mass did not increase within 24 h of cold exposure in muscles from chicks older than 8 days of age. Myostatin mRNA expression remained depressed in cold-tolerant muscles for 24 h, whereas cold-enhanced growth of the muscle continued for 48 h. Myostatin expression was depressed and muscle mass was increased only in chick leg muscles that comprised both fast- and slow-twitch fibers. These results suggest that the acute regulation of PGC-1alpha and myostatin gene expression in leg muscles is required for chicks to acquire cold tolerance up to 7 days of age. PMID: 19798921 [PubMed - indexed for MEDLINE] 98. Proc Nutr Soc. 2009 Aug;68(3):321-6. doi: 10.1017/S0029665109001402. Epub 2009 Jun 3. Session on 'Obesity'. Adipose tissue development, nutrition in early life and its impact on later obesity. Budge H(1), Sebert S, Sharkey D, Symonds ME. Author information: (1)Centre for Reproduction and Early Life, Institute of Clinical Research, University Hospital, Nottingham NG7 2UH, UK. helen.budge@nottingham.ac.uk It is now apparent that one key factor determining the current obesity epidemic within the developed world is the extent to which adipose tissue growth and function can be reset in early life. Adipose tissue can be either brown or white, with brown fat being characterised as possessing a unique uncoupling protein (uncoupling protein 1) that enables the rapid generation of heat by non-shivering thermogenesis. In large mammals this function is recruited at approximately the time of birth, after which brown fat is lost, not normally reappearing again throughout the life cycle. The origin and developmental regulation of brown fat in large mammals is therefore very different from that of small mammals in which brown fat is retained throughout the life cycle and may have the same origin as muscle cells. In contrast, white adipose tissue increases in mass after birth, paralleled by a rise in glucocorticoid action and macrophage accumulation. This process can be reset by changes in the maternal nutritional environment, with the magnitude of response being further determined by the timing at which such a challenge is imposed. Importantly, the long-term response within white adipocytes can occur in the absence of any change in total fat mass. The present review therefore emphasises the need to further understand the developmental regulation of the function of fat through the life cycle in order to optimise appropriate and sustainable intervention strategies necessary not only to prevent obesity in the first place but also to reverse excess fat mass in obese individuals. PMID: 19490741 [PubMed - indexed for MEDLINE] 99. Physiol Behav. 2009 Apr 20;97(1):76-86. doi: 10.1016/j.physbeh.2009.02.003. Epub 2009 Feb 10. Mice lacking brain-type creatine kinase activity show defective thermoregulation. Streijger F(1), Pluk H, Oerlemans F, Beckers G, Bianco AC, Ribeiro MO, Wieringa B, Van der Zee CE. Author information: (1)Department of Cell Biology, NCMLS, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. streijger@icord.org The cytosolic brain-type creatine kinase and mitochondrial ubiquitous creatine kinase (CK-B and UbCKmit) are expressed during the prepubescent and adult period of mammalian life. These creatine kinase (CK) isoforms are present in neural cell types throughout the central and peripheral nervous system and in smooth muscle containing tissues, where they have an important role in cellular energy homeostasis. Here, we report on the coupling of CK activity to body temperature rhythm and adaptive thermoregulation in mice. With both brain-type CK isoforms being absent, the body temperature reproducibly drops ~1.0 degrees C below normal during every morning (inactive) period in the daily cycle. Facultative non-shivering thermogenesis is also impaired, since CK--/-- mice develop severe hypothermia during 24 h cold exposure. A relationship with fat metabolism was suggested because comparison of CK--/-- mice with wildtype controls revealed decreased weight gain associated with less white and brown fat accumulation and smaller brown adipocytes. Also, circulating levels of glucose, triglycerides and leptin are reduced. Extensive physiological testing and uncoupling protein1 analysis showed, however, that the thermogenic problems are not due to abnormal responsiveness of brown adipocytes, since noradrenaline infusion produced a normal increase of body temperature. Moreover, we demonstrate that the cyclic drop in morning temperature is also not related to altered rhythmicity with reduced locomotion, diminished food intake or increased torpor sensitivity. Although several integral functions appear altered when CK is absent in the brain, combined findings point into the direction of inefficient neuronal transmission as the dominant factor in the thermoregulatory defect. PMCID: PMC3133955 PMID: 19419668 [PubMed - indexed for MEDLINE] 100. BMC Evol Biol. 2009 Jan 7;9:4. doi: 10.1186/1471-2148-9-4. Molecular evolution of UCP1 and the evolutionary history of mammalian non-shivering thermogenesis. Hughes DA(1), Jastroch M, Stoneking M, Klingenspor M. Author information: (1)Max-Planck-Institute for Evolutionary Anthropology, Department of Evolutionary Genetics, Leipzig, Germany. hughes@eva.mpg.de BACKGROUND: Uncoupling protein 1 (UCP1) is a mitochondrial anion carrier, expressed in brown adipose tissue (BAT) of Eutherians. UCP1 is responsible for uncoupling mitochondrial proton transport from the production of ATP, thereby dissipating heat; it is essential for non-shivering thermogenesis (NST) in mammalian BAT. UCP1 orthologs have been identified in non-Eutherian mammals, fish and amphibians. Yet, UCP1 has a unique function in Eutherians in that it is necessary in the production of heat (NST). As such, this study aims to determine the evolutionary mode of UCP1 in Eutherians, where there is clear evidence of UCP1-dependent NST in BAT. RESULTS: Models of adaptive evolution through phylogenetic analysis of amino acid sequences by maximum likelihood were implemented to determine the mode of UCP1 protein evolution in Eutherians. An increase in the rate of amino acid substitutions on the branch leading to Eutherians is observed, but is best explained by relaxed constraints, not positive selection. Further, evidence for branch and site heterogeneity in selection pressures, as well as divergent selection pressures between UCP1 and its paralogs (UCP2-3) is observed. CONCLUSION: We propose that the unique thermogenic function of UCP1 in Eutherians may be best explained by neutral processes. Along with other evidence, this suggests that the primary biochemical properties of UCP1 may not differ between Eutherians and non-Eutherians. PMCID: PMC2627829 PMID: 19128480 [PubMed - indexed for MEDLINE] 101. Bull Exp Biol Med. 2008 Mar;145(3):291-4. The role of alpha1- and beta-adrenoceptors in initiation and development of thermoregulatory reactions during fast and slow cooling. Tkachenko EY(1), Gonzalez EV, Kozaruk VP, Kozyreva TV. Author information: (1)Department of Thermophysiology, Institute of Physiology, Siberian Division of the Russian Academy of Medical Sciences, Novosibirsk. Ionophoretic application of alpha1- and beta-adrenoceptor blockers into the skin produces no effect on the parameters of thermal homeostasis under thermoneutral conditions. alpha1-Adrenoblocker verapamil inhibits cold shivering during fast and slow cold exposure; it elevates the temperature threshold and moderates the vasoconstrictor response during rapid cooling. These changes are accompanied by a compensatory decrease in the threshold and stimulation of non-shivering thermogenesis. Application of non-selective beta-blocker propranolol had no effect on the temperature thresholds of the thermoregulatory reactions, but augmented the maximum amplitude of shivering during both cooling protocols, thereby compensating the decrease in non-shivering thermogenesis. In the whole organism, block of one type adrenoceptors during cold exposure is accompanied by activation of the compensatory mechanisms mediated by adrenoceptors of the other type. PMID: 19039926 [PubMed - indexed for MEDLINE] 102. Biochem Biophys Res Commun. 2008 Dec 12;377(2):632-5. doi: 10.1016/j.bbrc.2008.10.041. Epub 2008 Oct 18. Induction of fatty acid-binding protein 3 in brown adipose tissue correlates with increased demand for adaptive thermogenesis in rodents. Yamashita H(1), Wang Z, Wang Y, Segawa M, Kusudo T, Kontani Y. Author information: (1)Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, 1200 Matsumoto-cho, Kasugai 487-8501, Japan. We investigated the contribution of fatty acid-binding protein 3 (FABP3) to adaptive thermogenesis in brown adipose tissue (BAT) in rodents. The expression of FABP3 mRNA in BAT was regulated discriminatively in response to alteration of the ambient temperature, which regulation was similar and reciprocal to the regulation of uncoupling protein 1 (UCP1) and leptin, respectively. FABP3 expression in the BAT was significantly higher in the UCP1-knockout (KO) mice than in the wild-type ones, and these KO mice showed a higher clearance rate of free fatty acid from the plasma. In addition, FABP3 expression in the BAT was increased greatly with the development of diet-induced obesity in mice. These results indicate that the induction of FABP3 in BAT correlates with an increased demand for adaptive thermogenesis in rodents. FABP3 appears to be essential for accelerating fatty acid flux and its oxidation through UCP1 activity for non-shivering thermogenesis in BAT. PMID: 18938135 [PubMed - indexed for MEDLINE] 103. J Biol Chem. 2008 Aug 1;283(31):21418-26. doi: 10.1074/jbc.M803654200. Epub 2008 Jun 6. Capsaicin stimulates uncoupled ATP hydrolysis by the sarcoplasmic reticulum calcium pump. Mahmmoud YA(1). Author information: (1)Institute of Physiology and Biophysics, University of Aarhus, Ole Worms Alle 1185, Aarhus C, Denmark. yam@biophys.au.dk In muscle cells the sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA) couples the free energy of ATP hydrolysis to pump Ca(2+) ions from the cytoplasm to the SR lumen. In addition, SERCA plays a key role in non-shivering thermogenesis through uncoupled reactions, where ATP hydrolysis takes place without active Ca(2+) translocation. Capsaicin (CPS) is a naturally occurring vanilloid, the consumption of which is linked with increased metabolic rate and core body temperature. Here we document the stimulation by CPS of the Ca(2+)-dependent ATP hydrolysis by SERCA without effects on Ca(2+) accumulation. The stimulation by CPS was significantly dependent on the presence of a Ca(2+) gradient across the SR membrane. ATP activation assays showed that the drug reduced the nucleotide affinity at the catalytic site, whereas the affinity at the regulatory site increased. Several biochemical analyses indicated that CPS stabilizes an ADP-insensitive E(2)P-related conformation that dephosphorylates at a higher rate than the control enzyme. Under conditions where uncoupled SERCA was specifically inhibited by the treatment with fluoride, low temperatures, or dimethyl sulfoxide, CPS had no stimulatory effect on ATP hydrolysis by SERCA. It is concluded that CPS stabilizes a SERCA sub-conformation where Ca(2+) is released from the phosphorylated intermediate to the cytoplasm instead of the SR lumen, increasing ATP hydrolysis not coupled with Ca(2+) transport. To the best of our knowledge CPS is the first natural drug that augments uncoupled SERCA, presumably resulting in thermogenesis. The role of CPS as a SERCA modulator is discussed. PMID: 18539598 [PubMed - indexed for MEDLINE] 104. J Comp Physiol B. 2008 Sep;178(7):887-97. doi: 10.1007/s00360-008-0277-5. Epub 2008 Jun 4. Hibernation and non-shivering thermogenesis in the Hottentot golden mole (Amblysomus hottentottus longiceps). Scantlebury M(1), Lovegrove BG, Jackson CR, Bennett NC, Lutermann H. Author information: (1)Mammal Research Institute, Department of Zoology and Entomology, University of Pretoria, Pretoria 0002, South Africa. m.scantlebury@qub.ac.uk Although heterothermy (hibernation and torpor) is a common feature among mammals, there is debate over whether it is a derived or ancestral trait relative to endothermic homeothermy. Determination of the physiological characteristics of primitive mammals is central to understanding the evolution of endothermy. Moreover, evaluation of physiological mechanisms responsible for endothermic heat production [e.g. non-shivering thermogenesis (NST)] is key to understanding how early mammals responded to historical climate changes and colonised different geographical regions. Here we investigated the capacity for NST and heterothermy in the Hottentot golden mole, a basal eutherian mammal. NST was measured as the metabolic response to injections of noradrenalin and heterothermy by recording body temperature in free-ranging animals. We found that hibernation and torpor occurred and that the seasonal phenotypic adjustment of NST capacity was similar to that found in other placental mammals. Using phylogenetically independent contrasts, we compared measured values of NST with those obtained from the literature. This showed that all variation in NST was accounted for by differences in phylogeny and not zoogeography. These findings lend support to the observation that NST and heterothermy occur in the Afrotheria, the basal placental mammalian clade. Furthermore, this work suggests that heterothermy, rather than homeothermy is a plesiomorphic trait in mammals and supports the notion that NST mechanisms are phylogenetically ancient. PMID: 18523787 [PubMed - indexed for MEDLINE] 105. BMC Biol. 2008 Apr 21;6:17. doi: 10.1186/1741-7007-6-17. The brown adipocyte differentiation pathway in birds: an evolutionary road not taken. Mezentseva NV(1), Kumaratilake JS, Newman SA. Author information: (1)Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, USA. nadya_mezentseva@nymc.edu BACKGROUND: Thermogenic brown adipose tissue has never been described in birds or other non-mammalian vertebrates. Brown adipocytes in mammals are distinguished from the more common white fat adipocytes by having numerous small lipid droplets rather than a single large one, elevated numbers of mitochondria, and mitochondrial expression of the nuclear gene UCP1, the uncoupler of oxidative phosphorylation responsible for non-shivering thermogenesis. RESULTS: We have identified in vitro inductive conditions in which mesenchymal cells isolated from the embryonic chicken limb bud differentiate into avian brown adipocyte-like cells (ABALCs) with the morphological and many of the biochemical properties of terminally differentiated brown adipocytes. Avian, and as we show here, lizard species lack the gene for UCP1, although it is present in amphibian and fish species. While ABALCs are therefore not functional brown adipocytes, they are generated by a developmental pathway virtually identical to brown fat differentiation in mammals: both the common adipogenic transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma), and a coactivator of that factor specific to brown fat differentiation in mammals, PGC1alpha, are elevated in expression, as are mitochondrial volume and DNA. Furthermore, ABALCs induction resulted in strong transcription from a transfected mouse UCP1 promoter. CONCLUSION: These findings strongly suggest that the brown fat differentiation pathway evolved in a common ancestor of birds and mammals and its thermogenicity was lost in the avian lineage, with the degradation of UCP1, after it separated from the mammalian lineage. Since this event occurred no later than the saurian ancestor of birds and lizards, an implication of this is that dinosaurs had neither UCP1 nor canonically thermogenic brown fat. PMCID: PMC2375860 PMID: 18426587 [PubMed - indexed for MEDLINE] 106. Curr Biol. 2008 Feb 26;18(4):R172-4. doi: 10.1016/j.cub.2007.12.040. Huddling: brown fat, genomic imprinting and the warm inner glow. Haig D(1). Author information: (1)Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138, USA. dhaig@oeb.harvard.edu Heat generated by huddling animals is a public good with a private cost and thus vulnerable to exploitation, as illustrated by recent work on rabbits and penguins. Effects of imprinted genes on brown adipose tissue suggest that non-shivering thermogenesis is an arena for intragenomic conflict. PMID: 18302923 [PubMed - indexed for MEDLINE] 107. Exp Anim. 2007 Jul;56(4):279-88. Changes in Ucp1, D2 (Dio2) and Glut4 (Slc2a4) mRNA expression in response to short-term cold exposure in the house musk shrew (Suncus murinus). Suzuki D(1), Murata Y, Oda S. Author information: (1)Laboratory of Animal Management & Resources, School of Bio-Agricultural Sciences, Nagoya University, Chikusa-ku, Nagoya 464-8601, Japan. The house musk shrew (Suncus murinus), or so-called suncus, is a cold-intolerant mammal, but it is unclear why it is susceptible to low temperatures. Cold-intolerance may be the result of lower thermogenic activity in brown adipose tissue (BAT). The early phase of severe cold exposure is a critical period for suncus. Therefore, we exposed suncus to mildly cold temperatures (10-12 degrees C) for 1 to 48 h to increase non-shivering thermogenesis without causing stress and measured changes in the expression of uncoupling protein 1 (Ucp1), type II iodothyronine 5'-deiodinase (Dio2=D2), and glucose transporter 4 (Slc2a4=Glut4) in BAT. These mRNAs play a major role in non-shivering thermogenesis and are mainly regulated by the sympathetic nervous system via direct beta-noradrenergic innervation of BAT. During cold exposure, Ucp1 expression in BAT increased steadily over time, albeit only slightly. Neither D2 nor Glut4 expression in BAT increased immediately; however, they had increased significantly after 24 h and 48 h of cold exposure. These findings suggest that the responsiveness of mRNA regulation is weak and thus may be involved in cold-intolerance in suncus. PMID: 17660682 [PubMed - indexed for MEDLINE] 108. J Therm Biol. 2006 Dec;31(8):634-638. Does Non-Exercise Activity Thermogenesis Contribute to Non-Shivering Thermogenesis? Harris AM(1), Macbride LR, Foster RC, McCrady SK, Levine JA. Author information: (1)Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota, 55905. We wanted to examine if spontaneous physical activity contributes to non-shivering thermogenesis. Ten lean, healthy male subjects wore a physical activity, micro-measurement system whilst the room temperature was randomly altered at two hourly intervals between thermoneutral (72°F), cool (62°F) and warm (82°F) temperatures. Physical activity measured during the thermoneutral, cooling and warming periods was not significantly different. Cooling, increased EE above basal and thermoneutral values 2061 ± 344 kcal/day (p <0.01). Thus, the increase in energy expenditure associated with short-term environmental cooling in lean, healthy males does not appear to be due to increased spontaneous physical activity or fidgeting. PMCID: PMC1847420 PMID: 17404604 [PubMed] 109. J Physiol. 2007 Apr 15;580(Pt. 2):677-84. Epub 2007 Feb 1. Upregulation of AMPK during cold exposure occurs via distinct mechanisms in brown and white adipose tissue of the mouse. Mulligan JD(1), Gonzalez AA, Stewart AM, Carey HV, Saupe KW. Author information: (1)Department of Medicine, University of Wisconsin, Madison, WI 53706, USA. kws@medicine.wisc.edu. AMPK (adenosine monophosphate-activated protein kinase), a key regulator of cellular energy metabolism and whole-body energy balance, is present in brown adipose tissue but its role in regulating the acute metabolic state and chronic thermogenic potential of this metabolically unique tissue is unknown. To address this, the AMPK signalling system in brown and white adipose tissue was studied in C57Bl/6 mice under control conditions, during acute and chronic cold exposure, and during chronic adrenergic stimulation. In control mice AMPK activity in brown adipose tissue was higher than in any tissue yet reported (3-fold the level in liver) secondary to a high level of expression of the alpha1 isoform. During the first day of cold, a time of intense non-shivering thermogenesis, AMPK activity remained at basal levels. However, chronic (>7 days) cold caused a progressive increase in brown adipose tissue AMPK activity secondary to increased expression of the alpha1 isoform. To investigate the signalling pathway involved, noradrenaline (norepinephrine) and the beta(3)-adrenergic-specific agonist CL 316, 243 were given for 14 days. This increased uncoupling protein-1 content in brown adipose tissue, but not AMPK activity. In white adipose tissue 15 days of cold increased alpha1 AMPK activity 98 +/- 20%, an effect reproduced by chronic noradrenaline or CL 316 243. We conclude that chronic cold not only increases AMPK activity in brown and white adipose tissue, but that it does so via distinct signalling pathways. Our data are consistent with AMPK acting primarily as a regulator of chronic thermogenic potential in brown adipose tissue, and not in the acute activation of non-shivering thermogenesis. PMCID: PMC2075554 PMID: 17272339 [PubMed - indexed for MEDLINE] 110. Exp Anim. 2006 Oct;55(5):467-71. Change in Ucp1 mRNA expression following long-term cold exposure under normal or high-fat diet regimes in the cold-intolerant mammal, Suncus murinus. Suzuki D(1), Murata Y, Oda S. Author information: (1)Laboratory of Animal Management & Resources, School of Bio-Agricultural Sciences, Department of Teratology and Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan. The house musk shrew (Suncus murinus), or suncus, is a unique experimental mammal that is cold intolerant. However, even basic knowledge of brown adipose tissue (BAT), which is important for non-shivering thermogenesis (NST), is minimal. Therefore, we exposed suncus for 18 days to mild cold temperatures (8-14 degrees C) and/or a high-fat diet, which are factors that increase NST, and measured two mRNAs that are critical for NST in BAT, uncoupling protein 1 (Ucp1) and type II 5'-deiodinase (D2). Neither mild cold exposure nor a high-fat diet alone induced up-regulation of the mRNAs. However, combinations of cold exposure and high-fat diet significantly increased both mRNAs. Therefore, cold intolerance in suncus may be partly caused by dietary components. PMID: 17090963 [PubMed - indexed for MEDLINE] 111. J Physiol. 2007 Feb 1;578(Pt 3):751-64. Epub 2006 Oct 12. Reduced nicotinic receptor function in sympathetic ganglia is responsible for the hypothermia in the acetylcholinesterase knockout mouse. Sun M(1), Lee CJ, Shin HS. Author information: (1)Center for Neural Science, Korea Institute of Science and Technology, Seoul, Republic of Korea. Cholinergic signalling in the sympathetic ganglia (SG) contributes to non-shivering thermogenesis by relaying the activation signal from the brain to SG neurons which activate many peripheral tissues to produce heat. Paradoxically, acetylcholinesterase (AChE) inhibitors, which should enhance cholinergic signalling, induce hypothermia. To understand the mechanism of how cholinergic signalling in the SG controls thermoregulation, we analysed infant AChE knockout mice, which are known to show hypothermia by postnatal day 15. Nicotinic receptor currents were reduced in acutely dissociated SG neurons of the AChE-deficient mice by over 40% compared with wild-type mice. When wild-type neurons were treated for 1 h with either oxotremorine-M, a muscarinic agonist, or nicotine, the amplitude of nicotinic receptor currents was also decreased by 40%. The hypothermia in AChE mutant mice was fully rescued by a peripheral injection of both ivermectin, which increases nicotinic receptor currents, and methyl-atropine, a muscarinic antagonist. Our results demonstrate that the hypothermia induced by the lack of AChE activity is primarily caused by a downregulation of nicotinic receptors via prolonged stimulation of muscarinic and nicotinic receptors in SG neurons. The stationary noise analysis of the nicotinic receptor current traces showed that the properties of single-channel activities were not different between the two genotypes, suggesting that the primary reason for downregulation of nicotinic receptors is due to a reduction of the receptors on the surface. PMCID: PMC2151339 PMID: 17038428 [PubMed - indexed for MEDLINE] 112. Physiol Behav. 2006 Dec 30;89(5):750-4. Epub 2006 Oct 3. Mole-rats from higher altitudes have greater thermoregulatory capabilities. Broekman M(1), Bennett NC, Jackson CR, Scantlebury M. Author information: (1)Mammal Research Institute, Department of Zoology and Entomology, University of Pretoria, Pretoria 0002, South Africa. Subterranean mammals (those that live and forage underground) inhabit a challenging microenvironment, with high levels of carbon dioxide and low levels of oxygen. Consequently, they have evolved specialised morphological and physiological adaptations. For small mammals that inhabit high altitudes, the effects of cold are compounded by low oxygen partial pressures. Hence, subterranean mammals living at high altitudes are faced with a uniquely demanding physiological environment, which presumably necessitates additional physiological adjustments. We examined the thermoregulatory capabilities of two populations of Lesotho mole-rat Cryptomys hottentotus mahali that inhabit a 'low' (1600 m) and a 'high' (3200 m) altitude. Mole-rats from the high altitude had a lower temperature of the lower critical point, a broader thermoneutral zone, a lower thermal conductance and greater regulatory non-shivering thermogenesis than animals from the lower altitude. However, minimum resting metabolic rate values were not significantly different between the populations and were low compared with allometric predictions. We suggest that thermoregulatory costs may in part be met by animals maintaining a low resting metabolic rate. High-altitude animals may adjust to their cooler, more oxygen-deficient environment by having an increased non-shivering thermogenesis whilst maintaining low thermal conductance. PMID: 17020776 [PubMed - indexed for MEDLINE] 113. Biochem Biophys Res Commun. 2006 Jul 14;345(4):1405-13. Epub 2006 May 17. Leptin cDNA cloning and its mRNA expression in plateau pikas (Ochotona curzoniae) from different altitudes on Qinghai-Tibet Plateau. Yang J(1), Zhao XQ, Guo SC, Li HG, Qi DL, Wang DP, Cao JH. Author information: (1)Northwest Plateau Institute of Biology, The Chinese Academy of Sciences, Xining, PR China. Leptin, an adipocyte-derived hormone, plays an important role in body energy homeostasis. Plateau pika (Ochotona curzoniae), an endemic and keystone species living only at 3000-5000 m above sea level on Qinghai-Tibet Plateau, is a typically high hypoxia and low temperature tolerant mammal with high resting metabolic rate (RMR), non-shivering thermogenesis (NST), and high ratio of oxygen utilization to cope with harsh plateau environment. To explore the molecular mechanism of ecological acclimation in plateau pika, we first cloned pika leptin cDNA and compared its mRNA expression in different altitudes (3200 and 3900 m) using real-time RT-PCR (Taqman probe) technology. The full-length pika leptin cDNA was 3015 with 504 bp open-reading frame encoding the precursor peptide of 167 amino acids including 21 residues of signal peptide. Pika leptin was 70-72% homologous to that of other species and was of similarly structural characteristics with other species. The pika-specific genetic diversity in leptin sequence occurred at twenty sites. With the increase in altitude, there were larger fat store and high level of ob gene expression in plateau pika. Our results indicated that leptin is sensitive to cold and hypoxia plateau environment and may play one of important roles in pika's ecological adaptation to harsh plateau environment. PMID: 16730654 [PubMed - indexed for MEDLINE] 114. Biochim Biophys Acta. 2006 May-Jun;1757(5-6):446-8. Epub 2006 Apr 19. A new look at UCP 1. Porter RK(1). Author information: (1)School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland. rkporter@tcd.ie There has been a resurgence of interest in mitochondrial uncoupling protein 1 due to a desire to understand the regulation of the prominent role it plays in control of metabolic flux in brown adipose tissue and non-shivering thermogenesis, combined with the fact that UCP 1 acts as a paradigm for other novel less abundant uncoupling proteins. In this manuscript, we review the recent evidence for detection, purification, identification and function of UCP 1 in thymus mitochondria. In addition, we review the two proposed mechanisms for fatty acid dependent UCP 1 activity, namely (a) the flippase (flip-flop) model and (b) the cofactor/activation model, and the implication for these models of recent data showing that glucose-O-omega-palmitate cannot facilitate UCP 1 activity. PMID: 16730638 [PubMed - indexed for MEDLINE] 115. J Exp Zool A Comp Exp Biol. 2006 Aug 1;305(8):620-30. Differential expression of selected mitochondrial genes in hibernating little brown bats, Myotis lucifugus. Eddy SF(1), Morin P Jr, Storey KB. Author information: (1)Institute of Biochemistry and Department of Chemistry Carleton University, Ottawa, Ont., Canada K1S 5B6. eddy@biochem.bumc.bu.edu High rates of non-shivering thermogenesis by brown adipose tissue accompanied by additional shivering thermogenesis in skeletal muscle provide the powerful reheating of body organs that allows hibernating mammals to return from their state of cold torpor back to euthermic function. Previous studies have suggested that changes to brown adipose mitochondria occur during hibernation and are partially responsible for its capacity for non-shivering thermogenesis. The current study shows that selected mitochondrial enzyme activities are elevated and selected genes and proteins are induced during torpor in brown adipose tissue of the little brown bat, Myotis lucifugus. Cytochrome oxidase activity in brown adipose tissue was more than 3-fold higher during torpor than in euthermic animals. Transcript levels of mitochondria-encoded genes, coxII and nad4, were also 3-4-fold higher during torpor, as evidenced by northern blotting. By contrast, transcripts of these genes were unchanged in skeletal muscle during torpor. Protein levels of carnitine palmitoyl transferase-1beta, an enzyme embedded in the outer membrane of the mitochondria that is the rate-limiting step enzyme in beta-oxidation, were also elevated by 2-fold during torpor in brown adipose but were unchanged in skeletal muscle. Cloning and sequencing of a 624 bp segment of cpt-1beta revealed a number of amino acid substitutions in the bat protein as compared to CPT-1beta from other mammals; these may be beneficial for enzyme function at low body temperatures during torpor. This study provides further evidence for a key role of mitochondria in hibernation. Copyright 2006 Wiley-Liss, Inc. PMID: 16721807 [PubMed - indexed for MEDLINE] 116. Peptides. 2006 Sep;27(9):2332-42. Epub 2006 Apr 18. Leptin transgene expression in the hypothalamus enforces euglycemia in diabetic, insulin-deficient nonobese Akita mice and leptin-deficient obese ob/ob mice. Ueno N(1), Inui A, Kalra PS, Kalra SP. Author information: (1)Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University, Kobe, Japan. We have tested the hypothesis that sustained leptin action in the hypothalamus alone can engender and maintain euglycemia in wild type mice and in two monogenic diabetic models, the insulin-deficient nonobese Akita mice and the hyperinsulinemic leptin-deficient obese, ob/ob mice. A single intracerebroventricular injection of recombinant adeno-associated virus vector encoding leptin (rAAV-lep) enhanced leptin transgene expression in the hypothalamus without any evidence of leptin leakage to the peripheral circulation, and promptly reinstated euglycemia that persisted along with severe insulinopenia in all three genotypes through the 7-week period of observation. A comparative evaluation of known etiologic factors of hyperglycemia showed that this long-term benefit on glucose homeostasis was not due to diminished energy consumption, weight and adiposity, but was conferred by at least two mechanisms operating simultaneously, enhanced glucose metabolism to meet the demand for the rAAV-lep induced increased non-shivering thermogenesis mediated by brown adipose tissue and insulin hypersensitivity. These findings endorse the hypothesis that increased leptin action locally in the hypothalamus can impose euglycemia independent of pancreatic insulin, and central leptin reinforcement may serve as a newer adjunct therapy to treat type 1 and type 2 diabetes. PMID: 16621153 [PubMed - indexed for MEDLINE] 117. J Comp Physiol B. 2006 Jan;176(1):75-84. Epub 2005 Nov 30. Noradrenalin induces thermogenesis in a phylogenetically ancient eutherian mammal, the rock elephant shrew, Elephantulus myurus. Mzilikazi N(1), Lovegrove BG. Author information: (1)Department of Zoology, Nelson Mandela Metropolitan University, Port Elizabeth, South Africa. nomakwezi.mzilikazi@nmmu.ac.usa The evolution of endothermy is thought to have been facilitated by the advent of endothermic energy sources such as brown adipose tissue (BAT), the principal site of non-shivering thermogenesis (NST). In marsupials, heat is primarily produced through shivering and NST in skeletal muscle because BAT is either absent or appears to be non-functional. The most basal group of the eutherian lineage are the Afrotheria. Rock elephant shrews, Elephantulus myurus are amongst the smallest members of the Afrotheria and are also known to use exogenous passive heating. The aim of this study was to determine whether the reliance on passive heating compromised the capacity for thermogenesis in E. myurus. We measured the thermogenic response to noradrenalin (NA) injection in E. myurus acclimated to short photoperiod. The thermogenic response at 25 degrees C was 1.58 ml O(2) g(-1) h(-1). We used phylogenetically independent analyses to establish how this thermogenic response compared to other eutherians that display classical NST. The thermogenic response of E. myurus was not significantly different from phylogenetically independent allometric predictions. However, it is unclear whether this thermogenic response is indicative of classical NST and molecular data are required to verify the presence of BAT and UCPs in elephant shrews. PMID: 16317548 [PubMed - indexed for MEDLINE] 118. Nat Rev Neurosci. 2005 Nov;6(11):829-40. Mitochondrial uncoupling proteins in the CNS: in support of function and survival. Andrews ZB(1), Diano S, Horvath TL. Author information: (1)Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, FMB 339, New Haven, Connecticut 06510, USA. Mitochondrial uncoupling mediated by uncoupling protein 1 (UCP1) is classically associated with non-shivering thermogenesis by brown fat. Recent evidence indicates that UCP family proteins are also present in selected neurons. Unlike UCP1, these proteins (UCP2, UCP4 and BMCP1/UCP5) are not constitutive uncouplers and are not crucial for non-shivering thermogenesis. However, they can be activated by free radicals and free fatty acids, and their activity has a profound influence on neuronal function. By regulating mitochondrial biogenesis, calcium flux, free radical production and local temperature, neuronal UCPs can directly influence neurotransmission, synaptic plasticity and neurodegenerative processes. Insights into the regulation and function of these proteins offer unsuspected avenues for a better understanding of synaptic transmission and neurodegeneration. PMID: 16224498 [PubMed - indexed for MEDLINE] 119. Antioxid Redox Signal. 2005 Sep-Oct;7(9-10):1173-81. Mitochondrial uncoupling proteins in the central nervous system. Kim-Han JS(1), Dugan LL. Author information: (1)Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. Mitochondrial uncoupling proteins (UCPs), a subfamily of the mitochondrial transporter family, are related by sequence homology to UCP1. This protein, which is located in the inner mitochondrial membrane, dissipates the proton gradient between the intermembrane space and the mitochondrial matrix to uncouple electron transport from ATP synthesis. UCP1 (thermogenin) was first discovered in brown adipose tissue and is responsible for non-shivering thermogenesis. Expression of mRNA for three other UCP isoforms, UCP2, UCP4, and BMCP1/UCP5, has been found at high levels in brain. However, the physiological function(s) of UCPs in the brain have not been determined, although it has recently been postulated that UCPs regulate free radical flux from mitochondria by physiologically modulating mitochondrial membrane potential. In the CNS, this hypothesis has been studied primarily for UCP2. UCP2 message has been shown to be up-regulated in the CNS by stress signals such as kainate administration or ischemia, and overexpression of UCP2 has been reported to be neuroprotective against oxidative stress in vivo and in vitro, although the exact mechanism has not been fully established. In this review, studies on UCPs in the nervous system will be reviewed, and the potential roles of these intriguing proteins in acute and chronic diseases of the nervous system will be discussed. PMID: 16115020 [PubMed - indexed for MEDLINE] 120. Acta Physiol Scand. 2005 Aug;184(4):255-64. Pituitary and autonomic responses to cold exposures in man. Leppäluoto J(1), Pääkkönen T, Korhonen I, Hassi J. Author information: (1)Department of Physiology and Centre for Arctic Medicine, University of Oulu, Oulun yliopisto, Finland. juhani.leppaluoto@oulu.fi This review presents hormonal responses to various cold exposures and their calorigenic effects in man and some animals. Previous studies in rats have shown that cold exposures activate the hypothalamic-pituitary-thyroid axis. Increased thyroid hormone concentrations lead to heat production via general stimulation of metabolism (obligatory thermogenesis) and possibly via activation of thyroid hormone receptors and uncoupling protein 1 (UCP 1) and deiodinase enzyme genes in the brown adipose tissue (BAT). In human subjects long-term cold exposures do not seem to activate the pituitary-thyroid axis, but rather accelerate the elimination of triiodothyronine (T3), leading to low serum concentrations of free T3 hormone. In corollary to this a hypothyreotic condition with increased serum thyroid-stimulating hormone and impaired mood and cognitive performance can be observed after long-term cold exposures such as wintering. During cold exposures the sympathetic nerve system is activated and noradrenaline is released to blood circulation and to BAT, where it leads to production of cAMP, lipolysis and free fatty acids. Free fatty acids open the mitochondrial proton channel protein in BAT. Protons enter the mitochondria and inhibit ATP synthesis (uncoupling). By this way energy is transformed into heat (facultatory or adaptive thermogenesis). In adult human subjects the amount of BAT is small and adaptive thermogenesis (non-shivering thermogenesis) has a smaller role. UCP 1 with other uncoupling proteins may have other functions in the control of body weight, sugar balance and formation of reactive oxygen species. PMID: 16026418 [PubMed - indexed for MEDLINE] 121. Neuroscience. 2005;133(4):1039-46. Fos activation in hypothalamic neurons during cold or warm exposure: projections to periaqueductal gray matter. Yoshida K(1), Konishi M, Nagashima K, Saper CB, Kanosue K. Author information: (1)Department of Physiology and Biosignalling, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan. The hypothalamus, especially the preoptic area, plays a crucial role in thermoregulation, and our previous studies showed that the periaqueductal gray matter is important for transmitting efferent signals to thermoregulatory effectors in rats. Neurons responsible for skin vasodilation are located in the lateral portion of the rostral periaqueductal gray matter, and neurons that mediate non-shivering thermogenesis are located in the ventrolateral part of the caudal periaqueductal gray matter. We investigated the distribution of neurons in the rat hypothalamus that are activated by exposure to neutral (26 degrees C), warm (33 degrees C), or cold (10 degrees C) ambient temperature and project to the rostral periaqueductal gray matter or caudal periaqueductal gray matter, by using the immunohistochemical analysis of Fos and a retrograde tracer, cholera toxin-b. When cholera toxin-b was injected into the rostral periaqueductal gray matter, many double-labeled cells were observed in the median preoptic nucleus in warm-exposed rats, but few were seen in cold-exposed rats. On the other hand, when cholera toxin-b was injected into the caudal periaqueductal gray matter, many double-labeled cells were seen in a cell group extending from the dorsomedial nucleus through the dorsal hypothalamic area in cold-exposed rats but few were seen in warm-exposed rats. These results suggest that the rostral periaqueductal gray matter receives input from the median preoptic nucleus neurons activated by warm exposure, and the caudal periaqueductal gray matter receives input from neurons in the dorsomedial nucleus/dorsal hypothalamic area region activated by cold exposure. These efferent pathways provide a substrate for thermoregulatory skin vasomotor response and non-shivering thermogenesis, respectively. PMID: 15927405 [PubMed - indexed for MEDLINE] 122. J Comp Physiol B. 2005 May;175(4):231-47. Epub 2005 Mar 8. Seasonal thermoregulatory responses in mammals. Lovegrove BG(1). Author information: (1)School of Biological and Conservation Sciences, University of KwaZulu-Natal, X01, Scottsville, 3209, South Africa. lovegrove@ukzn.ac.za This study examined the proportional seasonal winter adjustments of total and mass-specific basal power (watts and watts g-1, respectively), thermal conductance (watts g-1 degrees C-1), non-shivering thermogenesis capacity (ratio of NST/basal power), body temperature ( degrees C), and body mass (g) of mammals. The responses are best summarized for three different body size classes; small mammals (<100 g), intermediate-sized mammals (0.1-10 kg), and large mammals (>10 kg). The principal adjustments of the small mammals center on energy conservation, especially the Dehnel Effect, the winter reduction in body size of as much as 50%, accompanied by reductions in mass-specific basal power. On average, these reductions reduce the total basal power approximately in direct proportion to the mass reductions. Reductions in mass-specific basal power are matched by concomitant reductions in conductance to maintain the setpoint body temperature during winter. The overall thermoregulatory adjustments in small mammals serve to (a) lower overall winter power consumption, (b) maintain the setpoint body temperature, and (c) lower the lower critical limit of thermoneutrality and hence thermoregulatory costs. In intermediate-size mammals, the seasonal response is centered more on increasing thermogenic capacity by increasing basal power and NST capacity, accompanied by predictable and large reductions in conductance. The Dehnel effect is negligible. Very large mammals undergo the largest reductions in total and mass-specific basal power and conductance. However, there are too few data to resolve whether the reductions in total basal power can be attributed to the Dehnel effect, because the moderate decreases in body mass may also be caused by nutritional stress. Apart from the seasonal changes in basal power, these observations are consistent with the predictions of Heldmaier's seasonal acclimatization model. PMID: 15900504 [PubMed - indexed for MEDLINE] 123. Mol Genet Metab. 2005 Jan;84(1):39-47. Epub 2004 Nov 11. Differential induction of genes in liver and brown adipose tissue regulated by peroxisome proliferator-activated receptor-alpha during fasting and cold exposure in acyl-CoA dehydrogenase-deficient mice. Goetzman ES(1), Tian L, Wood PA. Author information: (1)Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Mice deficient for either long-chain acyl-CoA dehydrogenase (LCAD-/-) or very-long-chain acyl-CoA dehydrogenase (VLCAD-/-) develop hepatic steatosis upon fasting, due to disrupted mitochondrial fatty acid oxidation. Moreover, neither mouse model can maintain core body temperature when exposed to cold. We investigated the effects of fasting and cold exposure on gene expression in these mice. Non-fasted LCAD-/- mice showed gene expression changes indicative of fatty liver, including elevated mRNA levels for peroxisome proliferator-activated receptor-gamma (PPARgamma) and genes involved in lipogenesis. In LCAD-/- and VLCAD-/- mice challenged with fasting and cold exposure, expression of fatty acid oxidation genes was elevated in liver, consistent with increased PPARalpha activity. This effect was not seen in brown adipose tissue, suggesting that expression of these genes may be regulated differently than in liver. The effect of acute cold exposure on expression of fatty acid oxidation genes was measured in peroxisome proliferator-activated receptor (PPAR)-alpha-deficient mice (PPARalpha-/-) and controls. In PPARalpha-/- mice, basal expression of the acyl-CoA dehydrogenases was reduced in liver but was not altered in brown adipose tissue. While cold altered the expression of PPARgamma, sterol-regulatory element binding protein-1 (SREBP-1), ATP citrate lyase, and the uncoupling proteins in brown adipose tissue from both PPARalpha-/- and control mice, fatty acid oxidation genes were unaffected. Thus, while fatty acid oxidation appears critical for non-shivering thermogenesis, expression of the acyl-CoA dehydrogenases is not influenced by cold exposure. Moreover, mitochondrial fatty acid oxidation genes are not regulated by PPARalpha in brown adipose tissue as they are in liver. PMID: 15639194 [PubMed - indexed for MEDLINE] 124. Jpn J Physiol. 2004 Jun;54(3):295-305. Determination in vivo of newly synthesized gene expression in hamsters during phases of the hibernation cycle. Osborne PG(1), Gao B, Hashimoto M. Author information: (1)Department of Physiology, Asahikawa Medical University School of Medicine, Asahikawa, 078-8510 Japan. This study measured in vivo synthesis of total RNA and protein from cortex, cerebellum and midbrain/brainstem and 6 major organs from Syrian hamsters (Mesocricetus auratus) during (a) 33 h of torpor (body temperature 5-6 degrees C); (b) 90 min of the early arousal; (c) 90 min of the middle arousal; (d) 90 min in cold adapted cenothermic (CEN) hamsters of the same circannual period. Appropriate physiological parameters were used to confirm the phase of the hibernation cycle during infusion and incorporation of [3H]-uridine and [14C]-leucine. In torpor, RNA synthesis was 5-25% of CEN levels depending upon tissue. In brain and heart mRNA was not preferentially synthesized. Protein was synthesized at low, tissue specific levels during torpor. Initiation of arousal and the warming of anterior organs via non-shivering thermogenesis during the early arousal occurred without measurable synthesis of RNA or proteins. Tissue specific levels of RNA and protein synthesis occurred later after shivering thermogenesis had been recruited and was strongly influenced by thermal gradients in the body. In the middle arousal phase, protein synthesis is most active in the brain despite modest synthesis of RNA and mRNA. The majority of molecular processing required for the induction and maintenance of torpor and the arousal from torpor up until the onset of shivering thermogenesis occurs during the cenothermic period before the hamster initiates the hibernation cycle. PMID: 15541207 [PubMed - indexed for MEDLINE] 125. Ann Nucl Med. 2004 Sep;18(6):547-9. Brown adipose tissue: evaluation with 201Tl and 99mTc-sestamibi dual-tracer SPECT. Higuchi T(1), Kinuya S, Taki J, Nakajima K, Ikeda M, Namura M, Tonami N. Author information: (1)Department of Kanazawa, PET Center, Kanazawa Cardiovascular Hospital, Ishikawa, Japan. higuchi@med.kanazawa-u.ac.jp Brown adipose tissue is one kind of adipose tissue and regulates body temperature and balance of energy via non-shivering thermogenesis. The authors present a case that strongly suggested the presence of activated brown adipose tissue in the neck, shoulders and axillary space by increased 18F-FDG uptake. 99mTc-sestamibi and 201Tl dual-tracer SPECT study showed increased 99mTc-sestamibi uptake and non-increased 201Tl uptake in the corresponding 18F-FDG uptake sites. Brown adipose tissue has dense mitochondria in the cells, which play an important role in thermogenesis. 99mTc-sestamibi uptake and retention depend on the mitochondrial activity but 201Tl uptake does not. Therefore, the activity of mitochondria in activated brown adipose tissue may explain the discrepant uptake between 99mTc-sestamibi and 201Tl. PMID: 15515758 [PubMed - indexed for MEDLINE] 126. Tohoku J Exp Med. 2004 Sep;204(1):45-51. Effects of ethanol on the induction of uncoupling protein-1 (UCP1) mRNA in the mouse brown adipose tissue. Yoshimoto K(1), Yasuhara M, Komura S, Misumi Y, Uchiyama Y, Kogure A, Hioki C, Wakabayashi Y, Satomi Y, Nishimura A, Fukuda F, Hori M, Yokoyama C, Yoshida T. Author information: (1)Department of Legal Medicine, Kyoto Prefectural University of Medicine, Japan. kyoshimo@koto.kpu-m.ac.jp Expression of uncoupling protein-1 (UCP1) is increased by cold acclimation and overfeeding, and reduced in fasting and genetic obesity. It is known that the mitochondrial UCP1 in the brown adipose tissue (BAT) is an important key molecule for non-shivering thermogenesis. On the other hand, ethanol (EtOH) alters thermoregulation in humans and laboratory animals. However, the relationship between EtOH intake and UCP1 expression is not yet clear. Accordingly, the present study employed the technique of real-time quantitative polymerase-chain reaction (PCR) to investigate the effects of EtOH (0.5 or 2.0 g/kg) on the expression of UCP1 mRNA in the mouse BAT. Control mice were injected with the same volume of physiological saline intraperitoneally (IP). IP injection of EtOH (0.5 g/kg) caused a decrease and an increase of the expression of BAT UCP1 mRNA at 1 and 4 hours, respectively. Treatment with EtOH (2.0 g/kg) caused an increases of the expression of BAT UCP1 mRNA at both 2 and 4 hours. BAT UCP1 mRNA levels in both groups increased at 4 hours after EtOH administration. The levels of UCP1 mRNA returned to the control levels by 8 hours after EtOH administration. The expression of BAT UCP1 mRNA was upregulated following EtOH administration, although a lower dose of EtOH initially reduced the expression of UCP1 mRNA in BAT. These findings suggest that EtOH-induced UCP1 mRNA expression in BAT reflects an alteration of the set point of thermogenesis. PMID: 15329462 [PubMed - indexed for MEDLINE] 127. Int J Biochem Cell Biol. 2004 Nov;36(11):2098-104. The brown adipocyte: update on its metabolic role. Sell H(1), Deshaies Y, Richard D. Author information: (1)Department of Anatomy and Physiology, School of Medicine, Laval Hospital Research Center and D. B. Brown Obesity Research Chair, Laval University, Pavillon Ferdinand-Vandry, Local 3217, Quebec City, Que., Canada G1K 7P4. Brown adipocytes are multilocular lipid storage cells that play a crucial role in non-shivering thermogenesis. These cells are located in brown adipose tissue (BAT) depots which are found in abundance in small mammals as well as in newborns of larger mammals, including humans. Brown adipocytes comprise a very large number of mitochondria packed with cristae and are densely innervated by the sympathetic nervous system (SNS). Sympathetic nerve endings release noradrenaline (NA) in the proximity of brown fat cells, where noradrenaline activates G-protein-coupled beta-adrenergic receptors (AR) and by doing so initiates a cascade of metabolic events culminating in the activation of uncoupling protein 1 (UCP1). Uncoupling protein 1 is a unique feature of brown adipocytes that allows for the generation of heat upon sympathetic nervous system stimulation. It is found in the inner membrane of the mitochondrion, where uncoupling protein 1 uncouples the oxidation of fuel from adenosine triphosphate (ATP) production. The expression of uncoupling protein 1 is strongly induced by cold exposure, revealing the importance of this uncoupling protein in thermoregulation. The thermoregulatory role of uncoupling protein 1 has been emphasized in uncoupling protein 1-deficient mice, whose resistance to cold is impaired. Uncoupling protein 1 expression is modulated by diet and metabolic hormones such as leptin and glucocorticoids, which suggests that the protein is a player in energy balance regulation. PMID: 15313455 [PubMed - indexed for MEDLINE] 128. J Physiol. 2004 Jul 1;558(Pt 1):123-35. Epub 2004 May 14. Uncoupling protein and ATP/ADP carrier increase mitochondrial proton conductance after cold adaptation of king penguins. Talbot DA(1), Duchamp C, Rey B, Hanuise N, Rouanet JL, Sibille B, Brand MD. Author information: (1)Medical Research Council Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, UK. Juvenile king penguins develop adaptive thermogenesis after repeated immersion in cold water. However, the mechanisms of such metabolic adaptation in birds are unknown, as they lack brown adipose tissue and uncoupling protein-1 (UCP1), which mediate adaptive non-shivering thermogenesis in mammals. We used three different groups of juvenile king penguins to investigate the mitochondrial basis of avian adaptive thermogenesis in vitro. Skeletal muscle mitochondria isolated from penguins that had never been immersed in cold water showed no superoxide-stimulated proton conductance, indicating no functional avian UCP. Skeletal muscle mitochondria from penguins that had been either experimentally immersed or naturally adapted to cold water did possess functional avian UCP, demonstrated by a superoxide-stimulated, GDP-inhibitable proton conductance across their inner membrane. This was associated with a markedly greater abundance of avian UCP mRNA. In the presence (but not the absence) of fatty acids, these mitochondria also showed a greater adenine nucleotide translocase-catalysed proton conductance than those from never-immersed penguins. This was due to an increase in the amount of adenine nucleotide translocase. Therefore, adaptive thermogenesis in juvenile king penguins is linked to two separate mechanisms of uncoupling of oxidative phosphorylation in skeletal muscle mitochondria: increased proton transport activity of avian UCP (dependent on superoxide and inhibited by GDP) and increased proton transport activity of the adenine nucleotide translocase (dependent on fatty acids and inhibited by carboxyatractylate). PMCID: PMC1664926 PMID: 15146050 [PubMed - indexed for MEDLINE] 129. Gen Comp Endocrinol. 2004 Mar;136(1):17-22. Thyroid function and the development of endothermy in a marsupial, the Tasmanian bettong, Bettongia gaimardi (Demarest 1822). Rose RW(1), Kuswanti N. Author information: (1)School of Zoology, University of Tasmania, Private Bag 5, Hobart, Tasmania 7001, Australia. randy.rose@utas.edu.au The Tasmanian bettong (Bettongia gaimardi) is a small rat-kangaroo (marsupial) found only in Tasmania, Australia. The duration of pouch life is 15 weeks. Adults and older young display non-shivering thermogenesis and this paper examines the role of thyroxine in the development of endothermy in pouch young. Free thyroxine (T4) concentrations varied throughout pouch life. The mean (+/-SE) concentration was 6.2+/-1.9 pmol L(-1) in week 7, increased and peaked at 19.2+/-4.3 pmol L(-1) in week 12, and declined to 5.6+/-0.4 pmol L(-1) by week 20. This was similar to adult levels (3.2+/-3.8 pmol L(-1)). These concentrations showed significant differences. From pouch week 12 onwards, T4 injection raised oxygen consumption. Maximum levels of VO2 after T4 injection occurred at weeks 14-15. Although adult levels were lower, the increase in adult oxygen consumption after T4 injection was about 50%. Peak free T4 levels and metabolic responses to nor-adrenalin occur at week 12 and we hypothesize that thyroid hormone may facilitate the development of adrenergic-receptors in this species. The data presented in the paper further attest to the likely important role of the thyroid gland in the development of endothermy in marsupial pouch young. PMID: 14980792 [PubMed - indexed for MEDLINE] 130. J Physiol. 2004 Mar 1;555(Pt 2):503-13. Epub 2003 Oct 24. Thermogenesis elicited by skin cooling in anaesthetized rats: lack of contribution of the cerebral cortex. Osaka T(1). Author information: (1)National Institute of Health and Nutrition, Shinjuku 162-8636, Japan. osaka@nih.go.jp Non-noxious cooling stimuli were delivered to the shaved back of urethane-chloralose-anaesthetized, artificially ventilated rats using a plastic bag containing water at 24-40 degrees C. Cooling of the skin by 2-6 degrees C increased the rate of whole body oxygen consumption (.V(O(2)) and triggered electromyographic (EMG) activity recorded from the neck or femoral muscles. The cooling-induced (.V(O(2)) responses did not depend on core (colonic) temperature and followed skin temperature in a graded manner. Pretreatment with the beta-blocker propranolol (10 mg kg(-1), i.v.) greatly attenuated the (.V(O(2)) response but did not affect the EMG response. On the other hand, pretreatment with the muscle relaxant pancuronium bromide (2 mg kg(-1), i.v.) affected the (.V(O(2)) response very slightly but completely abolished the EMG activity. Accordingly, the cooling stimulus activated mainly non-shivering thermogenesis. Next, the contribution of the cerebral cortex to the cooling-induced thermogenesis was examined. Power spectral analysis of the electroencephalogram (EEG) showed that the cooling stimulus largely inhibited delta (0.5-3 Hz) waves, enhanced theta (3-8 Hz) waves, and slightly increased frequencies higher than 8 Hz. Pinching the hindpaw elicited changes in EEG similar to those elicited by skin cooling but did not increase the (.V(O(2)). Therefore, there was no relationship between changes in the EEG and the magnitude of thermogenesis. Finally, skin cooling increased the (.V(O(2)) of decorticated rats but did not increase that of decerebrated rats. The results suggest that the subcortical forebrain structure, but not cortical activation, is indispensable for non-shivering thermogenesis elicited by cooling stimulation of the skin. PMCID: PMC1664850 PMID: 14578483 [PubMed - indexed for MEDLINE] 131. Acta Physiol Scand. 2003 Aug;178(4):405-12. The role of uncoupling proteins in the regulation of metabolism. Erlanson-Albertsson C(1). Author information: (1)Department of Cell and Molecular Biology, Medical Faculty, University of Lund, Lund, Sweden. Investigations of variations in metabolic efficiency and thermogenesis have a short and turbulent history. In small animals, non-shivering thermogenesis and diet-induced thermogenesis have a great impact on overall body weight, and the question is whether mechanisms to waste energy have evolved also in human energy metabolism. The candidate molecules for this adaptive thermogenesis are the uncoupling proteins. This is a newly discovered family of proteins, consisting of at least five proteins, namely UCP1, UCP2, UCP3, UCP4 and UCP5. Although a role for UCP1 in thermogenesis is unequivocal, the physiological function of the newer uncoupling proteins is as yet unclear. UCP1 is present in brown adipose tissue and has a well-documented role in cold-induced thermogenesis. The targeted disruption of the UCP1-gene rendered animals that were cold sensitive, but not obese. UCP2 mRNA has a ubiquitous distribution in tissue, namely, in skeletal muscle, white and brown adipose tissue, the gastro-intestinal tract, the lung and the spleen. By targeting the UCP2-gene there was no effect on whole body energy metabolism, but instead, a reduced ability to protect against free-radical oxygen species. UCP2 has also been shown to act as a negative regulator for insulin secretion. UCP3 is present in skeletal muscle. Targeted disruption of the UCP3-gene gave no effect on whole body energy metabolism, but showed the mitochondria in muscle to be more coupled. In conclusion, the uncoupling proteins may be important in various specific ways, as protectors of free radical oxygen species and as regulators of ATP-dependent processes. PMID: 12864746 [PubMed - indexed for MEDLINE] 132. J Exp Biol. 2003 Jul;206(Pt 13):2145-57. Body size as a latent variable in a structural equation model: thermal acclimation and energetics of the leaf-eared mouse. Nespolo RF(1), Arim M, Bozinovic F. Author information: (1)Centro de estudios avanzados en Ecología y Biodiversidad, Departamento de Ecología, Facultad Ciencias Biológicas, Pontificia Universidad Católica de Chile, PO Box 6513677, Santiago, Chile. robertonespolo@uach.cl Body size is one of the most important determinants of energy metabolism in mammals. However, the usual physiological variables measured to characterize energy metabolism and heat dissipation in endotherms are strongly affected by thermal acclimation, and are also correlated among themselves. In addition to choosing the appropriate measurement of body size, these problems create additional complications when analyzing the relationships among physiological variables such as basal metabolism, non-shivering thermogenesis, thermoregulatory maximum metabolic rate and minimum thermal conductance, body size dependence, and the effect of thermal acclimation on them. We measured these variables in Phyllotis darwini, a murid rodent from central Chile, under conditions of warm and cold acclimation. In addition to standard statistical analyses to determine the effect of thermal acclimation on each variable and the body-mass-controlled correlation among them, we performed a Structural Equation Modeling analysis to evaluate the effects of three different measurements of body size (body mass, m(b); body length, L(b) and foot length, L(f)) on energy metabolism and thermal conductance. We found that thermal acclimation changed the correlation among physiological variables. Only cold-acclimated animals supported our a priori path models, and m(b) appeared to be the best descriptor of body size (compared with L(b) and L(f)) when dealing with energy metabolism and thermal conductance. However, while m(b) appeared to be the strongest determinant of energy metabolism, there was an important and significant contribution of L(b) (but not L(f)) to thermal conductance. This study demonstrates how additional information can be drawn from physiological ecology and general organismal studies by applying Structural Equation Modeling when multiple variables are measured in the same individuals. PMID: 12771164 [PubMed - indexed for MEDLINE] 133. J Comp Physiol B. 2003 Jul;173(5):379-89. Epub 2003 May 23. Defining torpor in free-ranging bats: experimental evaluation of external temperature-sensitive radiotransmitters and the concept of active temperature. Willis CK(1), Brigham RM. Author information: (1)Department of Biology, University of Regina, Regina, Saskatchewan, S4S 0A2, Canada. willis1c@uregina.ca A variety of definitions involving body temperature (Tb), metabolic rate and behavior have been used to define torpor in mammals and birds. This problem is confounded in some studies of free-ranging animals that employ only skin temperature (Tsk), a measure that approximates but may not precisely reflect Tb. We assess the accuracy of Tsk in the context of a recent definition for torpor called active temperature. We compared the active temperatures of individual big brown bats (Eptesicus fuscus), which aggregate in cavities, with solitary, foliage-roosting hoary bats (Lasiurus cinereus). In captive big brown bats, we compared Tsk and core Tb at a range of ambient temperatures for clustered and solitary roosting animals, compared Tsk and Tb during arousal from torpor, and quantified the effect of flight on warming from torpor. Hoary bats had significantly lower active temperatures than big brown bats despite having the same normothermic Tsk. Tsk was significantly lower than Tb during normothermia but often greater than Tb during torpor. Flight increased the rate of warming from torpor. This effect was more pronounced for Tsk than Tb. This suggests that bats could rely on heat generated by flight muscles to complete the final stages of arousal. Using active temperature to define torpor may underestimate torpor due to ambient cooling of external transmitters or animals leaving roosts while still torpid. Conversely, active temperature may also overestimate shallow torpor use if it is recorded during active arousal when shivering and non-shivering thermogenesis warm external transmitters. Our findings illuminate the need for laboratory studies that quantify the relationship between metabolic rate and Tsk over a range of ambient temperatures. PMID: 12764630 [PubMed - indexed for MEDLINE] 134. Brain Res. 2003 Mar 14;966(1):103-9. Involvement of the raphé pallidus in the suppressive effect of preoptic warming on non-shivering thermogenesis in rats. Taniguchi A(1), Chen XM, Nagashima K, Tanaka M, Kanosue K. Author information: (1)Department of Physiology, School of Allied Health Sciences, Faculty of Medicine, Osaka University, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan. Thermogenesis in the brown adipose tissue (BAT) is activated by the stimulation of the ventromedial hypothalamic nucleus (VMH). Local warming of the preoptic area (PO) suppresses this response. Injection of the GABA(A) receptor antagonist bicuculline into the caudal periaqueductal gray (cPAG), where excitatory neurons for BAT thermogenesis are located, did not influence the suppressive effect of PO warming. On the other hand, after bicuculline injection into the raphé pallidus, where excitatory neurons for BAT thermogenesis are also located, VMH stimulation produced BAT thermogenesis even during PO warming. The present results suggest that the inhibitory signal from the PO reaches the raphé pallidus and not the cPAG for the control of BAT thermogenesis. PMID: 12646313 [PubMed - indexed for MEDLINE] 135. Exp Physiol. 2003 Jan;88(1):141-8. Cold-induced recruitment of brown adipose tissue thermogenesis. Klingenspor M(1). Author information: (1)Animal Physiology, Department of Biology, Philipps-University, Marburg, Germany. klingens@mailer.uni-marburg.de Non-shivering thermogenesis in brown adipose tissue is the main mechanism for thermoregulatory heat production in small mammals and newborns. During cold acclimation the sympathetic innervation triggers the recruitment of brown adipose tissue by hyperplasia, which involves the proliferation and differentiation of precursor cells, and by hypertrophy of mature brown adipocytes. Mitochondrial biogenesis and increased synthesis of the uncoupling protein 1 (UCP-1) are hallmarks of the thermogenic recruitment process. The severalfold increase of mitochondrial protein content during cold acclimation recruits a large capacity for oxidative phosphorylation. However, UCP-1 increases proton leakage across the inner membrane of brown adipocyte mitochondria and thereby dissipates proton motive force as heat instead of ATP synthesis. During recent years considerable progress has been achieved in the analysis of transcriptional mechanisms controlling Ucp1 gene expression. However, so far only little is known about the molecular basis of cold-induced mitochondrial biogenesis in brown adipose tissue. PMID: 12525862 [PubMed - indexed for MEDLINE] 136. Comp Biochem Physiol B Biochem Mol Biol. 2003 Jan;134(1):71-7. Molecular identification of uncoupling proteins (UCP2 and UCP3) and absence of UCP1 in the marsupial Tasmanian bettong, Bettongia gaimardi. Kabat AP(1), Rose RW, Harris J, West AK. Author information: (1)School of Zoology, University of Tasmania, G.P.O. Box 252-05, Sandy Bay, Hobart, Tasmania 7005, Australia. alexander.kabat@utas.edu.au This study has identified the expression of uncoupling proteins in a marsupial using molecular techniques. The Tasmanian bettong, Bettongia gaimardi, increases non-shivering thermogenesis (NST) in response to cold exposure and norepinephrine, although previous studies have been unable to demonstrate the presence of brown adipose tissue or uncoupling protein 1 (UCP1). This study used molecular techniques to confirm the absence of UCP1 as well as ascertain if this species expresses UCP2 and/or UCP3. Tissue samples from four B. gaimardi were taken prior to and post-cold exposure at 4-5 degrees C for 2 weeks. The tissues were then examined for UCP1, UCP2 and UCP3 expression using Western blotting. UCP2 and UCP3 were amplified through RT-PCR and subsequently sequenced to confirm molecular identity. Our work confirms that B. gaimardi does not express UCP1 and that this species expresses both uncoupling proteins 2 and 3. The sequencing of the amplified B. gaimardi UCP2 and UCP3 cDNAs have revealed a 74% homology with rat UCP2 cDNA, and 65% homology with rat UCP3 cDNA. Although this work has not yet characterised the functional properties of these proteins in the marsupial, it does suggest a possible mechanism to explain the existence of NST in B. gaimardi. PMID: 12524035 [PubMed - indexed for MEDLINE] 137. Pol Merkur Lekarski. 2002 Sep;13(75):266-70. [Disorders of thermoregulatory mechanisms of the organism and their metabolic consequences. Part I. Hypothermia]. [Article in Polish] Otto-Buczkowska E(1). Author information: (1)Górnoślaskie Centrum Zdrowia Dziecka i Matki. Poradnia Diabetologiczna w Katowicach. em.buczkowski@pro.onet.pl The maintenance of thermal equilibrium depends on the normal functioning of numerous body systems and their appropriate interaction with the environment. Man has a complicated neural and neuroendocrine control system that is designed to maintain a constant core temperature despite changes in environmental temperature or level of activity. Heat exchange is a bidirectional process involving the transfer of heat between an object and its environment. There are four mechanisms of heat dissipation: evaporation, conduction, convection, and radiation. Heat production is the sum of basal metabolism and shivering and non-shivering thermogenesis. The hypothalamus is the central control centre that ensures thermal homeostasis. Although many schemes exist for the classification of hypothermia, from the clinical point of view it is recommended to consider any temperature below 35 degrees C significant. Accurate temperature measurement and core temperature monitoring are essential for diagnosing hypothermia. PMID: 12474586 [PubMed - indexed for MEDLINE] 138. Neurosci Lett. 2002 Oct 4;331(1):17-20. The caudal periaqueductal gray participates in the activation of brown adipose tissue in rats. Chen XM(1), Nishi M, Taniguchi A, Nagashima K, Shibata M, Kanosue K. Author information: (1)Department of Physiology, School of Allied Health Sciences, Osaka University Faculty of Medicine, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan. To investigate the involvement of the periaqueductal gray (PAG) in the control of non-shivering thermogenesis, we tested the effects of electrical or chemical stimulation of the PAG on thermogenesis of brown adipose tissue (BAT) in urethane anesthetized rats. Electrical stimulation (0.1 mA, 33 Hz, 0.5 ms) or application of D,L-homocysteic acid (0.5 mM, 0.3 micro l) into the lateral region of the caudal PAG (cPAG) elicited BAT thermogenesis, measured as a rise in the local temperature of interscapular BAT. These results suggest that neurons in the cPAG send excitatory efferent signals for BAT thermogenesis. PMID: 12359313 [PubMed - indexed for MEDLINE] 139. Proc Nutr Soc. 2002 Aug;61(3):337-43. Peri-operative amino acid administration and the metabolic response to surgery. Selldén E(1). Author information: (1)Department of Anaesthesia and Intensive Care, Karolinska Hospital, Stockholm, Sweden. eva.sellden@ks.se General anaesthesia causes hypothermia due to decreased metabolic rate and impaired thermoregulation. Many warming devices are in use to prevent heat loss, but little attention has been paid to stimulating the body's own heat generation. All nutrients raise energy expenditure, and the highest thermic effect is ascribed to amino acids and proteins, 30-40 % in the awake state. Amino acids infused during general anaesthesia exert a thermic effect that is enhanced compared with that in the awake state. At awakening from anaesthesia, post-operative hypothermia may be prevented without shivering. The tissues involved and the mechanisms by which nutrients stimulate heat production are still not completely understood. However, these findings support the existence of an inhibitory action normally exerted by central thermosensors, in order to maintain oxidative metabolism within certain limits, to prevent hyperthermia. During anaesthesia central thermosensors are silenced and, hence, amino acid thermogenesis is exaggerated. The amino acid-induced heat generation during anaesthesia predominantly occurs in extra-splanchnic tissues, most probably in skeletal muscle. It may reflect an increased protein turnover, as both protein breakdown and synthesis are energy-consuming processes known to generate heat. Possibly, amino acid infusion provides substrates, otherwise mobilized from the body's own tissues, needed for wound healing and immunological function. However, other cellular mechanisms may also contribute to this non-shivering thermogenesis. PMID: 12296293 [PubMed - indexed for MEDLINE] 140. Cryo Letters. 2000 Mar-Apr;21(2):91-98. Mammalian hibernation: lessons for organ preparation? Green C(1). Author information: (1)Northwick Park Institute for Medical Research, Northwick Park Hospital, Harrow, Middlesex, HA1 3UJ. The adaptations to low environmental temperatures exhibited in mammalian hibernation are many and varied, and involve molecular and cellular mechanisms as well as the systematic physiology of the whole organism. Natural torpidity is characterised by a profound reduction in body temperature and other functions lasting from a few hours to several weeks. Controlled reduction of heart rate, respiration and oxygen consumption is followed by the fall in body temperature. However, thermoregulation persists such that a decrease in ambient temperature below dangerous levels typically triggers arousal, and shivering and non-shivering thermogenesis from brown fat provide the heat to restore body temperature to normal levels. Many of the cellular mechanisms for survival are similar to those brought into play during medium-term storage of organs destined for transplantation. For example maintenance of ionic regulation and membrane fluxes is fundamental to cell survival and function at low body temperatures. Differences between hibernating and non-hibernating species are marked by differences in Na+/K+ transport and Ca++pumps. These in turn are probably associated with alterations in the lipoproteins of the plasma membrane and inner mitochondrial membrane. We have accordingly conducted a series of pilot studies in captured Richardson's ground squirrels kept in laboratory conditions as a model for hypothermic organ preservation. Tissue function was compared during the summer (non-hibernating season) with that in the winter when the animals could be: (i) in deep hibernation in a cold chamber at 4 degree C; (ii) maintained in an ambient temperature of 4 degree C but active and awake; or (iii) active at an ambient temperature of 22 degree C. The studies involved: whole animal monitoring of standard physiological parameters; whole organ (kidney) storage and transplantation for viability assessment; storage and functional assessment on an ex vivo test circuit with capacity for perfusion at normothermic and hypothermic temperatures; measurement of thyroid function; measurements of total nucleotides (ATP, ADP and AMP)and ratios by standard techniques after freeze-clamping of organs; similar nucleotide and pH measurements using31P-NMR as a non-invasive whole animal technique; and measurement of O2 uptake and gluconeogenesis using isolated renal tubules and isolated hepatocytes. Marked differences in cold tolerance were demonstrated between organs taken from hibernating versus non-hibernating individuals. In particular kidneys transplanted from animals in deep hibernation were capable of withstanding up to 72 hours of cold storage as compared with up to 24 hours in non-hibernating squirrels or in comparable sized rats. Adaptations which might provide valuable clues in our attempts to better preserve human organs for transplantation are explored in some depth in this report. PMID: 12148053 [PubMed - as supplied by publisher] 141. J Exp Biol. 2002 Aug;205(Pt 15):2267-73. Adaptive thermogenesis in hummingbirds. Bicudo JE(1), Bianco AC, Vianna CR. Author information: (1)Department of Physiology, Biosciences Institute, University of São Paulo, SP, Brazil. jebicudo@usp.br The occurrence of non-shivering thermogenesis in birds has long been a controversial issue. Although birds are endothermic vertebrates, sharing with mammals (placental mammals and marsupials) a common ancestor, they do not possess brown adipose tissue or a similar type of tissue, unlike their mammalian counterparts. Some bird species are, however, able to withstand very low ambient temperatures (-70 degrees C) or undergo periods of heterothermia, and there is now good experimental evidence showing that non-shivering thermogenesis may indeed occur in birds under such conditions. The skeletal muscles of birds, particularly the flight muscles, occupy a significant fraction (approximately 30 %) of the total body mass, and recent results have shown that they are likely to be the main sites for non-shivering thermogenesis. The precise mechanisms involved in adaptive thermogenesis in birds are still not fully understood. The translocation of Ca(2+) between intracellular compartments and the cystosol mediated by the sarcoplasmic reticulum Ca(2+)-ATPase, uncoupled from ATP synthesis, is one mechanism whereby chemi-osmotic energy can be converted into heat, and it has been proposed as one of the possible mechanisms underlying non-shivering thermogenesis in birds on the basis of data obtained mainly from ducklings acclimatized to cold conditions. The recent characterization of an uncoupling protein homolog in avian skeletal muscle and the expression of its mRNA at different stages of the torpor/rewarming cycle of hummingbirds indicate that it has the potential to function as an uncoupling protein and could play a thermogenic role during rewarming in these birds. PMID: 12110660 [PubMed - indexed for MEDLINE] 142. J Comp Physiol B. 2002 Feb;172(2):137-43. Simple roost nests confer large energetic savings for sparrow-weavers. Ferguson JW(1), Nijland MJ, Bennett NC. Author information: (1)Department Zoology and Entomology, Pretoria University, South Africa. White-browed sparrow-weavers (Plocepasser mahali, body mass 40 g) are group-living passerines adapted to the semi-arid environment of north-eastern and south-western Africa. During winter, the nocturnal ambient temperature of these regions often falls below 0 degrees C. imposing conditions demanding an increase in thermoregulatory heat production. Individuals roost throughout the year in inverted U-shaped roost nests. We investigated the energetic advantages of roosting by measuring nest and ambient temperatures in the field, as well as the resting metabolic rate (RMR) of the birds. The sparrow-weavers exhibited a wide thermoneutral zone (13 degrees C - 32 degrees C). Although RMR at thermoneutrality (40.2 J g.h(-1)) conforms with those of other passerines. the value at 0 degrees C (74.8 J g.h(-1)) is significantly lower than expected. The slope of the line below the lower critical temperature is unexpectedly steep, however, and appears to cause the physiological requirement for nest roosting due to a high cost of thermoregulation at low temperatures, perhaps due to shivering or non-shivering thermogenesis. The nest temperature at 0 degrees C ambient is 5 degrees C. resulting in a saving of some 7% in the energy spent during winter nights when food resources are in short supply compared with the rest of the year. PMID: 11924563 [PubMed - indexed for MEDLINE] 143. Comp Biochem Physiol A Mol Integr Physiol. 2002 Apr;131(4):765-73. Ontogeny of thermoregulatory mechanisms in king penguin chicks (Aptenodytes patagonicus). Duchamp C(1), Rouanet JL, Barré H. Author information: (1)Laboratoire de Physiologie des Régulations Energétiques, Cellulaires et Moléculaires, Centre National de la Recherche Scientifique-Université Claude Bernard Lyon I, Villeurbanne, France. claude.duchamp@univ-lyon1.fr The rapid maturation of thermoregulatory mechanisms may be of critical importance for optimising chick growth and survival and parental energy investment under harsh climatic conditions. The ontogeny of thermoregulatory mechanisms was studied in growing king penguin chicks from hatching to the full emancipation observed at 1 month of age in the sub-Antarctic area (Crozet Archipelago). Newly hatched chicks showed small, but significant regulatory thermogenesis (21% rise in heat production assessed by indirect calorimetry), but rapidly became hypothermic. Within a few days, both resting (+32%) and peak (+52%) metabolic rates increased. The first week of life was characterised by a two-fold rise in thermogenic capacity in the cold, while thermal insulation was not improved. During the second and third weeks of age, thermal insulation markedly rose (two-fold drop in thermal conductance) in relation to down growth, while resting heat production was slightly reduced (-13%). Shivering (assessed by electromyography) was visible right after hatching, although its efficiency was limited. Thermogenic efficiency of shivering increased five-fold with age during the first weeks of life, but there was no sign of non-shivering thermogenesis. We conclude that thermal emancipation of king penguin chicks may be primarily determined by improvement of thermal insulation after thermogenic processes have become sufficiently matured. Both insulative and metabolic adaptations are required for the rapid ontogeny of thermoregulation and thermal emancipation in growing king penguin chicks. PMID: 11897187 [PubMed - indexed for MEDLINE] 144. Comp Biochem Physiol A Mol Integr Physiol. 2002 Apr;131(4):733-9. Facultative and obligatory thermogenesis in young birds: a cautionary note. Hohtola E(1). Author information: (1)University of Oulu, Department of Biology, P.O. Box 3000, FIN-90014, Oulu, Finland. esa.hohtola@oulu.fi A brief overview on thermogenic mechanisms in young precocial birds is given. While shivering thermogenesis is well documented in these birds, evidence for a facultative non-shivering component of heat production, comparable to that found in the brown adipose tissue of mammals, is ambiguous. One reason for this is the confusion between thermoregulatory and obligatory thermogenesis. In particular, the existence of a thermogenic reaction, even a futile one, does not by itself constitute proof of true thermoregulatory non-shivering thermogenesis. More probably, such a reaction is another obligatory component of heat production. Heat increment of feeding and motor activity are classical examples of such mechanisms. Thermogenesis arising from such mechanisms can often be adaptively used by the thermoregulatory systems in young birds, as well as in adults. PMID: 11897184 [PubMed - indexed for MEDLINE] 145. Brain Res. 2002 Feb 22;928(1-2):113-25. Chemical stimulation of the dorsomedial hypothalamus evokes non-shivering thermogenesis in anesthetized rats. Zaretskaia MV(1), Zaretsky DV, Shekhar A, DiMicco JA. Author information: (1)Department of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, MS-A421 Indianapolis, IN 46202, USA. Disinhibition of neurons in the dorsomedial hypothalamus (DMH) by microinjection of the GABA(A) receptor antagonist bicuculline methiodide (BMI) elicits a range of autonomic and endocrine changes resembling those seen in experimental paradigms for emotional stress. Stress in rats is also known to provoke increases in body temperature resulting in part from sympathetically mediated activation of brown fat. The purpose of the present study was to examine the effect of microinjection of BMI into the DMH on core body temperature and temperature of brown fat in rats. In anesthetized preparations, microinjection of BMI 10 pmol/50 nl into the DMH and adjoining posterior hypothalamus elicited marked and rapid increases in temperature in interscapular brown adipose tissue (IBAT) and lesser delayed elevations in rectal temperature. Similar injections into the paraventricular nucleus or ventromedial hypothalamus had no effect on either parameter. Peak increases in IBAT were significantly correlated with both peak increases in core temperature and maximal increases in heart rate that accompanied these changes, and all of these effects were abolished by systemic treatment with propranolol 1 mg/kg. In conscious rats instrumented for telemetry, microinjection of BMI 10 pmol/100 nl into the DMH evoked marked increases in core temperature as well as heart rate, locomotor activity, and plasma ACTH. The increase in core temperature occurred with a delayed time course similar to that seen in anesthetized preparations. These results indicate that activation of neurons in the DMH provokes increases in body temperature resulting in large part from sympathoadrenally-mediated activation of brown fat. PMID: 11844478 [PubMed - indexed for MEDLINE] 146. J Comp Physiol B. 2002 Jan;172(1):1-5. Comparative non-shivering thermogenesis in adjacent populations of the common spiny mouse (Acomys cahirinus) from opposite slopes: the effects of increasing salinity. Scantlebury M(1), Afik D, Shanas U, Haim A. Author information: (1)Department of Biology, University of Haifa at Oranim, Tivon, Israel. We compared non-shivering thermogenesis between two adjacent populations of the common spiny mouse Acomys cahirinus from different habitats, in relation to increasing salinity. Individuals were captured from the north- and south-facing slopes of the same valley, that represent "Mediterranean" and "desert" habitats, respectively. We hypothesized that the two populations of mice would differ in their thermoregulatory capacities, reflecting their need to cope with the environmental stress in each habitat. We measured resting metabolic rate by recording oxygen consumption, body temperature and response to an injection of exogenous noradrenaline. Mice were maintained on diets with increasing levels of salt intake to examine their abilities to cope with increasing osmotic stress. Mice from north-facing slopes generally had a higher resting metabolic rate and a higher increase in oxygen consumption in response to noradrenaline than mice from south-facing slopes. Increasing salinity decreased resting metabolic rate values, body temperature, and oxygen consumption in response to noradrenaline in both populations, and diminished slope-dependant differences. We suggest that these differences could be a result of an ongoing adaptive process to different climatic conditions, typical of the Mediterranean region, that are a demonstrable example of evolution in action. PMID: 11824399 [PubMed - indexed for MEDLINE] 147. Biochem J. 2002 Jan 15;361(Pt 2):277-86. Sarcolipin uncouples hydrolysis of ATP from accumulation of Ca2+ by the Ca2+-ATPase of skeletal-muscle sarcoplasmic reticulum. Smith WS(1), Broadbridge R, East JM, Lee AG. Author information: (1)Division of Biochemistry and Molecular Biology, School of Biological Sciences, University of Southampton, Southampton SO16 7PX, UK. Sarcolipin (SLN) is a small peptide found in the sarcoplasmic reticulum of skeletal muscle. It is predicted to contain a single hydrophobic transmembrane alpha-helix. Fluorescence emission spectra for the single Trp residue of SLN suggest that SLN incorporates fully into bilayers of dioleoylphosphatidylcholine, but only partially into bilayers of phosphatidylcholines with long (C(22) or C(24)) fatty acyl chains. The fluorescence of SLN is quenched in bilayers of dibromostearoylphosphatidylcholine, also consistent with incorporation into the lipid bilayer. SLN was reconstituted with the Ca(2+)-ATPase of skeletal-muscle sarcoplasmic reticulum. Even at a 50:1 molar ratio of SLN/ATPase, SLN had no significant effect on the rate of ATP hydrolysis by the ATPase or on the Ca(2+)-dependence of ATP hydrolysis. However, at a molar ratio of SLN/ATPase of 2:1 or higher the presence of SLN resulted in a marked decrease in the level of accumulation of Ca(2+) by reconstituted vesicles. The effect of SLN was structurally specific and did not result from a breakdown in the vesicular structure or from the formation of non-specific ion channels. Vesicles were impermeable to Ca(2+) in the absence of ATP in the external medium. The effects of SLN on accumulation of Ca(2+) can be simulated assuming that SLN increases the rate of slippage on the ATPase and the rate of passive leak of Ca(2+) mediated by the ATPase. It is suggested that the presence of SLN could be important in non-shivering thermogenesis, a process in which heat is generated by hydrolysis of ATP by skeletal-muscle sarcoplasmic reticulum. PMCID: PMC1222307 PMID: 11772399 [PubMed - indexed for MEDLINE] 148. Biosci Rep. 2001 Apr;21(2):201-12. Mitochondrial uncoupling proteins in mammals and plants. Borecký J(1), Maia IG, Arruda P. Author information: (1)Department of Membrane Transport Biophysics. Institute of Physiology, Academy of Sciences of the Czech Republic, Prague. Uncoupling proteins (UCPs) belong to a distinct cluster of the mitochondrial anion carrier family. Up to five different uncoupling protein types were found in mitochondria of mammals and plants, and recently in fishes, fungi and protozoa. They exhibit a significantly conserved structure with several motifs specific to either the whole cluster or protein type. Uncoupling proteins, as well as the whole mitochondrial anion carrier gene family, probably emerged in evolution before the separation of animal, fungi, and plant kingdoms and originate from an anion/nucleotide or anion/anion transporter ancestor. Mammalian UCP1, UCP2, UCP3, and plant uncoupling proteins pUCP1 and pUCP2 are similar and seem to form one subgroup, whereas UCP4 and BMCP1 belong to a different group. Molecular, biochemical, and phylogenic data suggest that UCP2 could be considered as an UCP-prototype. UCP1 plays its biological role mainly in the non-shivering thermogenesis while the role of the other types is unknown. However, hypotheses have suggested that they are involved in the general balance of basic energy expenditure, protection from reactive oxygen species, and, in plants, in fruit ripening and seed ontogeny. PMID: 11725869 [PubMed - indexed for MEDLINE] 149. Biosci Rep. 2001 Apr;21(2):181-8. Thermogenesis in birds. Bicudo JE(1), Vianna CR, Chaui-Berlinck JG. Author information: (1)Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, SP, Brazil. jebicudo@usp.br The article discusses the importance of avian skeletal muscle as a source for heat generation by means of both shivering and non-shivering. Non-shivering thermogenesis in birds is still a polemic issue. Recent evidence at the molecular/cellular level indicates, however, that this type of heat generation may also exist among birds. The involvement of the sarcoplasmic reticulum calcium ATPase in non-shivering thermogenesis is discussed in-depth. PMID: 11725866 [PubMed - indexed for MEDLINE] 150. Biosci Rep. 2001 Apr;21(2):139-54. Mechanism of thyroid-hormone regulated expression of the SERCA genes in skeletal muscle: implications for thermogenesis. Simonides WS(1), Thelen MH, van der Linden CG, Muller A, van Hardeveld C. Author information: (1)Institute for Cardiovascular Research, Vrije Universiteit, Amsterdam, The Netherlands. simonides@physiol.med.vu.nl Thyroid hormone increases the Ca2+-ATPase activity of the sarcoplasmic reticulum (SR) in skeletal muscle, thereby increasing the energy-turnover associated with Ca2+-cycling during contraction and rest. The fast-muscle isoform of the Ca2+-ATPase (SERCA1) and the slow-muscle isoform (SERCA2a), are encoded by two genes that are transcriptionally regulated by T3. The SERCA1 isoform can be expressed to considerably higher levels than the SERCA2a isoform. The stimulation of transcription of the SERCA1 gene by T3 is mediated by two thyroid hormone response elements, located in the promoter of this gene. The intracellular [Ca2+] can modulate the effect of T3. The increase in SR Ca2+-ATPase activity seen when T3-levels rise above normal, results from the induction of SERCA1 expression in slow muscle fibers. Concomitant high levels of Ca2+-ATPase activity are associated with down-regulation of SERCA2a expression in these fibers. The observed T3-dependent increase in SERCAI expression and associated Ca2+ATPase activity will increase the overall metabolic rate of the organism significantly under normal conditions, because of the high average level of contractile activity of slow fibers. Given the rise in serum T3-levels during prolonged cold exposure, these data suggest that fiber-specific stimulation of SERCA1 expression contributes to the thermogenic response in non-shivering thermogenesis. This mechanism may be particularly relevant in larger mammals, which have a relatively high percentage of slow fibers in skeletal muscle, and which need to rely on tissues other than brown fat for the generation of extra heat. PMID: 11725863 [PubMed - indexed for MEDLINE] 151. Medicina (B Aires). 2001;61(5 Pt 1):597-602. [Thyroid hormones, obesity and brown adipose tissue thermogenesis]. [Article in Spanish] Zaninovich AA(1). Author information: (1)Centro de Investigaciones de la Glándula Tiroides (CONICET), Centro de Medicina Nuclear, Hospital de Clínicas José de San Martín, Facultad de Medicina, Universidad de Buenos Aires, Argentina. azaninovich@sinectis.com.ar Brown adipose tissue (BAT) is the main site for hormone-dependent (non-shivering) thermogenesis in response to cold in lower mammals. The hypothalamus controls the cold-induced BAT activation by stimulating the sympathetic nerves and the secretion of norepinephrine (NE) in BAT. Mediated by beta-3 noradrenergic receptor and in the presence of triiodothyronine (T3), NE promotes the synthesis of the uncoupling protein 1 (UCP1). UCP1 is a 32 kDa protein located in the inner membrane of BAT mitochondria, where it dissipates the proton gradient created by oxidations in the mitochondria. UCP1 functions as a proton translocator, substituting for another translocator, the ATP synthetase. The uncoupling of oxidations and phosphorylations and the inhibition of ATP synthesis lead to dissipation as heat of all energy produced in the respiratory chain. The supply of adequate amounts of T3 is ensured by the cold-induced enhancement of the enzyme 5'-deiodinase type II activity, which deiodinates thyroxine (T4) to T3. The absence of T3 blocks UCP1 synthesis, leading to hypothermia. BAT has a limited significance in humans, except in the newborn, where it serves for a rapid acclimation to ambient temperature. The study of BAT physiology will provide more insight into the mechanisms regulating energy balance and body weight in humans, thus contributing to prevent and treat human obesity. PMID: 11721329 [PubMed - indexed for MEDLINE] 152. Biochem Soc Trans. 2001 Nov;29(Pt 6):756-63. Life without UCP1: mitochondrial, cellular and organismal characteristics of the UCP1-ablated mice. Nedergaard J(1), Golozoubova V, Matthias A, Shabalina I, Ohba K, Ohlson K, Jacobsson A, Cannon B. Author information: (1)The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden. jan@metabol.su.se Mice devoid of the original uncoupling protein UCP1 have provided opportunities to delineate UCP1 function in a series of biochemical and physiological contexts. The isolated brown-fat mitochondria from such mice are fully coupled (without the addition of GDP), but still exhibit a depressed capacity for ATP synthesis. However, they only show a 2-fold decrease in sensitivity to the de-energizing effect of free fatty acids, compared with UCP1-containing mitochondria, whereas they possess a (UCP1-independent) 50-fold higher sensitivity than liver mitochondria; the fatty acid sensitivities in wild-type and UCP1-deficient mitochondria may, however, be of different natures. Despite the fact that brown-fat cells from UCP1-ablated mice cannot produce heat when stimulated by noradrenaline ('norepinephrine') or fatty acids, UCP1-ablated mice can be induced to tolerate extended cold exposure, but the heat then fully results from shivering thermogenesis. Recruitable or adaptive (by cold acclimation or adaptation to a cafeteria diet) adrenergically-stimulated thermogenesis does not exist in the UCP1-ablated animals, demonstrating the unique ability of UCP1 to mediate recruitable non-shivering thermogenesis. In addition to information on the function of UCP1, the UCP1-ablated mice can be used to gain information concerning the function of the UCP1 homologues. Thus whereas an uncoupling function of the UCP1 homologues cannot be excluded, UCP1-ablated animals clearly lack any ability to recruit any UCP1 homologue to functionally replace the loss of thermogenesis resulting from UCP1. UCP1 (thermogenin) thus remains the only protein the activity of which can be recruited for the purpose of facultative thermogenesis. PMID: 11709070 [PubMed - indexed for MEDLINE] 153. Proc Nutr Soc. 2001 May;60(2):187-94. The role of leptin in the transition from fetus to neonate. Mostyn A(1), Keisler DH, Webb R, Stephenson T, Symonds ME. Author information: (1)Academic Division of Child Health, School of Human Development, University Hospital, Nottingham, UK. mgxam2@nottingham.ac.uk Leptin is a 16 kDa hormone which has been shown to have a major physiological role in the control of energy balance. Leptin is produced primarily in white adipose tissue, although there is evidence for its production in brown adipose tissue (BAT) and the placenta. BAT is critically important for the initiation of non-shivering thermogenesis in the newborn through the BAT-specific uncoupling protein (UCP), UCPI. This factor is particularly important in lambs in which levels of UCP1 peak at birth, concomitant with a rapid decline in plasma leptin levels. Our studies have examined the effect of acute and chronic administration of leptin to neonatal lambs, investigating effects on colonic temperature, UCP1 and thermogenic potential of BAT. Administration of leptin in sequential physiological doses of 10, 100 and 100 microg to neonatal lambs caused a modest increase in colonic temperature which was not observed in weight-matched vehicle-treated controls. This increase in colonic temperature was not mediated by an increase in either abundance or thermogenic potential of UCPI, as previously shown in adult rodents. UCP1 mRNA levels were 30 % lower in leptin-treated lambs, which is also contradictory to findings in adult rodents. Leptin treatment resulted in a dose-dependent rise in plasma leptin, with levels at the end of the study being almost twenty times greater in leptin-treated animals. To determine whether these findings in neonatal lambs were transient due to the complex milieu of hormones present after birth, we examined the effect of chronic leptin treatment over 6 d. Pairs of lambs were treated daily, from the second to seventh day of life with 100 microg leptin or vehicle. Colonic temperatures of leptin- and vehicle-treated animals remained similar throughout the study. UCP1 abundance was significantly lower in the leptin-treated animals, suggesting that the drop in UCP1 mRNA seen in the previous study had been translated to protein levels. In conclusion, the decline in plasma leptin levels at birth may be a signal to initiate enteral feeding. In lambs, the rapid loss of UCP1 mRNA, which occurs within the first few days of life, appears to be accelerated by leptin administration, possibly stimulating the development of white adipose tissue and generation of body heat through mechanisms other than non-shivering thermogenesis by UCP1 in BAT. PMID: 11681634 [PubMed - indexed for MEDLINE] 154. J Biol Chem. 2001 Dec 14;276(50):47291-5. Epub 2001 Sep 25. Brown fat UCP1 is specifically expressed in uterine longitudinal smooth muscle cells. Nibbelink M(1), Moulin K, Arnaud E, Duval C, Pénicaud L, Casteilla L. Author information: (1)Unité Mixte de Recherche 5018-CNRS, IFR31 Rangueil University Hospital, F-31403 Toulouse Cedex 4, France. Until now, uncoupling protein 1 (UCP1) was considered as unique to brown adipocytes. It supports a highly regulated uncoupling of oxidative phosphorylation that is associated with diet as well as with non-shivering thermogenesis. Here we report that UCP1 is not specific to brown adipocytes and can be expressed in longitudinal smooth muscle layers. In the uterus, this conclusion was drawn from different convergent data. A specific antibody against mouse UCP1 revealed, in mitochondrial fractions, a protein with the same molecular weight as brown fat UCP1. Sensitive and specific reverse transcriptase-polymerase chain reaction detected a mRNA whose sequence was totally homologous to that of brown fat UCP1 mRNA. Antibody against UCP1 as well as a UCP1 antisense probe specifically stained uterine longitudinal smooth muscles. UCP1 was also expressed in longitudinal smooth muscle of digestive and male reproductive tracts but was never expressed in other types of smooth muscle, including those of arterial vessels. In uterine tract, UCP1 content was increased after cold exposure or beta-adrenergic agonist treatment. It was also up-regulated during the postovulatory period after sexual cycle synchronization. Its content transiently increased during gestation and decreased markedly after birth. These regulations strongly argue about a role for UCP1 in thermogenesis as well as in relaxation of longitudinal smooth muscle layers. PMID: 11572862 [PubMed - indexed for MEDLINE] 155. Comp Biochem Physiol A Mol Integr Physiol. 2001 Jul;129(4):949-61. Cold adaptive thermogenesis in small mammals from different geographical zones of China. Li Q(1), Sun R, Huang C, Wang Z, Liu X, Hou J, Liu J, Cai L, Li N, Zhang S, Wang Y. Author information: (1)Ministry of Education Key Laboratory for Biodiversity Science and Ecological Engineering, College of Life Sciences, Beijing Normal University, 19 Xinwai Street, 100875, Beijing, PR China. lidu@bnu.edu.cn The mechanisms of thermogenesis and thermoregulation were studied in the tree shrew (Tupaia belangeri) and greater vole (Eothenomys miletus) of the subtropical region, and Brandt's vole (Microtus brandti), Mongolian gerbil (Meriones unguiculatus), Daurian ground squirrel (Spermophilus dauricus) and plateau pika (Ochotona curzoniae) of the northern temperate zone. Resting metabolic rate (RMR) and non-shivering thermogenesis (NST) increased significantly in T. belangeri, E. miletus, M. brandti and M. unguiculatus after cold acclimation (4 degrees C) for 4 weeks. In T. belangeri, the increase in RMR and thermogenesis at liver cellular level were responsible for enhancing the capacity of enduring cold stress, and homeothermia was simultaneously extended. Stable body temperature in M. brandti, E. miletus, M. unguiculatus and O. curzoniae was maintained mainly through increase in NST, brown adipose tissue (BAT) mass and its mitochondrial protein content, and the upregulation of uncoupling protein (UCP1) mRNA, as well as enhancement of the activity of cytochrome C oxidase, alpha-glycerophosphate oxidase and T(4) 5'-deiodinase in BAT mitochondria. The RMR in O. curzoniae and euthermic S. dauricus was not changed, while NST significantly increased during cold exposure; the former maintained their stable body temperature and mass, while body temperature in the latter declined by 4.8 degrees C. The serum T(3) concentration or ratio of T(3)/T(4) in all the species was enhanced after cold acclimation. Results indicated that: (1) the adaptive mechanisms of T. belangeri residing in the subtropical region to cold are primarily by increasing RMR and secondly by increasing NST, and the mechanisms of thermogenesis are similar to those in tropical mammals; (2) in small mammals residing in northern regions, the adaptation to cold is chiefly to increase NST; (3) the mechanism of cold-induced thermogenesis in E. miletus residing in subtropical and high mountain regions is similar to that in the north; (4) a low RMR in warm environments and peak RMR and NST in cold environments enabled M. unguiculatus to tolerate a semi-desert climate; (5) O. curzoniae has unusually high RMR and high NST, acting mainly via increasing NST to adapt to extreme cold of the Qinghai-Tibet Plateau; (6) the adaptation of euthermic S. dauricus to cold is due to an increase in NST and a relaxed homeothermia; and lastly (7) the thyroid hormone is involved in the regulation of cold adaptive thermogenesis in all the species studied. PMID: 11440879 [PubMed - indexed for MEDLINE] 156. Int J Biometeorol. 2001 Feb;45(1):41-4. Fatty acid composition of brown adipose tissue in genetically heat-tolerant FOK rats. Ohno T(1), Furuyama F, Kuroshima A. Author information: (1)Hokkaido University of Education, Asahikawa 070-8621, Japan. The phospholipid fatty acid composition of brown adipose tissue (BAT) was examined in inbred heat-tolerant FOK rats and compared with that in conventional Wistar rats not previously exposed to heat. The FOK rats showed higher unsaturation states, as indicated by higher levels of polyunsaturated fatty acids and a higher unsaturation index and polyunsaturated fatty acids/saturated fatty acids ratio. This higher level of unsaturation was characterized by the higher amount of polyunsaturated fatty acids such as linoleic acid, arachidonic acid and docosahexaenoic acid. It may be concluded that the increased docosahexaenoic acid level in BAT phospholipids brings about the hyperplasia of BAT, causing an enhancement of its in vivo thermogenic activity as well as the systemic non-shivering thermogenesis observed in heat-tolerant FOK rats. PMID: 11411414 [PubMed - indexed for MEDLINE] 157. Biochim Biophys Acta. 2001 Mar 1;1504(1):82-106. UCP1: the only protein able to mediate adaptive non-shivering thermogenesis and metabolic inefficiency. Nedergaard J(1), Golozoubova V, Matthias A, Asadi A, Jacobsson A, Cannon B. Author information: (1)The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden. jan@metabol.su.se The uniqueness of UCP1 (as compared to UCP2/UCP3) is evident from expression analysis and ablation studies. UCP1 expression is positively correlated with metabolic inefficiency, being increased by cold acclimation (in adults or perinatally) and overfeeding, and reduced in fasting and genetic obesity. Such a simple relationship is not observable for UCP2/UCP3. Studies with UCP1-ablated animals substantiate the unique role of UCP1: the phenomenon of adaptive adrenergic non-shivering thermogenesis in the intact animal is fully dependent on the presence of UCP1, and so is any kind of cold acclimation-recruited non-shivering thermogenesis; thus UCP2/UCP3 (or any other proteins or metabolic processes) cannot substitute for UCP1 physiologically, irrespective of their demonstrated ability to show uncoupling in reconstituted systems or when ectopically expressed. Norepinephrine-induced thermogenesis in brown-fat cells is absolutely dependent on UCP1, as is the uncoupled state and the recoupling by purine nucleotides in isolated brown-fat mitochondria. Although very high UCP2/UCP3 mRNA levels are observed in brown adipose tissue of UCP1-ablated mice, there is no indication that the isolated brown-fat mitochondria are uncoupled; thus, high expression of UCP2/UCP3 does not necessarily confer to the mitochondria of a tissue a propensity for being innately uncoupled. Whereas the thermogenic effect of fatty acids in brown-fat cells is fully UCP1-dependent, this is not the case in brown-fat mitochondria; this adds complexity to the issues concerning the mechanisms of UCP1 function and the pathway from beta(3)-adrenoceptor stimulation to UCP1 activation and thermogenesis. In addition to amino acid sequences conserved in all UCPs as part of the tripartite structure, all UCPs contain certain residues associated with nucleotide binding. However, conserved amongst all UCP1s so far sequenced, and without parallel in all UCP2/UCP3, are two sequences: 144SHLHGIKP and the C-terminal sequence RQTVDC(A/T)T; these sequences may therefore be essential for the unique thermogenic function of UCP1. The level of UCP1 in the organism is basically regulated at the transcriptional level (physiologically probably mainly through the beta(3)-adrenoceptor/CREB pathway), with influences from UCP1 mRNA stability and from the delay caused by translation. It is concluded that UCP1 is unique amongst the uncoupling proteins and is the only protein able to mediate adaptive non-shivering thermogenesis and the ensuing metabolic inefficiency. PMID: 11239487 [PubMed - indexed for MEDLINE] 158. Biochem J. 2001 Feb 1;353(Pt 3):441-4. An uncoupling protein homologue putatively involved in facultative muscle thermogenesis in birds. Raimbault S(1), Dridi S, Denjean F, Lachuer J, Couplan E, Bouillaud F, Bordas A, Duchamp C, Taouis M, Ricquier D. Author information: (1)Centre de Recherches sur l'Endocrinologie Moléculaire et le Développement, CNRS, 9 rue Jules Hetzel, F-92190 Meudon, France. The cDNA of an uncoupling protein (UCP) homologue was obtained by screening a chicken skeletal-muscle library. The predicted 307-amino-acid sequence of avian UCP (avUCP) is 55, 70, 70 and 46% identical with mammalian UCP1, UCP2 and UCP3 and plant UCP respectively. avUCP mRNA expression is restricted to skeletal muscle and its abundance was increased 1.3-fold in a chicken line showing diet-induced thermogenesis, and 3.6- and 2.6-fold in cold-acclimated and glucagon-treated ducklings developing muscle non-shivering thermogenesis respectively. The present data support the implication of avUCP in avian energy expenditure. PMCID: PMC1221587 PMID: 11171038 [PubMed - indexed for MEDLINE] 159. J Therm Biol. 2001 Apr;26(2):85-93. Can non-shivering thermogenesis in brown adipose tissue following NA injection be quantified by changes in overlying surface temperatures using infrared thermography? Jackson DM(1), Hambly C, Trayhurn P, Speakman JR. Author information: (1)Department of Zoology, Aberdeen Centre for Energy Regulation and Obesity (ACERO) University of Aberdeen, AB24 2TZ, Scotland, UK We aimed to investigate whether infra red thermography (IRT) can be used to measure and quantify non-shivering thermogenesis (NST) in the short-tailed field vole Microtus agrestis, by directly comparing it with a standard method, i.e. metabolic response following Noradrenaline injection (NA). Mean skin surface temperature overlying Brown adipose tissue (BAT) depot was 0.82 degrees C higher than mean surface temperature that did not overly BAT. The difference in temperature increased by 1.26 degrees C after NA was administered. Mean skin surface temperature overlying BAT increased by 0.32 degrees C after NA was administered; however, surface temperature decreased by 1.32 degrees C after saline was administered. Mean skin surface temperature overlying BAT did not change significantly between warm and cold acclimated voles; in contrast metabolic peak following NA injection significantly increased in cold acclimated voles. There was no significant correlation between change in surface temperature after NA injection and metabolic peak following NA injection. The results of this study suggest that IRT is not a sensitive enough method to measure changes in NST capacity in BAT following NA injection, or to detect changes in NST capacity induced by cold acclimation. However, IRT can distinguish between skin surfaces overlying BAT and skin surfaces that do not. PMID: 11163923 [PubMed - as supplied by publisher] 160. Exp Physiol. 2000 May;85(3):321-6. Thermoregulation in winter swimmers and physiological significance of human catecholamine thermogenesis. Vybíral S(1), Lesná I, Jansky L, Zeman V. Author information: (1)Department of Physiology and Developmental Biology, Faculty of Science, Charles University, Prague and Faculty of Medicine, Pilsen, Czech Republic. stvyb@natur.cuni.cz Thermoregulation in control subjects and cold-adapted winter swimmers was examined during 1 h of cold water immersion (13 C). It was found that the thermoregulatory functions of winter swimmers differ from those of non-cold-adapted subjects. As evident from the relationship between rectal temperature and the magnitude of cold thermogenesis, in controls a significant part of cold thermogenesis during the early phase of cooling was induced by changes in peripheral temperature input, while in the late phase of cooling it was the central temperature input which was mainly engaged in induction of cold thermogenesis. In winter swimmers the magnitude of cold thermogenesis was solely related to changes in rectal temperature, indicating the predominance of the central temperature input in activation of heat production mechanisms. The thermoregulatory threshold for induction of cold thermogenesis was lowered (by 0.34 C), but the apparent hypothalamic thermosensitivity was the same as in non-cold-adapted subjects. These differences are indicative of adaptation of thermoregulatory control centres. Additionally, the activity of thermoregulatory effectors was also changed. Shivering was induced later during cooling (after 40 min) in winter swimmers than in controls, which suggests an important participation of non-shivering thermogenesis in the early thermogenic response. Winter swimmers also showed bradycardia and a greater reduction in plasma volume during cooling. The data indirectly indicate restriction of heat loss from the body. Only a non-significant increase in quantity of subcutaneous fat was observed in winter swimmers. Thus, winter swimmers were able to survive a significantly greater temperature gradient between body and environment than non-cold-adapted subjects by modifying the sensory functions of hypothalamic thermoregulatory centres to lower heat loss and produce less heat during cold exposure. Additionally, the capacity of the total cold thermogenesis due to potentiation of non-shivering heat production was also increased. Heat produced due to thermogenic action of adrenaline may represent more than a quarter of the total cold thermogenesis. In conclusion, the data suggest that winter swimmers exhibit metabolic, hypothermic and insulative types of cold adaptation. PMID: 10825419 [PubMed - indexed for MEDLINE] 161. Int J Biochem Cell Biol. 1999 Nov;31(11):1261-78. The mitochondrial uncoupling protein-2: current status. Fleury C(1), Sanchis D. Author information: (1)CEREMOD CNRS UPR 9078, Meudon, France. cfleury@genetique.uvsq.fr In eukaryotic cells ATP is generated by oxidative phosphorylation, an energetic coupling at the mitochondrial level. The oxidative reactions occurring in the respiratory chain generate an electrochemical proton gradient on both sides of the inner membrane. This gradient is used by the ATPsynthase to phosphorylate ADP into ATP. The coupling between respiration and ADP phosphorylation is only partial in brown adipose tissue (BAT) mitochondria, where the uncoupling protein UCP1 causes a reentry of protons into the matrix and abolishes the electrochemical proton gradient. The liberated energy is then dissipated as heat and ATP synthesis is reduced. This property was for a long time considered as an exception and specific to the non-shivering thermogenesis found in BAT. The recent cloning of new UCPs expressed in other tissues revealed the importance of this kind of regulation of respiratory control in metabolism and energy expenditure. The newly characterised UCPs are potential targets for obesity treatment drugs which could favour energy expenditure and diminish the metabolic efficiency. In 1997, we cloned UCP2 and proposed a role for this new uncoupling protein in diet-induced thermogenesis, obesity, hyperinsulinemia, fever and resting metabolic rate. Currently, an abundant literature deals with UCP2, but its biochemical and physiological functions and regulation remain unclear. The present review reports the status of our knowledge of this mitochondrial carrier in terms of sequence, activity, tissue distribution and regulation of expression. The putative physiological roles of UCP2 will be introduced and discussed. PMID: 10605819 [PubMed - indexed for MEDLINE] 162. Comp Biochem Physiol A Mol Integr Physiol. 1999 Sep;124(1):35-7. Myoglobin content in skeletal muscles of hibernating ground squirrels rises in autumn and winter. Postnikova GB(1), Tselikova SV, Kolaeva SG, Solomonov NG. Author information: (1)Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia. gbpost@mail.ru The content of myoglobin (Mb) in skeletal muscles of Arctic Yakutian ground squirrel (Citellus undulatus Pallas) was measured in the active euthermic summer and prehibernating autumn animals as well as in hibernating and awake animals in winter. The myoglobin content in winter, irrespective of the state of the animal, was found to be about three times higher than in summer. The content of myoglobin in autumn was also two-fold increased compared to summer, suggesting that high myoglobin level is necessary for hibernation. Analysis of biochemical data available suggests that the increase in myoglobin content in winter is probably related to a high oxygen demand of muscles at the first stage of arousal (non-shivering thermogenesis) when rectal temperature rises from 0 to 10-12 degrees C. At this stage, the oxygen-dependent processes in muscles proceed under the conditions when peripheral blood flow is blocked and anaerobic glycolysis is switched off. PMID: 10605065 [PubMed - indexed for MEDLINE] 163. Comp Biochem Physiol A Mol Integr Physiol. 1999 Aug;123(4):393-7. Arousal from torpor in the Chilean mouse-opposum (Thylamys elegans): does non-shivering thermogenesis play a role? Opazo JC(1), Nespolo RF, Bozinovic F. Author information: (1)Departamento de Ecología, Facultad de Ciencias Biológicas, Universidad Católica de Chile, Santiago, Chile. We examined the effect of norepinephrine injections on non-shivering thermogenesis (NST), rewarming rate, and metabolic cost during torpor arousal in warm- and cool-acclimated Chilean mouse-opposums, Thylamys elegans. Warm- and cool-acclimated animals did not display NST in response to NE injections. Values of VO2 (resting, after saline and NE injections) were not significantly different within treatments. Rewarming rates of warm-acclimated animals did not differ significantly from those in cool-acclimated animals. In contrast, the metabolic cost of torpor arousal was significantly affected by acclimation temperature. Warm-acclimated animals required more energy for arousal than cool-acclimated animals. Our study suggests that the main thermoregulatory mechanism during torpor arousal in this Chilean marsupial is shivering thermogenesis, and that its amount can be changed by thermal acclimation. PMID: 10581704 [PubMed - indexed for MEDLINE] 164. Int J Obes Relat Metab Disord. 1999 Nov;23(11):1105-17. Gluttony and thermogenesis revisited. Stock MJ(1). Author information: (1)Department of Physiology, St George's Hospital Medical School, University of London, London SW17 0RE, UK. m.stock@sghm.ac.uk The evolutionary and biological significance of adaptive, homeostatic forms of heat production (thermogenesis) is reviewed. After summarizing the role and selective value of thermogenesis in body temperature regulation (shivering and non-shivering thermogenesis) and the febrile response to infection (fever), the review concentrates on diet-induced thermogenesis (DIT). Animal studies indicate that DIT evolved mainly to deal with nutrient-deficient or unbalanced diets, and re-analysis of twelve overfeeding studies carried out between 1967 and 1999 suggests the same may be so for humans, particularly when dietary protein concentration is varied. This implies that the role of DIT in the regulation of energy balance is secondary to its function in regulating the metabolic supply of essential nutrients. However, individual differences in DIT are much more marked when high- or low-protein diets are overfed, and this could provide a very sensitive method for discriminating between those who are, in metabolic terms, resistant and those who are susceptible to obesity. PMID: 10578199 [PubMed - indexed for MEDLINE] 165. J Neuroendocrinol. 1999 Nov;11(11):849-56. Effect of maternal dexamethasone treatment and ambient temperature on prolactin receptor abundance in Brown adipose and hepatic tissue in the foetus and new-born lamb. Bispham J(1), Heasman L, Clarke L, Ingleton PM, Stephenson T, Symonds ME. Author information: (1)Academic Division of Child Health, School of Human Development, University Hospital, Queen's Medical Centre, Nottingham, UK. We investigated the influence of maternal dexamethasone treatment and ambient temperature on prolactin receptor (PRLR) abundance in brown adipose tissue (BAT) and hepatic tissue from foetuses and 6-h-old lambs delivered by caesarean section. Lambs were either delivered into a warm (30 degrees C; WD) or cool (15 degrees C; CD) ambient temperature at 140 days gestation, 2 days after dexamethasone treatment, or at 146 days gestation for controls. Uncoupling protein-1 (UCP1) content of BAT was higher in dexamethasone-treated groups compared to controls. A range of tissue-specific PRLR isoforms was detected. For the long form of PRLR in BAT these isoforms had molecular weights of 66, 54, 34 and 19 kD compared with 88, 76, 66, 58, 54 and 48 kD in liver. In BAT, isoforms of the short form of PRLR had molecular weights of 66, 62, 54, 48, 33 and 31 kD compared with 82, 66, 56, 54, 48, 40 and 33 kD in liver. Dexamethasone treatment in CD lambs resulted in higher abundance of the 54 kD isoform of the short form of PRLR in liver, whilst in BAT dexamethasone resulted in a greater abundance of the 48 kD isoform of the short form, and lower abundance of the 66 kD isoform of the long form of PRLR, compared to controls. A negative correlation (r2 = 0.52) was observed between abundance of 66 kD isoform for the long form of PRLR and UCP1, compared with positive correlations (r2 = 0.58-0.60) for the abundance of the 54 and 48 kD isoforms for the short form of PRLR and UCP1. In conclusion, maternal dexamethasone treatment 1 week before term alters the abundance of PRLR isoforms in a tissue-specific manner. This response is dependent on ambient temperature after birth and may provide a critical endocrine signal for maximising non-shivering thermogenesis. PMID: 10520135 [PubMed - indexed for MEDLINE] 166. Exp Physiol. 1999 Sep;84(5):979-87. Influence of thyrotrophin-releasing hormone on thermoregulatory adaptation after birth in near-term lambs delivered by caesarean section. Heasman L(1), Clarke L, Symonds ME. Author information: (1)Academic Division of Child Health, School of Human Development, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH, UK. We investigated the hypothesis that exogenous stimulation with thyrotrophin-releasing hormone (TRH) immediately prior to umbilical cord clamping can improve thermoregulatory adaptation after birth in near-term lambs delivered by Caesarean section. Lambs received an umbilical vein injection of saline +/- TRH (8 microg) prior to cord clamping. The rate of change in colonic temperature and oxygen consumption after birth were not influenced by TRH, but TRH-treated lambs exhibited a greater incidence of shivering compared with controls over the first hour of neonatal life. Two and a half hours after birth, TRH-treated lambs possessed brown adipose tissue (BAT) with a higher thermogenic activity (i.e. GDP binding to mitochondrial protein), but their BAT had a reduced DNA content and they had less hepatic glycogen than control lambs. TRH administration had no effect on iodothyronine 5' deiodinase activity in BAT and liver, or on plasma concentrations of total triiodothyronine, thyroxine, cortisol or free fatty acids. Three TRH-treated but no control lambs, failed to establish continuous breathing, so tissues from these treated lambs together with time-matched controls were sampled 25 min after birth. These 'non-surviving' TRH-treated lambs had very high plasma catecholamine concentrations, but their lung weights were similar to controls. 'Surviving' TRH-treated lambs possessed lungs with less DNA than non-surviving TRH-treated lambs. It is concluded that umbilical vein injection of TRH prior to umbilical cord clamping increases the recruitment of both shivering and non-shivering thermogenesis after birth. PMID: 10502665 [PubMed - indexed for MEDLINE] 167. J Biol Chem. 1999 Aug 13;274(33):23368-77. Rat peroxisome proliferator-activated receptors and brown adipose tissue function during cold acclimatization. Guardiola-Diaz HM(1), Rehnmark S, Usuda N, Albrektsen T, Feltkamp D, Gustafsson JA, Alexson SE. Author information: (1)Center for Biotechnology, Huddinge University Hospital, Karolinska Institute, S-141 86, Huddinge, Sweden. Brown adipose tissue (BAT) hyperplasia is a fundamental physiological response to cold; it involves an acute phase of mitotic cell growth followed by a prolonged differentiation phase. Peroxisome proliferator-activated receptors (PPARs) are key regulators of fatty acid metabolism and adipocyte differentiation and may therefore mediate important metabolic changes during non-shivering thermogenesis. In the present study we have investigated PPAR mRNA expression in relation to peroxisome proliferation in rat BAT during cold acclimatization. By immunoelectron microscopy we show that the number of peroxisomes per cytoplasmic volume and acyl-CoA oxidase immunolabeling density remained constant (thus increasing in parallel with tissue mass and cell number) during the initial proliferative phase and the acute thermogenic response but increased after 14 days of cold exposure, correlating with terminal differentiation of BAT. A pronounced decrease in BAT PPARalpha and PPARgamma mRNA levels was found within hours of exposure to cold, which was reversed after 14 days, suggesting a role for either or both of these subtypes in the proliferation and induction of peroxisomes and peroxisomal beta-oxidation enzymes. In contrast, PPARdelta mRNA levels increased progressively during cold exposure. Transactivation assays in HIB 1B and HEK-293 cells demonstrated an adrenergic stimulation of peroxisome proliferator response element reporter activity via PPAR, establishing a role for these nuclear receptors in hormonal regulation of gene transcription in BAT. PMID: 10438514 [PubMed - indexed for MEDLINE] 168. Brain Res. 1999 Jul 3;833(2):242-50. Disinhibition of lower midbrain neurons enhances non-shivering thermogenesis in anesthetized rats. Shibata M(1), Uno T, Hashimoto M. Author information: (1)Department of Biometeorology, Yamanashi Institute of Environmental Sciences, Fuji-Yoshida, Yamanashi 403-0005, Japan. mshibata@yies.pref.yamanashi.jp The hypothesis that the lower midbrain, specifically in and around the retrorubral field (RRF) and/or rubrospinal tract (rs), contains a tonic inhibitory mechanism on non-shivering thermogenesis (NST) was examined in urethane-anesthetized rats. It has been proposed that removal of the tonic inhibitory mechanism in the lower midbrain causes body temperature increase through disinhibition-induced activation of the central sympathetic nervous system. The present experiments were carried out to examine whether and where the proposed midbrain region contains cell bodies that tonically inhibit the NST, and if so, whether they receive any influence from the hypothalamus. Male Wistar rats were anesthetized with urethane (1. 0-1.2 g/kg, i.p.), and various agents were microinjected into the RRF and rs areas of one side before and after knife-cut in the other side of the lower midbrain or isolation of the hypothalamus from the midbrain. Changes in interscapular brown adipose tissue (IBAT), rectum, and tail skin temperatures were monitored.RESULTS: (1) unilateral midbrain procaine increased IBAT and rectal temperatures only after un-injected side of the midbrain had been pre-transected. (2) Effective midbrain sites for procaine to increase IBAT and rectal temperatures was laterally extended. (3) Tetrodotoxin microinjected into the midbrain site where procaine increased IBAT and rectal temperatures also raised both temperatures. (4) l-glutamate decreased IBAT and rectal temperatures when microinjected into one of the most inner midbrain area of procaine-sensitive sites without affecting tail skin temperature. (5) Isolation of the hypothalamus from the lower midbrain did not affect midbrain procaine-induced IBAT and rectal temperature increases. These results suggest that neurons that tonically inhibit the NST are located in the area close to the midline adjacent to the RRF and rs, and that the integrity of the neurons to tonically inhibit the NST is not affected by disconnecting the hypothalamus from the midbrain. Copyright 1999 Elsevier Science B.V. PMID: 10375700 [PubMed - indexed for MEDLINE] 169. FEBS Lett. 1999 Apr 30;450(1-2):8-12. Regulation of UCP3 by nucleotides is different from regulation of UCP1. Echtay KS(1), Liu Q, Caskey T, Winkler E, Frischmuth K, Bienengräber M, Klingenberg M. Author information: (1)Institute for Physical Biochemistry, University of Munich, Germany. UCP3 is an isoform of UCP1, expressed primarily in skeletal muscle. Functional properties of UCP3 are still largely unknown. Here, we report about the expression of UCP3 and of UCP1 in inclusion bodies of Escherichia coli. On solubilization and reconstitution into proteoliposomes, both UCP3 and UCP1 transport Cl- at rates equal to the reconstituted native UCP1. Cl- transport is inhibited by low concentrations of ATP, ADP, GTP and GDP. However, no H+ transport activity is found possibly due to the lack of a cofactor presents in UCP from mitochondria. The specificity of inhibition by nucleoside tri- and diphosphate is different between UCP1 and UCP3. UCP1 is more sensitive to tri- than diphosphate whereas in UCP3, the gradient is reverse. These results show a new paradigm for the regulation of thermogenesis at various tissues by the ATP/ADP ratio. In brown adipose tissue, the thermogenesis is correlated with a low ATP/ADP whereas in skeletal muscle, non-shivering thermogenesis is active at a high ATP/ADP ratio, i.e. in the resting state. PMID: 10350047 [PubMed - indexed for MEDLINE] 170. J Vet Med Sci. 1999 Apr;61(4):403-9. Cold-induced mRNA expression of angiogenic factors in rat brown adipose tissue. Asano A(1), Kimura K, Saito M. Author information: (1)Department of Biomedical Sciences, School of Veterinary Medicine, Hokkaido University, Sapporo, Japan. Brown adipose tissue (BAT) is the major site of non-shivering thermogenesis in rodents. Rapid angiogenesis is induced in association with adaptive hyperplasia of this tissue when the animal is exposed to cold. We demonstrated previously adrenergic activation of mRNA expression of vascular endothelial growth factor (VEGF) in rat BAT and its possible contribution to the cold-induced angiogenesis in this tissue. In the present study, we examined the effect of cold exposure on mRNA expression of other two angiogenic factors, VEGF-B and basic fibroblast growth factor (bFGF), in rats. Conventional Northern blot analysis revealed abundant mRNA expression of VEGF-B as well as VEGF, but not bFGF, in BAT. When rats were exposed to cold at 4 degrees C, the VEGF mRNA level was increased by 2.7-fold in 1-4 hr and returned to the basal level within 24 hr. In contrast, the VEGF-B mRNA level did not change throughout the course of cold exposure. A significant expression of bFGF mRNA was detected in BAT by reverse transcription-polymerase chain reaction (RT-PCR). To evaluate the tissue bFGF mRNA level quantitatively, a competitive RT-PCR method was developed using a shorter RNA fragment as a competitor. The bFGF mRNA level in BAT was found to increase by 2.3-fold in 4 hr and decreased to the basal level within 24 hr after cold exposure. These results suggest that cold exposure leads to induce VEGF and bFGF rapidly and transiently in BAT, which in turn stimulate the proliferation of vascular endothelial cells in this tissue. PMID: 10342292 [PubMed - indexed for MEDLINE] 171. Pflugers Arch. 1999 Jan;437(2):255-60. Blood flow to the brown adipose tissue of conscious young rabbits during hypoxia in cold and warm conditions. Mortola JP(1), Merazzi D, Naso L. Author information: (1)Department of Physiology, McGill University, 3655 Drummond Str., Montreal, Quebec, H3G 1Y6 Canada. jacopo@physio.mcgill.ca Brown adipose tissue (BAT) non-shivering thermogenesis is stimulated by cold temperature and depressed by hypoxia. We investigated the extent to which changes in metabolic rate during cold and hypoxia, singly or combined, were accompanied by changes in BAT perfusion. One-month-old rabbits were instrumented for measurements of regional blood flow by the coloured microsphere technique. One group of rabbits was tested in warm (24 degrees C, n=17), and the other in cold (13 degrees C, n=9) conditions, first in normoxia (inspired oxygen concentration FIO2 about 21%, arterial oxygen saturation SaO2 approximately 88%) followed by hypoxia (FIO2 approximately 10%, SaO2 approximately 54%). In warm conditions, oxygen consumption (VO2, measured by an open-flow method) averaged 22 ml.kg-1.min-1 (STPD), and BAT blood flow 98 ml.100g-1.min-1. In hypoxia, VO2 dropped on average to 87%, whereas BAT flow dropped to 43% of the normoxic values. In the cold during normoxia, VO2 averaged 31 ml.kg-1.min-1 (STPD), and BAT blood flow was 155 ml.100g-1.min-1. In cold and hypoxia VO2 dropped to 19 ml.kg-1.min-1 (STPD) (i.e. 60% of the normoxic value), whereas BAT blood flow was not altered significantly (148 ml.100g-1.min-1). Hence, BAT blood flow decreased in hypoxia in absence of cold stimuli, whereas it remained high when hypoxia occurred during cold, despite the major drop in VO2. We conclude that cold is more important than hypoxia in determining BAT perfusion, and that changes in BAT blood flow are not a mechanism for the hypoxic control of V.O2. PMID: 9929567 [PubMed - indexed for MEDLINE] 172. FEBS Lett. 1998 Nov 20;439(3):258-62. Effects of cold acclimation and palmitate on energy coupling in duckling skeletal muscle mitochondria. Roussel D(1), Rouanet JL, Duchamp C, Barré H. Author information: (1)Laboratoire de Physiologie des Régulations Energétiques, Cellulaires et Moléculaires, UMR 5578 CNRS-UCBL, Lyon, France. dbjr1@le.ac.uk Gastrocnemius subsarcolemmal and intermyofibrillar mitochondria were isolated from 5-week-old cold-acclimated and thermoneutral control ducklings. In vitro respiration (polarography) and ATP synthesis (bioluminescence) were determined at 25 degrees C. Subsarcolemmal mitochondria showed a higher state 4 respiration and lower respiratory control and ADP/O ratio in cold-acclimated than in thermoneutral ducklings. Palmitate decreased the rate of ATP synthesis in both mitochondrial populations to about 30% of maximal but failed to abolish this process even at high concentrations. It is suggested that both expensive ATP synthesis and increased ATP hydrolysis could contribute synergistically to muscle non-shivering thermogenesis in cold-acclimated ducklings. PMID: 9845333 [PubMed - indexed for MEDLINE] 173. Respir Physiol. 1998 Sep;113(3):213-22. Hypoxia inhibits cold-induced huddling in rat pups. Mortola JP(1), Feher C. Author information: (1)Department of Physiology, McGill University, Montreal, Que., Canada. jacopo@physio.mcgill.ca We asked to what extent hypoxia would modify the huddling behaviour of young rats during cold exposure. Sets of five animals (postnatal age 9+/-1 days) were placed at predetermined positions in a chamber maintained at approximately 33 degrees C (warm) or approximately 15 degrees C (cold), in normoxia or hypoxia (10% inspired O2), and their movements monitored for 30 min by a video camera. The surface areas (SA) of each individual pup (SAi) and of the whole set of pups (SAset) was measured every 5 min. In warm, the rats spread out, and both SAi and SAset were the greatest, whether in normoxia or hypoxia. In hypoxia, the total travelled distance (TTD) was much greater than in normoxia. In cold, during normoxia, SAi and SAset were decreased because of postural changes and huddling, and body temperature, measured at the end of the exposure, was also decreased. In hypoxic-cold, compared to normoxic-cold, fewer pups were in contact with one another, SAi and SAset did not decrease and the drop in body temperature was larger. Differently from hypoxia, hypercapnia (5% CO2) did not modify the responses observed during breathing air, whether in warm or cold conditions. We conclude that hypoxia, in addition to inhibiting shivering and non-shivering thermogenesis, can also limit behavioural thermogenesis, with the effect of further lowering body temperature. PMID: 9840330 [PubMed - indexed for MEDLINE] 174. J Biol Chem. 1998 Nov 20;273(47):31092-6. The guanosine monophosphate reductase gene is conserved in rats and its expression increases rapidly in brown adipose tissue during cold exposure. Salvatore D(1), Bartha T, Larsen PR. Author information: (1)Thyroid Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. Non-shivering thermogenesis is required for survival of rodents during cold stress. Uncoupling protein-1 acts in brown adipose tissue (BAT) to transport protons, thus dissipating the proton gradient across the inner mitochondrial membrane. This permits respiration uncoupled from ATP synthesis. UCP-1 function is inhibited by the binding of purine nucleotides, with GTP/GDP being more potent than ATP/ADP. We used a cDNA subtraction analysis to identify cDNAs rapidly induced by cold exposure. One of these encodes rat guanosine monophosphate reductase (GMP-r). This was surprising in that previous data had suggested that this enzyme was absent in rodents. Rat GMP-r is 96% identical to human GMP-r, and its mRNA is increased 30-fold in BAT within 6 h of cold exposure. The gene is also expressed (but not cold-responsive) in muscle and kidney, but not in white fat. We speculate that the physiological function of the marked increase in BAT GMP-r during cold stress may be to deplete the brown adipocyte of guanine nucleotides, converting them to IMP, thus permitting enhanced UCP-1 function. This is a previously unrecognized regulatory aspect of thermogenesis, an essential physiological response of rodents to cold. PMID: 9813009 [PubMed - indexed for MEDLINE] 175. Cell Tissue Res. 1998 Dec;294(3):461-6. An immunohistochemical and in situ hybridisation study of the postnatal development of uncoupling protein-1 and uncoupling protein-1 mRNA in lamb perirenal adipose tissue. Finn D(1), Lomax MA, Trayhurn P. Author information: (1)Department of Agriculture, University of Aberdeen, MacRobert Building, 581 King Street, Aberdeen, AB24 5UA, Scotland, UK. In the lamb, the uncoupling protein-1 (UCP1) content of perirenal adipose tissue at birth is an important factor in heat production by non-shivering thermogenesis and the prevention of hypothermia. This study examines UCP1 gene expression and protein content in perirenal adipose tissue over the first 15 days of life by in situ hybridisation and immunohistochemistry. UCP1 mRNA was detected at birth in 30% of adipocytes, and in approximately 24% of fat cells at 2 days of life. However, by 5 days of age and thereafter UCP1 mRNA was undetectable. Immunoreactive UCP1 was present in all adipocytes at birth and at 2 days of age, and remained detectable in a decreasing proportion of cells until day 10 of life. By 15 days of age no immunoreactive UCP1 was detected and the perirenal adipose tissue had the appearance of white fat. It is concluded that UCP1 gene expression is suppressed in most adipocytes in perirenal adipose tissue of newborn lambs, and gene expression rapidly falls in the remaining adipocytes over the first 5 days of postnatal life. In contrast, immunoreactive UCP1, a characteristic of brown adipose tissue, was present in many adipocytes for up to 10 days of age, suggesting that UCP1 has a long half-life in lambs. All adipocytes in perirenal adipose tissue of newborn lambs appear to be functionally brown, but over the first 2 weeks of postnatal life there is a complete transformation to white adipocytes. PMID: 9799463 [PubMed - indexed for MEDLINE] 176. Comp Biochem Physiol A Mol Integr Physiol. 1998 May;120(1):187-91. Thermoregulatory responses of mesic and xeric rodent species to photoperiod manipulations. Haim A(1), Shabtay A, Arad Z. Author information: (1)Department of Biology, University of Haifa at Oranim, Israel. zeac614@uvm.haifa.ac.il Thermoregulatory mechanisms in rodents were found to respond to photoperiod manipulations. In desert adapted species, non-shivering thermogenesis NST-capacity (the ratio between the maximal VO2 response to noradrenaline injection and RMR, measured 1 degree C below the lower critical point) increased, as due to long scotophase acclimation. The aim of the present study is to compare the thermoregulatory responses of mesic rodents with those of desert ones, to photoperiod manipulations. Heat production, body temperature and NST were studied in the Levant vole, Microtus guentheri, the Migratory hamster, Cricetulus migratorius, and the Macedonian mouse, Mus macedonicus, acclimated to long (16L:8D) and short (8L:16D) photoperiod regimes at a constant ambient temperature of 25 +/- 1 degree C. The results of our study show that the three mesic species did not significantly change their NST capacity due to increase in the dark hours, as observed in desert species. However, in all three mesic species the increase in photophase resulted in a better resistance to high ambient temperatures by elevating the higher critical point and decreasing metabolic rates at the thermoneutral zone. PMID: 9773501 [PubMed - indexed for MEDLINE] 177. J Physiol. 1998 Nov 1;512 ( Pt 3):883-92. Efferent projection from the preoptic area for the control of non-shivering thermogenesis in rats. Chen XM(1), Hosono T, Yoda T, Fukuda Y, Kanosue K. Author information: (1)Department of Physiology, Osaka University Medical School, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan. 1. To investigate the characteristics of efferent projections from the preoptic area for the control of non-shivering thermogenesis, we tested the effects of thermal or chemical stimulation, and transections of the preoptic area on the activity of interscapular brown adipose tissue in cold-acclimated and non-acclimated anaesthetized rats. 2. Electrical stimulation of the ventromedial hypothalamic nucleus (VMH) elicited non-shivering thermogenesis in the brown adipose tissue (BAT); warming the preoptic area to 41.5 C completely suppressed the thermogenic response. 3. Injections of d, l-homocysteic acid (DLH; 0.5 mM, 0.3 microliter) into the preoptic area also significantly attenuated BAT thermogenesis, whereas injections of control vehicle had no effect. 4. Transections of the whole hypothalamus in the coronal plane at the level of the paraventricular nucleus induced rapid and large rises in BAT and rectal temperatures. This response was not blocked by pretreatment with indomethacin. The high rectal and BAT temperatures were sustained more than 1 h, till the end of the experiment. Bilateral knife cuts that included the medial forebrain bundle but not the paraventricular nuclei elicited similar rises in BAT and rectal temperatures. Medial knife cuts had no effect. 5. These results suggest that warm-sensitive neurones in the preoptic area contribute a larger efferent signal for non-shivering thermogenesis than do cold-sensitive neurones, and that the preoptic area contributes a tonic inhibitory input to loci involved with non-shivering thermogenesis. This efferent inhibitory signal passes via lateral, but not medial, hypothalamic pathways. PMCID: PMC2231233 PMID: 9769429 [PubMed - indexed for MEDLINE] 178. J Comp Physiol B. 1998 Jul;168(5):359-63. Development of endothermy in a Tasmanian marsupial, Bettongia gaimardi and its response to cold and noradrenaline. Rose RW(1), Kuswanti N, Colquhoun EQ. Author information: (1)Zoology Department, University of Tasmania, Australia. randy.rose@utas.edu.au Marsupials at birth are ectothermic and gradually attain the ability to change their metabolic heat production during pouch life. How this process occurs in the bettong has been measured on 13 pouch young from week 1 until 3 weeks after pouch vacation (week 18). Oxygen consumption was measured at 35 degrees C (pouch temperature) and at 22 degrees C. The results at 35 degrees C showed an increase in metabolic rate from week 1 until week 12 when there was a decrease to near adult levels after pouch vacation. At 22 degrees C young bettongs had a lower metabolic rate (compared with measurements made at 35 degrees C) until week 9 after which there was an increase above measurements made at 35 degrees C. Noradrenaline had little effect until week 10 after which the metabolic rate (although measured at 35 degrees C) paralleled the levels measured at 22 degrees C. The free thyroxine level was low in early pouch life, increased to a peak at week 12 then decreased. Thermal conductance increased until week 10 after which it decreased, reaching values similar to those of adult bettongs by week 20. The results indicate that non-shivering thermogenesis occurs in this macropodoid marsupial. This phenomenon may be a phylogenetic difference between macropodid and non-macropodid marsupials as also suggested by Nicol et al. (1997). PMID: 9706706 [PubMed - indexed for MEDLINE] 179. Gene. 1998 Jul 17;215(1):77-84. Cloning of mouse uncoupling protein 3 cDNA and 5'-flanking region, and its genetic map. Yoshitomi H(1), Yamazaki K, Tanaka I. Author information: (1)Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, Japan. h1-yoshitomi@eisai.co.jp Brown adipose tissue and skeletal muscle are important sites of non-shivering thermogenesis. It has been known that UCP1 and UCP2 function as the main effector of the thermogenesis: the former is expressed exclusively in brown adipose tissue, whereas the latter is distributed widely. Recently, the third UCP homologue was discovered in humans, which was designated as UCP3. We now report molecular cloning of full-length mouse UCP3 cDNA and its 5'-flanking genomic region. The mouse UCP3 cDNA sequence predicted a 308-amino acid protein, and the overall identity between the mouse and human UCP3 proteins was 85.6%. The mouse UCP3 amino acid sequence was 54.7% and 73.1% identical to the mouse UCP1 and UCP2, respectively. Expression of the mouse UCP3 was found to be abundant in skeletal muscle and somewhat less abundant in heart, but was minimally expressed in other critical organs. The sequences of 5'-flanking regions of the mouse UCP1 and UCP3 were very different, resulting in different distributions of putative transcriptional factor binding sites. The differences could reflect tissue-specific expression of the UCPs. The mouse Ucp3 gene was mapped near Ucp2 on chromosome 7, suggesting that the Ucp2 and Ucp3 are clustered genes. This region is boundary of synteny between human chromosome 11q13 and 11p15. As Solanes et al. reported that both human UCP2 and UCP3 genes are assigned to chromosome 11q13, the region where the mouse Ucp2 and Ucp3 are localized is syntenic to human chromosome 11q13. PMID: 9666083 [PubMed - indexed for MEDLINE] 180. Eur J Pharmacol. 1998 Apr 24;347(2-3):265-74. Effects of ZD7114, a selective beta3-adrenoceptor agonist, on neuroendocrine mechanisms controlling energy balance. Savontaus E(1), Pesonen U, Rouru J, Huupponen R, Koulu M. Author information: (1)Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland. erisan@utu.fi Selective beta3-adrenoceptor agonists increase energy expenditure by increasing non-shivering thermogenesis in brown adipose tissue. The aim of this study was to investigate how changes in energy balance affect energy intake and interaction of peripheral metabolic feedback signals with central neuroendocrine mechanisms participating in the control of body energy balance. Expression of preproneuropeptide Y (preproNPY) mRNA in the arcuate nucleus and preprocorticotropin-releasing factor (CRF) mRNA in the paraventricular nucleus were measured by in situ hybridisation technique after 1 day, 1 and 5 weeks of treatment with ZD7114 ((S)-4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]-N-(2-methoxyet hyl)phenoxyacetamide, 3 mg kg(-1) day(-1) in drinking water) in obese fa/fa Zucker rats. In addition, expression of leptin mRNA in epididymal fat and serum levels of leptin were analysed. Food intake, body weights, binding of GDP to brown adipose tissue mitochondria, plasma insulin and glucose were also measured. Treatment with ZD7114 significantly reduced weight gain and activated brown adipose tissue thermogenesis, but had no effect on food intake. Expressions of preproNPY or preproCRF mRNAs were similarly not changed by treatment with ZD7114. Furthermore, ZD7114 had no effect on plasma insulin or leptin and the expression of leptin mRNA in epididymal fat. However, statistically significant correlations were found between preproNPY and preproCRF mRNA expressions and brown fat thermogenic activity and plasma insulin levels in the ZD7114 treated rats, but not in the control rats. It is concluded that treatment with ZD7114 markedly activated brown fat thermogenesis, but did not affect neuropeptide Y (NPY) and CRF gene expression per se. However, the correlation analyses suggest that ZD7114 may modulate feedback connections of brown adipose tissue thermogenesis and plasma insulin with the hypothalamic neuroendocrine mechanisms integrating body energy balance. PMID: 9653893 [PubMed - indexed for MEDLINE] 181. Brain Res. 1998 May 25;794(1):80-7. Thermoresponsiveness of posterior hypothalamic (PH) neurons of rats to scrotal and abdominal thermal stimulation. Li Q(1), Thornhill J. Author information: (1)Department of Physiology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, Canada. The thermoresponsiveness of posterior hypothalamic (PH) neurons to localized, incremental thermal heating and cooling between 10-40 degrees C of the abdomen or scrotum was determined in urethane anesthetized, male Sprague-Dawley rats whose core temperature was maintained at 37 degrees C during testing. PH extracellular neuronal activity was recorded along with changes in gastrocnemius muscle EMG activity and temperature (Tms, indicative of shivering thermogenesis) and intrascapular brown adipose tissue temperature (TIBATs, indicative of non-shivering thermogenesis). Seventy-five PH neurons were recorded following both scrotal and abdominal trials of thermal stimulation. Nine percent of PH neurons were classified as warm responsive neurons (WRNs), 20% as cold responsive (CRNs), and 71% as temperature nonresponsive neurons (TNRNs), based on their thermal coefficients (TCs). Mean TC for warm PH neurons was significantly increased with scrotal warming between 30-40 degrees C from the mean TC of the same PH WRNs following abdominal warming. Similarly, the thermal coefficient was increased (i.e., was more negative) for cold responsive PH neurons to scrotal cooling (20-10 degrees C) as opposed to the TC of the same PH CRNs for abdominal cooling. No shivering thermogenesis (no change in temperature or EMG activity from gastrocnemius muscle) or non-shivering thermogenesis (no significant increase in IBAT temperatures) occurred with scrotal or abdominal cooling in these 21 degrees C acclimatized rats. The results indicate that a small population of PH neurons are thermoresponsive to localized physiological changes in temperature of the scrotum and abdomen with greater thermoresponsiveness shown of both warm and cold PH neurons to scrotal vs. abdominal thermal stimulation. Copyright 1998 Elsevier Science B.V. All rights reserved. PMID: 9630533 [PubMed - indexed for MEDLINE] 182. Biochem J. 1997 Nov 15;328 ( Pt 1):179-83. Adrenergic activation of vascular endothelial growth factor mRNA expression in rat brown adipose tissue: implication in cold-induced angiogenesis. Asano A(1), Morimatsu M, Nikami H, Yoshida T, Saito M. Author information: (1)Department of Biomedical Sciences, School of Veterinary Medicine, Hokkaido University, Sapporo, Japan. Cold exposure produces adaptive hyperplasia and growth of brown adipose tissue (BAT), the major site of non-shivering thermogenesis in rodents, associated with increased angiogenesis in this tissue. Vascular endothelial growth factor (VEGF), one of the most potent angiogenic factors, was found to be expressed abundantly in BAT of the rat. When rats were exposed to cold at 4 degrees C, the VEGF mRNA level in BAT was increased by 2-3-fold in 1-4 h, but returned to the basal level within 24 h. VEGF expression in other tissues such as heart, kidney and lung did not change after cold exposure. The cold-induced increase in VEGF mRNA was abolished by surgical sympathetic denervation, but mimicked by administration of noradrenaline or a beta3-adrenoceptor agonist CL316,243, indicating the critical role of the beta-adrenergic pathway in VEGF expression in BAT. Among three isoforms of VEGF, the mRNA of a short form (VEGF120) lacking heparin-binding activity was preferentially increased after cold exposure and treatment with the adrenergic agonists. These results suggest that cold exposure activates the sympathetic nerves and leads to a rapid increase in synthesis of VEGF in BAT, which in turn stimulates the proliferation of surrounding vascular endothelial cells. PMCID: PMC1218903 PMID: 9359850 [PubMed - indexed for MEDLINE] 183. Clin Sci (Lond). 1997 Oct;93(4):349-54. Brown adipose tissue and its uncoupling protein in chronically hypoxic rats. Mortola JP(1), Naso L. Author information: (1)Department of Physiology, McGill University, Montreal, Quebec, Canada. 1. Hypoxia is known to decrease thermogenesis. We set out to determine whether this is accompanied by alterations in the brown adipose tissue, which is a major source of non-shivering thermogenesis. 2. Measurements were performed on 25- and 64-day-old rats, after 4 days of hypoxia (10% inspired O2), and on approximately 3.5-month-old rats in hypobaric hypoxia since birth, at an ambient temperature of 25 degrees C. 3. All hypoxic rats had higher haematocrit and lower body mass than corresponding controls. 4. In the 25-day-old rats, hypoxia had minimal and non significant effects on brown adipose tissue mass, proteins and DNA concentration. The content of the mitochondrial uncoupling protein thermogenin, evaluated by immunoblot after electrophoretic separation, relative to the cytoskeleton actin (UCP/Act), was not significantly altered. 5. In 25-day-old rats exposed for 4 days to cold (ambient temperature = 7-9 degrees C), brown adipose tissue was hyperplastic, with increased UCP/Act; hypoxia did not appreciably alter the response to cold. 6. In the 2-month-old rats, after 4 days of hypoxia UCP/Act was reduced to about 40% of control. 7. In the 3.5-month-old rats maintained in hypoxia since birth, brown adipose tissue mass was reduced in proportion to body mass, with little effect on total proteins and DNA; UCP/Act was decreased to about 50% of control. 8. We conclude that chronic hypoxia had a minimal effect on brown adipose tissue total proteins and DNA content. However, the uncoupling protein content can be greatly reduced, depending upon age and duration of hypoxia. PMID: 9404227 [PubMed - indexed for MEDLINE] 184. Comp Biochem Physiol A Physiol. 1997 Aug;117(4):545-54. Potential for non-shivering thermogenesis in perfused chicken (Gallus domesticus) muscle. Eldershaw TP(1), Duchamp C, Ye J, Clark MG, Colquhoun EQ. Author information: (1)Division of Biochemistry, Faculty of Medicine and Pharmacy, University of Tasmania, Hobart, Australia. The humoral modulation of resting muscle heat production of chickens (Gallus domesticus) was investigated in vitro. The resting distal lower limb was perfused via the popliteal artery at 25 degrees C without erythrocytes at constant flow. The preparation was stable for at least 3 hr, showing a constant oxygen uptake (MO2) and perfusion pressure as well as adequately maintaining muscle energy charge and creatine phosphate: creatine ratio. Noradrenaline (NOR), adrenaline (ADR) and serotonin (5-HT) each caused a dose-dependent rise in perfusion pressure. NOR and ADR evoked increased MO2 at low doses eventually followed by decreased MO2 at higher agonist concentrations. 5-HT gave smaller but qualitatively similar MO2 effects. The actions of 50 nM NOR were blocked by prazosin (10 microM) and nitroprusside (0.5 mM), but not altered by propranolol (10 microM). NOR-induced stimulatory MO2 changes in the presence of pharmacological concentrations (1 microM) of glucagon were more pronounced and the thermogenic concentration range of NOR was increased. Taken together, these in vitro findings demonstrate a potential for vasoconstrictor-controlled muscle nonshivering thermogenesis in birds as in marsupials and mammals, suggesting that vascular control of muscle MO2 may be a widespread biological mechanism. The possible implications of these findings for avian nonshivering thermogenesis are discussed. PMID: 9219357 [PubMed - indexed for MEDLINE] 185. Eur J Pharmacol. 1997 Jun 11;328(2-3):207-15. Anti-obesity effect of MPV-1743 A III, a novel imidazoline derivative, in genetic obesity. Savontaus E(1), Raasmaja A, Rouru J, Koulu M, Pesonen U, Virtanen R, Savola JM, Huupponen R. Author information: (1)Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland. erisan@utu.fi MPV-1743 A III ((+/-)-4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole) is a novel imidazoline derivative. In this study, it was shown to bind with high affinity to alpha2-adrenoceptor subtypes alpha2A (IC50) = 0.66 +/- 0.06 nM), alpha2B (IC50) = 3.8 +/- 0.53 nM), alpha2C (IC50) = 3.1 +/- 0.61 nM) in the recombinant S115 cells and to alpha2D (IC50 = 0.94 +/- 0.10 nM) in the rat submandibular gland. MPV-1743 A III also showed remarkably high affinity to alpha1-adrenoceptors (IC50 = 150 +/- 12 nM) in the rat cerebral cortex and to imidazoline I2b-binding sites (IC50) = 150 +/- 5.0 nM) in the rat liver. The functional alpha2-adrenoceptor antagonistic effect of MPV-1743 A III was demonstrated by studying the ability of orally administered MPV-1743 A III to reverse and prevent the alpha2-adrenoceptor agonist detomidine-induced mydriasis in rat. The anti-obesity effect of MPV-1743 A III was investigated in genetically obese (fa/fa) Zucker rats in two different phases of obesity. Chronic treatment with MPV-1743 A III (0.3 3 mg/kg per day p.o. for 3 weeks) dose dependently decreased weight gain in early-phase obesity. In fully established obesity, GDP binding to mitochondria and expression of uncoupling protein mRNA were increased in brown adipose tissue by MPV-1743 A III indicating an activation of non-shivering thermogenesis. The present study shows that MPV- 1743 A III has a modest anti-obesity effect in the genetic rodent model of obesity. The relative importance of alpha2- and alpha1-adrenoceptors and imidazoline I2b-binding sites in mediating the effects of MPV-1743 A III needs further evaluation. PMID: 9218703 [PubMed - indexed for MEDLINE] 186. Exp Physiol. 1997 Mar;82(2):403-14. Engine and radiator: fetal and placental interactions for heat dissipation. Schröder HJ(1), Power GG. Author information: (1)Abteilung für experimentelle Medizin, Universitäts-Frauenklinik, Hamburg, Germany. The 'engine' of fetal metabolism generates heat (3-4 W kg-1 in fetal sheep) which has to be dissipated to the maternal organism. Fetal heat may move through the amniotic/allantoic fluids to the uterine wall (conductive pathway; total conductance, 1.1 W degrees C-1 kg-1) and with the umbilical arterial blood flow (convective pathway) to the placenta. Because resistance to heat flow is larger than zero fetal temperature exceeds maternal temperature by about 0.5 degree C (0.3-1 degree C). Probably 85% of fetal heat is lost to the maternal organism through the placenta, which thus serves as the main 'radiator'. Placental heat conductivity appears to be extremely high and this may lead to impaired heat exchange (guinea-pig placenta). A computer simulation demonstrates that fetal temperature is essentially clamped to maternal temperature, and that fetal thermoregulatory efforts to gain thermal independence would be futile. Indeed, when the late gestational fetus in utero is challenged by cold stress, direct and indirect indicators of (non-shivering) thermogenesis (oxygen consumption, increase of plasma glycerol and free fatty acid levels) change only moderately. In prematurely delivered lambs, however, cold stress provokes summit metabolism and maximum heat production. Only when birth is imitated in utero (by cord clamping, external artificial lung ventilation and cooling) do thermogenic efforts approach levels typical of extra-uterine life. This suggests the presence of inhibitors of thermogenesis of placental origin, e.g. prostaglandins and adenosine. When the synthesis of prostaglandins is blocked by pretreatment with indomethacin, sheep fetuses react to intra-uterine cooling with vigorous thermogenic responses, which can be subdued by infusion of prostaglandin E2 (PGE2). Since the sheep placenta is known to produce sufficient amounts of PGE2, it seems that the placenta controls fetal thermogenic responses to some extent. This transforms the fetus into an ectothermic organism, and yet allows the newborn the full exploitation of thermoregulatory responses typical of endothermic animals. PMID: 9129954 [PubMed - indexed for MEDLINE] 187. Biochemistry (Mosc). 1997 Feb;62(2):141-4. Seasonal changes in myoglobin content in muscles of hibernating Yakutian ground squirrels. Postnikova GB(1), Tselikova SV, Ignat'ev DA, Kolaeva SG. Author information: (1)Group of Biophysics of Redox Proteins, Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia. Myoglobin content in skeletal muscles of the Yakutian ground squirrel Citellus undulatus was measured during different periods of the annual life cycle: in active animals in summer, and in hibernating and awake animals in winter. It was found that the Mb content in winter, irrespective of the state of the animal (hibernating or awake), is 2.5-3-fold higher than in summer. Analysis of biochemical data available in the literature suggests that the increase in Mb content in winter is most probably related to a high oxygen demand of muscles at the first stage of arousal when the body temperature rises from 0 to 10-12 degrees C (non-shivering thermogenesis or thermoregulatory tonus). At this stage, the oxygen-dependent processes in muscles proceed under conditions of blocked peripheral blood flow and failure of anaerobic glycolysis. PMID: 9159866 [PubMed - indexed for MEDLINE] 188. Life Sci. 1997;61(7):703-9. The impact of beta-adrenergic blockade on daily rhythms of melatonin and body temperature of golden spiny mice Acomys russatus. Haim A(1), Zisapel N. Author information: (1)Department of Biology, University of Haifa at Oranim, Kiryat Tivon, Israel. zeac614@uvm.haifa.ac.il Beta-adrenergic stimulation induces melatonin synthesis and non-shivering thermogenesis (NST) in rodents. The golden spiny mouse, Acomys russatus is a nocturnal species capable of diurnal activity when coexisting with its congenitor the common spiny mouse A. cahirinus. We have investigated the impact of beta-adrenergic blockade on 6-sulphatoxymelatonin (6-SMT--a metabolite and index of melatonin production) and body temperature (Tb) daily rhythms in male A. russatus. Mice were acclimated to an ambient temperature (Ta) of 28 degrees C, under two photoperiod regimes (16L:8D; 8L:16D). The daily rhythms of Tb and urinary 6-SMT were measured for a period of 30 h at intervals of 4 h. Propranolol (4.5 mg/kg, i.p.) was administered one hour before lights went off (i.e. when beta blockade does not affect NST in this species) and both variables were measured for another 30 h. The beta blocker markedly augmented melatonin output of A. russatus under both photoperiod regimes. The elevation in melatonin secretion was accompanied with an increase in Tb of only 16L:8D-acclimated mice (i.e. shorten duration of melatonin peak). However, in 8L:16D-acclimated mice, a phase advance of about 4 h was noted in 6-SMT daily rhythm. These results indicate that the role of sympathetic innervation in regulation of melatonin synthesis in A. russatus differs from that in the rat. In addition, these data are compatible with the hyperthermic action of melatonin in this species. Therefore, it is suggested that in A. russatus, other neural pathways are involved in its pineal regulation. PMID: 9252245 [PubMed - indexed for MEDLINE] 189. Appetite. 1996 Jun;26(3):203-19. Cold-induced salt intake in mice and catecholamine, renin and thermogenesis mechanisms. Dejima Y(1), Fukuda S, Ichijoh Y, Takasaka K, Ohtsuka R. Author information: (1)Department of Human Ecology, Faculty of Health Sciences, Kyorin University, Tokyo, Japan. Cold induces increased intake of salt in mice. To examine involvement of renin and catecholamines, male ICR mice were exposed to cold (7-9 degrees C; 6 h/day; 4 days), and half of them were allowed to choose between water and 0.9% NaCl. Plasma renin activity (PRA) and catecholamine concentrations in plasma, adrenal gland, kidney, brown adipose tissue (BAT) and brain were examined in three phases: for 9 h before exposure to cold, during 6 h of cold exposure and for 9 h after the exposure. The amount of salt intake from NaCl solution and from food, PRA and noradrenaline (NE) concentrations in kidney and medulla oblongata were higher during cold and the 9 h after exposure to cold than during the 9 h before the exposure. These results are consistent with the suggestion that cold induced catecholamine metabolism enhanced activity in the renin-angiotensin system, which played an important role in the arousal of salt appetite. During cold exposure, concentrations of NE and dopamine in BAT were higher in mice with access to NaCl solution than those without NaCl to drink. These results suggest that cold-induced salt intake enhanced non-shivering thermogenesis, and are consistent with our previous report that high salt intake helped to maintain colonic temperature under cold exposure. PMID: 8800478 [PubMed - indexed for MEDLINE] 190. Soud Lek. 1996 May;41(2):20-2. Brown adipose tissue. III. Effect of ethanol, nicotine and caffeine exposure. Sidlo J(1), Zaviacic M, Trutzová H. Author information: (1)Institute of Pathology, Comenius University, Bratislava, Slovakia. Brown adipose tissue is known to be the most important organ for generating heat in non-shivering thermogenesis. Process of thermogenesis and thermoregulation may be affected by many drugs. The paper deals with actual literary data of effect of ethanol, nicotine and caffeine on brown adipose tissue, heat production and its regulation in experimental animals and in human. PMID: 9560910 [PubMed - indexed for MEDLINE] 191. Cesk Patol. 1996 Feb;32(1):45-7. Brown adipose tissue. II. Effect of pathologic and environmental conditions (Review). Sidlo J(1), Zaviacic M, Trutzová H. Author information: (1)Institute of Pathology, Comenius University, Bratislava, Slovakia. Brown adipose tissue is an important source of non-shivering thermogenesis. Its metabolic activity and development are regulated by adrenalin secretion. The greatest amount of brown adipose tissue in humans was observed during the first decade of life. Later it disappears from many sites, but is preserved in the neck and around the kidneys and the adrenal glands. Increased amounts of brown adipose tissue have been reported to occur in association with certain situations and diseases. A review of these literary data is presented. PMID: 9560896 [PubMed - indexed for MEDLINE] 192. J Comp Physiol B. 1996;166(4):286-93. Summer acclimatization in the short-tailed field vole, Microtus agrestis. McDevitt RM(1), Speakman JR. Author information: (1)Department of Zoology, University of Aberdeen, Scotland, UK. We investigated the changes that occurred in basal and noradrenaline-induced metabolic rate, body temperature and body mass in short-tailed field voles, Microtus agrestis, during exposure to naturally increasing photoperiod and ambient temperature. These parameters were first measured in winter-acclimatized voles (n = 8) and then in the same voles which had been allowed to seasonally acclimatize to photoperiod and ambient temperature (6 months later). Noradrenaline induced metabolic rate, basal metabolic rate and non-shivering thermogenesis were significantly higher in winter-acclimatized compared to summer-acclimatized voles. There was a significant positive relationship between basal metabolic rate and noradrenaline-induced metabolic rate. Body mass was significantly higher in summer-acclimatized compared to winter-acclimatized voles. There was a significant positive relationship between body mass and noradrenaline-induced metabolic rate in both winter-acclimatized and summer-acclimatized voles; however, there was no relationship between basal metabolic rate and body mass in either seasonal group of voles. Body temperature after measurements of basal metabolic rate was not significantly different in the seasonal cohorts of voles. However, body temperature was significantly higher in winter-acclimatized compared to summer-acclimatized voles after injection of noradrenaline. Previously we have found that a long photoperiod was not a sufficient stimulus to reduce thermogenic capacity in winter-acclimatized voles during cold exposure, since basal metabolic rate increased to compensate for a reduction in regulatory non-shivering thermogenesis. Here we found that a combination of increased ambient temperature and photoperiod did significantly reduce thermogenic capacity in winter-acclimatized voles. This provided evidence that the two aspects of non-shivering thermogenesis, obligatory and regulatory, are stimulated by different exogenous cues. Summer acclimatization in the short-tailed field vole is manifest as a significant decrease in both basal and noradrenaline-induced metabolic rate, combined with a significant increase in body mass. PMID: 8810068 [PubMed - indexed for MEDLINE] 193. Brain Res. 1995 Dec 8;702(1-2):49-54. Inhibition of shivering thermogenesis by centrally applied glucagon in muscovy ducklings. Montaron A(1), Rouanet JL, Barré H. Author information: (1)Laboratoire de Physiologie Générale et Comparée, Université Claude Bernard/Lyon, France. Glucagon has marked thermogenic and lipolytic effects in birds but could also be involved in the central modulation of neural activity on the basis of the recently discovered glucagon receptors in several areas of the brain in ducklings. The aim of this work was to investigate the possible role of these receptors in the modulation of thermogenic processes. Glucagon was infused into the lateral ventricle of the brain in ducklings after an acute cold exposure (4 degrees C, 2 h) or at thermoneutrality (25 degrees C). Electromyographic (EMG) data were simultaneously recorded with electrodes implanted in the gastrocnemius muscle. Glucagon (10(-4) M) was infused at a rate of 8 microliters/min. When acutely exposed to cold, ducklings increased their metabolic rate by shivering thermogenesis. A significant decrease in shivering activity was elicited after 5 min of glucagon infusion. After 16 +/- 2 min of glucagon infusion, shivering was completely inhibited, corresponding to a total dose of 36 +/- 4 micrograms/kg. The suppression of shivering was accompanied by a diminution of metabolic rate (5.3 +/- 0.3 vs. 8.5 +/- 0.2 W/kg, P < 0.05). The values of metabolic rate obtained at 4 degrees C after glucagon infusion were not significantly different from those measured at 25 degrees C before glucagon infusion (6.4 +/- 0.3 W/kg, P > 0.05). The infusion of the same dose of glucagon did not induce any change in EMG activity and resting metabolic rate at 25 degrees C. These findings suggest that glucagon infused into the brain has no thermogenic effect but could be involved in the central control of somatic motricity. Although the origin and the mechanisms of action of the endogenous peptide still remain unknown, glucagon might have a role in the development of non shivering thermogenesis during prolonged cold exposure via an inhibition of shivering in birds. PMID: 8846095 [PubMed - indexed for MEDLINE] 194. Indian J Exp Biol. 1995 Feb;33(2):105-8. Exercise induced changes in the energy expenditure of female Wistar rats. Pinto ML(1), Shetty PS. Author information: (1)Department of Physiology, St. John's Medical College, Bangalore. Changes in body weight and energy expenditure following exercise training was assessed in female Wistar rats. Rats were trained to swim in a tank filled with water for 2 hr everyday, 6 days a week. Changes in energy intake and body weight were recorded. The resting metabolic rate (RMR) was measured by indirect calorimetry and the capacity for non shivering thermogenesis (NST) was determined by measuring the stimulated oxygen consumption following a sc injection of norepinephrine (250 micrograms/kgbw). The RMR of exercised rats was 14% higher and the capacity for NST was 22% higher than that of sedentary rats. Energy intake of the exercised rats increased significantly while the body weights were maintained at levels comparable to that of the sedentary rats. Results indicate that body weight regulation is achieved by increasing food intake in response to the increased energy expenditure due to forced exercise as well as the stimulatory effect of exercise on RMR and NST. PMID: 7759122 [PubMed - indexed for MEDLINE] 195. J Exp Biol. 1995;198(Pt 2):561-5. Daily variations in the response of wood mice Apodemus sylvaticus to noradrenaline Haim A, Mcdevitt R, Speakman J. Non-shivering thermogenesis (NST) is an important mechanism for heat production in many small rodent species. Daily rhythms of body (rectal) temperature (Tb) reflect the relationship between heat production and heat dissipation. The roles of photoperiod and the time of day at which NST is measured were studied in wood mice Apodemus sylvaticus. Mice of both sexes (N=18) were acclimated to two different photoperiod regimes (16 h:8 h L:D and 8 h:16 h L:D) at a constant ambient temperature (Ta) of 24 °C. Non-shivering thermogenesis was measured as the maximal response of oxygen consumption (V(dot)O2NA) and body temperature (TbNA) to a noradrenaline (NA) injection (1.5 mg kg-1 subcutaneously) in unanaesthetized mice at three different times in the daily rhythm of Tb (N=6 in each group). Mice acclimated to 8 h:16 h L:D had a greater response to noradrenaline at the three different times of the day compared with those acclimated to 16 h:8 h L:D. The extent of the response to noradrenaline within each group varied with time of day; the smallest response was recorded at 18:00±1.5 h, and the greatest was at 01:00 h. These results suggest that photoperiod is an important cue for seasonal acclimatization in this species and that the response to noradrenaline follows a daily rhythm. PMID: 9318261 [PubMed - as supplied by publisher] 196. Tissue Cell. 1994 Oct;26(5):667-76. Quantitative evaluations of gap junctions in old rat brown adipose tissue after cold acclimation: a freeze-fracture and ultra-structural study. Barbatelli G(1), Heinzelmann M, Ferrara P, Morroni M, Cinti S. Author information: (1)Institute of Normal Human Morphology, University of Ancona, Italy. The morphological and functional modifications of brown adipose tissue (BAT), the tissue responsible for non-shivering thermogenesis, are well established during the phases of active stimulation (i.e. neonatal period and cold acclimation) in young animals. The 'active' brown adipocytes are filled with numerous small lipid vacuoles and large mitochondria packed with cristae rich in the protonophore uncoupling protein (UCP), whereas the 'quiescent' cell shows larger, confluent vacuoles and smaller mitochondria with rarefied cristae poor of the uncoupling protein. It is well known from literature that also gap junctions (gjs), responsible for the electrical coupling among adjacent adipocytes, modify their size following the physiological stimulus in young animals. This is in agreement with the morphology of the functionally active brown adipocyte, i.e. the multilocular, UCP-positive cell. Although the presence of the BAT in old animals is well documented, less is known about its reactivity to physiological stimuli. The present work demonstrates that after cold acclimation brown adipocytes of old rats (2 years) change their ultrastructure in a similar way as in young rats. A quantitative analysis of gap junction areas on replicas obtained by the freeze fracture technique, showed that gj increase in size (mean area 53.2 vs 110.4 x 10(-3) microns2, p = 0.003). All these morphological modifications are quite similar to those observed in BAT of young and young adult rats, supporting the hypothesis of a physiological role of brown adipose tissue at every age. PMID: 9437245 [PubMed - indexed for MEDLINE] 197. Brain Res. 1994 Sep 12;656(2):367-74. Activation of shivering and non-shivering thermogenesis by electrical stimulation of the lateral and medial preoptic areas. Thornhill J(1), Halvorson I. Author information: (1)Department of Physiology, University of Saskatchewan, Saskatoon, Canada. Experiments were conducted to determine if the area of stimulation within the preoptic area and/or the magnitude of the electrical stimulus applied to the preoptic region would selectively alter the evoked thermogenic responses of normothermic and hypothermic rats. Urethane anesthetized male, Long-Evans rats kept at 37 degrees C, and later cooled to 34 degrees C, were given unilateral electrical stimulation (0.5 ms pulses of 200 microA at 50 Hz for 30 and 300 s) into either the medial preoptic area (MPO) or the lateral preoptic area (LPO). Temperature changes of intrascapular brown adipose tissue, TIBATs; of gastrocnemius muscle, Tms, tail, Tts and colonic Tcs via thermistor probes were recorded before and after stimulation along with differential, multi-unit EMG activity of the gastrocnemius muscle via implanted stainless steel electrodes. The group kept at 37 degrees C and given MPO electrical stimulations evoked graded increases in TIBATs above core dependent on the duration of the electrical stimulus but shivering did not occur and Tms did not rise. When kept at 34 degrees C the MPO-stimulated group showed greater increases in TIBATs than respective responses seen when the same stimuli were applied at 37 degrees C. The group maintained at 37 degrees C and given LPO stimuli over 300 s increased Tms as shivering occurred, yet no change in TIBATs were observed. When cooled to 34 degrees C LPO stimulation (30 or 300 s duration) showed greater shivering activity. Interesting, LPO stimulation of animals maintained at 34 degrees C also caused TIBAT to increase.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 7820598 [PubMed - indexed for MEDLINE] 198. Hokkaido Igaku Zasshi. 1994 Sep;69(5):1102-14. [Regulatory mechanism of non-shivering thermogenesis in cold acclimation--with special reference to in vitro thermogenic activity and lipolysis of brown adipose tissue]. [Article in Japanese] Kikuchi K(1). Author information: (1)First Department of Physiology, Asahikawa Medical College, Japan. In vitro brown adipose tissue (BAT) thermogenesis from cold-acclimated (CA) rats has been shown to exhibit the decreased responses to noradrenaline (NA) and glucagon (G), although an enhanced biochemical machinery for thermogenesis develops in the tissue. The present study was undertaken to clarify the inhibitory mechanism of in vitro thermogenic responses of BAT in CA rats. NA-treated rats were injected NA (40 micrograms/100g BW) twice a day for 2 or 4 weeks. The other rats were kept at 25 +/- 1 degree C (warm controls: WC), 5 +/- 1 degree C (CA), or 5 +/- 1 degree C/6h/day (intermittent cold exposure: ICE) for 5-6 weeks. The oxygen consumption, and glycerol as well as free fatty acids (FFA) release were measured on finely minced tissue blocks in Krebs-Ringer phosphate buffer at 37 degrees C. In vitro BAT thermogenic responses to NA and G in NA-treated rats did not differ from those in vehicle-injected controls. NA as well as G increased-oxygen consumption was greatest in WC, followed by ICE and CA. NA as well as G increased glycerol and FFA releases in WC and ICE, but the degree of increment was greater in WC than that in ICE, while NA or G did not increase glycerol and FFA releases in CA. FFA/glycerol ratio in WC was decreased by NA as well as G, but it was not changed in ICE, and increased in CA. Mitochondrial GDP binding as an index of BAT thermogenic capacity did not differ between CA and WC under resting state (CA rats were transferred in warm condition before 18h at the beginning of the experiment), but it was significantly greater in ICE. GDP binding was significantly greater in CA sacrificed at 5 degrees C compared with WC and CA resting. Acute cold exposure (5 degrees C/1h) enhanced GDP binding in WC, resting CA and ICE resting, but the degree of increment was greater in CA and ICE than in WC. These findings suggest that cold exposure inhibits BAT thermogenic responses according to the duration NA action during cold exposure, by means of suppressing fatty acid utilization and/or masking uncoupling protein. PMID: 7868051 [PubMed - indexed for MEDLINE] 199. J Physiol. 1994 Aug 15;479 ( Pt 1):29-39. Effects of palmitoyl carnitine and related metabolites on the avian Ca(2+)-ATPase and Ca2+ release channel. Dumonteil E(1), Barré H, Meissner G. Author information: (1)Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill 27599-7260. 1. In birds, prolonged cold exposure induces the development of a non-shivering thermogenesis (NST) of muscular origin that may result from an increase in ATP-dependent cycling of Ca2+ between the sarcoplasmic reticulum (SR) and the cytosol. 2. Because fatty acids are thought to play a significant role in NST, we investigated the effects of palmitic acid and related metabolites on skeletal SR Ca2+ uptake and release in ducklings. 3. Ca(2+)-ATPase activity, 45Ca2+ release and [3H]ryanodine-binding measurements indicated that palmitic acid was without effect on the Ca(2+)-ATPase and Ca2+ release channel. Palmitoyl carnitine and palmitoyl coenzyme A inhibited the Ca(2+)-ATPase at concentrations > 20 microM whereas both activated the Ca2+ release channel at concentrations < or = 20 microM in a dose-dependent manner. 4. Palmitoyl carnitine stimulated [3H]ryanodine binding to skeletal but not cardiac SR vesicles. Induction of 45Ca2+ release was observed with long-chain (C > or = 14) but not with short-chain acyl carnitines (C < or = 12). 5. Long-chain acyl carnitines accumulated significantly in duckling skeletal muscle during cold acclimation. Accordingly, these results suggest that long-chain acyl metabolites may modulate SR Ca2+ cycling and its associated thermogenesis in vivo. PMCID: PMC1155723 PMID: 7990033 [PubMed - indexed for MEDLINE] 200. Brain Res. 1994 Jul 18;651(1-2):148-54. Non-shivering thermogenesis during prostaglandin E1 fever in rats: role of the cerebral cortex. Monda M(1), Amaro S, De Luca B. Author information: (1)Department of Human Physiology, Faculty of Medicine and Surgery, Second University of Naples, Italy. We have tested the hypothesis that there is a role for the cerebral cortex in the control of non-shivering thermogenesis during fever induced by prostaglandin E1 (PGE1). While under urethan anesthesia, the firing rate of nerves innervating interscapular brown adipose tissue (IBAT), IBAT and colonic temperatures (TIBAT and Tc) and oxygen (O2) consumption were monitored during the fever from PGE1 injection (400 and 800 ng) in a lateral cerebral ventricle in controls and in functionally decorticated Sprague-Dawley rats. Rats were functionally decorticated by applying 3.3 M KCl solution on the frontal cortex which causes cortical spreading depression (CSD). Pyrogen injections caused dose-related increases in firing rate, TIBAT, Tc and O2 consumption and CSD reduced these enhancements. Our findings indicate that the cerebral cortex could be involved in the control of non-shivering thermogenesis during PGE1-induced febrile response. PMID: 7922562 [PubMed - indexed for MEDLINE] 201. Respir Physiol. 1994 Jun;97(1):79-91. Ventilatory and metabolic responses to cold and CO-induced hypoxia in awake rats. Gautier H(1), Bonora M. Author information: (1)Faculté de Médecine Saint-Antoine, Paris, France. Experiments were carried out in awake rats to compare the effects of ambient and CO-induced hypoxia on thermoregulation and ventilatory control. Measurements of metabolic rate (VO2), ventilation (V), shivering (EMG) and colonic temperature (Tc) were made at fixed ambient temperature (Ta) of 25, 15 and 5 degrees C. Animals were exposed to ambient hypoxia (FIO2 of 21, 17, 14, 12 and 10%) or to CO hypoxia (FICO of 0.03% in air). The results show that: (1) Both ambient and CO-induced hypoxia provoked decreases in VO2 and Tc which were more marked at low Ta values; non-shivering thermogenesis was depressed with both types of hypoxia, whereas shivering was depressed only with ambient hypoxia; (2) Ventilatory response to ambient hypoxia was blunted at low Ta values and CO-induced hypoxia did not affect ventilation. It is concluded that: (1) hypoxia affects markedly the control of Tc by altering thermogenesis: inhibition of non-shivering thermogenesis seems to result from a decrease in CaO2 whereas inhibition of shivering seems to result from a decrease in PaO2; (2) during hypoxia, ventilation is controlled by the opposite stimulation from chemoreceptors and inhibition from hypometabolism. However, as revealed by CO-induced hypoxia, another stimulatory factor may also interact with the control of breathing. PMID: 8091026 [PubMed - indexed for MEDLINE] 202. J Comp Physiol B. 1994;163(8):664-70. Effect of unilateral surgical denervation of brown adipose tissue on uncoupling protein mRNA level and cytochrom-c-oxidase activity in the Djungarian hamster. Klingenspor M(1), Meywirth A, Stöhr S, Heldmaier G. Author information: (1)Philipps-Universität Marburg, Department of Zoology, Germany. The bilateral lobe of interscapular brown adipose tissue of the Djungarian hamster was unilaterally denervated in order to study the role of the sympathetic innervation for maintenance and cold-induced increase of non-shivering thermogenesis. Denervation decreased the noradrenaline content of brown adipose tissue to less than 9% of the intact contralateral pad. This low noradrenaline level was maintained for 1-14 days after denervation. First, to study the role of the sympathetic innervation of brown adipose tissue in the maintenance of the high thermogenic capacity characteristic of the cold acclimated state, brown adipose tissue was denervated in hamsters either kept at thermoneutrality or acclimated to 5 degrees C ambient temperature for 4 weeks. Cold-acclimated hamsters had elevated levels of uncoupling protein messenger ribonucleic acid (8.1-fold) and cytochrom-c oxidase-activity (3-fold). Denervation of brown adipose tissue decreased uncoupling protein-messenger ribonucleic acid level and cytochrom-c-oxidase-activity as compared to the intact pad in thermoneutral and in cold-acclimated hamsters. However, in cold-acclimated hamsters uncoupling protein-messenger ribonucleic acid level and cytochrom-c-oxidase-activity in denervated brown adipose tissue both were maintained on an elevated 6-fold higher level as compared to thermoneutral controls. Second, to study the role of the sympathetic innervation of brown adipose tissue in the cold-induced increase in thermogenic capacity, hamsters were denervated prior to cold acclimation and responses were measured after 3 and 14 days of cold exposure. Uncoupling protein-messenger ribonucleic acid level and cytochrom-c-oxidase-activity of intact brown adipose tissue increased after 14 days cold acclimation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 8195470 [PubMed - indexed for MEDLINE] 203. FEBS Lett. 1993 Dec 20;336(1):90-4. A threshold membrane potential accounts for controversial effects of fatty acids on mitochondrial oxidative phosphorylation. Köhnke D(1), Ludwig B, Kadenbach B. Author information: (1)Fachbereich Chemie, Philipps-Universität, Marburg, Germany. The uncoupling effect of free fatty acids on oxidative phosphorylation in mitochondria has been known for more than 35 years. The mechanism of action, however, remains controversial. In this report the physicochemical basis of uncoupling was elucidated by studying the effect of free fatty acids on the proton permeability and membrane potential of proteoliposomes containing reconstituted cytochrome c oxidase (COX). A threshold membrane potential of about 125 mV was identified for fatty acid-induced proton permeability. Only above this potential do free fatty acids translocate protons across the biological membrane. The data explain the controversial effects of long-chain fatty acids on oxidative phosphorylation as well as their role on non-shivering thermogenesis in larger mammals. PMID: 8262225 [PubMed - indexed for MEDLINE] 204. Comp Biochem Physiol B. 1993 Sep;106(1):95-101. Effect of cold acclimation on oxidative capacity and respiratory properties of liver and muscle mitochondria in ducklings, Cairina moschata. Goglia F(1), Lanni A, Duchamp C, Rouanet JL, Barré H. Author information: (1)Dipartimento di Fisiologia Generale ed Ambientale Università di Napoli, Italy. 1. The effect of cold acclimation on the oxidative capacity of the skeletal muscle (gastrocnemius and pectoralis) and the liver of ducklings was investigated. 2. In cold-acclimated (CA) ducklings, the oxidative capacity of the liver was higher (+40%) than in ducklings reared at thermoneutraility (TN). In these animals an increase in state 4 respiration and a decrease in the respiratory control index (RCI) was also found. 3. The oxidative capacity of both pectoralis and gastrocnemius muscles also increased in CA animals. 4. In these muscles the oxidatibe capacity of the subsarcolemmal mitochrondrial fraction of CA ducklings was higher (+96% in the gastrocnemius and +58% in the pectoralis) than the intermyofibrillar one (+51% in the gastrocnemius and +33% in the pectoralis). No variations were observed in either the RCI or the ADP/O ratios. 5. These findings indicate that the energy expenditure needed for non-shivering thermogenesis (NST) in cold-acclimated ducklings can be met by the increase in the oxidative capacity of the skeletal muscle and the liver, each by different mechanisms; the gastrocnemius muscle would seem to play a prominent role. PMID: 9445773 [PubMed - indexed for MEDLINE] 205. Pathol Res Pract. 1993 Feb;189(1):73-82. Differentiation of brown adipose cells in three-dimensional collagen gel culture. Hikichi Y(1), Sugihara H, Sugimoto E. Author information: (1)Department of Pathology, Saga Medical School, Japan. Brown adipose cells are heat-producing cells through non-shivering thermogenesis by intramitochondrial "thermogenin". This specific protein is a marker for their cellular differentiation. It has long been known that cultured brown adipose cells in monolayer rapidly lose the thermogenin bioactivity. In this study, we cultured brown adipose cells in three-dimensional type I collagen gel matrix. Under this culture condition, they were able to survive, and differentiated morphologically and functionally for a long period of time, especially exhibited the characteristic immunohistochemical activity of thermogenin. These findings suggest that brown adipose cells differentiate in type I collagen gel. In this condition, cholera toxin or BRL 37344, one of beta 3-adrenoceptor agonists, specifically stimulated the brown adipose cells. PMID: 8516219 [PubMed - indexed for MEDLINE] 206. J Comp Physiol B. 1993;163(7):602-7. Comparative thermoregulatory adaptations of field mice of the genus Apodemus to habitat challenges. Haim A(1), Rubal A, Harari J. Author information: (1)Department of Biology, University of Haifa at Oranim, Israel. Thermoregulatory abilities, which may play a role in physiological adaptations, were compared between two field mouse species (Apodemus mystacinus and A. hermonensis) from Mount Hermon. While A. hermonensis is common at altitudes above 2100 m, A. mystacinus is common at 1650 m. The following variables were compared in mice acclimated to an ambient temperature of 24 degrees C with a photoperiod of 12L:12D, body temperature during exposure to 4 degrees C for 6 h, O2 consumption and body temperature at various ambient temperature, non-shivering thermogenesis measured as a response to a noradrenaline injection, and the daily rhythm of body temperature. Both species could regulate their body temperature at ambient temperatures between 6 and 34 degrees C. The thermoneutral zone for A. mystacinus lies between 28 and 32 degrees C, while for A. hermonensis a thermoneutral point is noted at 28 degrees C. Both species increased O2 consumption and body temperature as a response to noradrenalin. However, maximal VO2 consumption as an response to noradrenaline and non-shivering thermogenesis capacity were higher in A. mystacinus, even though A. hermonensis is half the size of A. mystacinus. The body temperature rhythm in A. hermonensis has a clear daily pattern, while A. mystacinus can be considered arhythmic. The results suggest that A. hermonensis is adapted to its environment by an increase in resting metabolic rate but also depends on behavioural thermoregulation. A. mystacinus depends more on an increased non-shivering thermogenesis capacity. PMID: 8151019 [PubMed - indexed for MEDLINE] 207. J Comp Physiol B. 1993;163(7):546-55. Metabolism, thermogenesis and daily rhythm of body temperature in the wood lemming, Myopus schisticolor. Saarela S(1), Hissa R. Author information: (1)University of Oulu, Department of Zoology, Finland. Wood lemmings (Myopus schisticolor) were captured during their autumnal migration in September and October. The animals were maintained at 12 degrees C and under 12L:12D photoperiod. Basal metabolic rate and thermogenic capacity of the wood lemming were studied. Basal metabolic rate was 3.54 ml O2.g-1.h-1, which is 215-238% of the expected value. The high basal metabolic rate seems to be typical of rodents living in high latitudes. The body temperature of the wood lemming was high (38.0-38.8 degrees C), and did not fluctuate much during the 24-h recording. The high basal metabolic rate and the high body temperature are discussed with regard to behavioural adaptation to a low-quality winter diet. Thermogenic capacity, thermal insulation and non-shivering thermogenesis of the wood lemming displayed higher values than expected: 53.0 mW.g-1, 0.53 mW.g-1.degrees C-1 and 53.2 mW.g-1, respectively. Brown adipose tissue showed typical thermogenic properties, although its respiratory property was fairly low, but mitochondrial protein content was high compared to other small mammals. The 24-h recording of body temperature and motor activity did not reveal whether the wood lemming is a nocturnal animal. Possibly, the expression of a circadian rhythm was masked by peculiar feeding behaviour. It is concluded that the wood lemming is well adapted to living in cold-temperature climates. PMID: 8151013 [PubMed - indexed for MEDLINE] 208. J Physiol. 1992 Nov;457:27-45. Histochemical arguments for muscular non-shivering thermogenesis in muscovy ducklings. Duchamp C(1), Cohen-Adad F, Rouanet JL, Barré H. Author information: (1)Laboratoire de Thermorégulation et Energétique de l'Exercise, URA 1341 CNRS, Lyon, France. 1. The histochemical characteristics of gastrocnemius muscle were investigated in 6-week-old cold-acclimated (5 weeks, 4 degrees C) and glucagon-treated (5 weeks, 25 degrees C, 103 nmol/kg I.P. twice daily) muscovy ducklings, two groups able to develop non-shivering thermogenesis in vivo. A comparison was made with thermoneutral controls (25 degrees C) of the same age. All animals were fed ad libitum. Fibre type, fibre area and capillary supply have been studied. Further, a quantitative histochemical method for mitochondrial Mg(2+)-ATPase activity was developed to characterize the mitochondrial coupling state in situ. 2. White gastrocnemius was composed of fast glycolytic (FG) and fast oxidative glycolytic (FOG) fibres, while red gastrocnemius contained FOG and slow oxidative (SO) fibres. In white gastrocnemius, the proportion of FG fibres was higher in glucagon-treated than in control or cold-acclimated ducklings. In red gastrocnemius, the proportion of SO fibres was higher in both cold-acclimated and glucagon-treated ducklings than in controls. The area of all fibres was generally lower in glucagon-treated than in other ducklings. 3. The capillary density was higher in both red and white components of the gastrocnemius muscle in cold-acclimated and glucagon-treated than in control ducklings, as a result of an increased number of capillaries around each fibre. 4. In all fibres, except the FG type in cold-acclimated ducklings, the staining intensity of the Mg(2+)-ATPase reaction was higher in cold-acclimated and glucagon-treated than in control ducklings whereas the staining intensity with maximal decoupling of oxidative phosphorylation by dinitrophenol was unchanged. This indicated a more loose-coupled state of mitochondria in situ in all fibres of cold-acclimated ducklings, and in FOG fibres of white gastrocnemius and SO fibres of red gastrocnemius in glucagon-treated ducklings. 5. These results indicated a higher oxidative metabolism of skeletal muscle in both cold-acclimated and glucagon-treated than in control ducklings, and for most of the parameters studied, a similarity between cold acclimation and glucagon treatment. Because of the higher loose-coupled state of muscle mitochondria in cold-acclimated and glucagon-treated than in control ducklings, the higher oxidative capacity of skeletal muscle in these ducklings could be used for heat production rather than ATP synthesis and account for muscular non-shivering thermogenesis. PMCID: PMC1175716 PMID: 1297835 [PubMed - indexed for MEDLINE] 209. J Physiol. 1992 Sep;455:487-502. Effect of maternal cold exposure on brown adipose tissue and thermogenesis in the neonatal lamb. Symonds ME(1), Bryant MJ, Clarke L, Darby CJ, Lomax MA. Author information: (1)Department of Biochemistry & Physiology, School of Animal and Microbial Sciences, University of Reading, Whiteknights. 1. This study examines the effect of chronic cold exposure during pregnancy, induced by winter shearing twin-bearing ewes 4 weeks before predicted lambing date, on O2 consumption and CO2 production during non-rapid-eye-movement (REM) sleep in lambs maintained for at least 1 h at warm (28-18 degrees C) and cold (14-5 degrees C) ambient temperatures at 1, 4, 14 and 30 days of age. This was combined with measurement of the thermogenic activity (GDP binding to uncoupling protein in mitochondrial preparations) of perirenal adipose tissue from lambs immediately after birth and at 33 days of age. 2. Lambs born from shorn (cold-exposed) ewes were 15% heavier (P < 0.01) and possessed 21% (P < 0.01) more perirenal adipose tissue that contained 40% more protein and mitochondrial protein than unshorn (P < 0.05) controls. Total GDP binding in perirenal adipose tissue was 40% greater (P < 0.05) in lambs born from shorn ewes but there was no difference in lipid content of this tissue between the two groups. 3. At 1 day of age, lambs born from shorn ewes exhibited a 16% higher (P < 0.05) rate of O2 consumption (per kilogram bodyweight) at the warm temperature and a 40% greater metabolic response to the cold ambient temperature. All lambs born from shorn ewes responded to cold exposure without shivering (i.e. via non-shivering thermogenesis) whilst shivering was measured in four out of seven lambs in the unshorn group. These differences had disappeared by 4 days of age as a result of a 25% increased (P < 0.01) rate of O2 consumption in the warm in lambs born from unshorn ewes and a 20% decrease (P < 0.05) in the response to the cold in lambs from shorn ewes. Shivering during cold exposure was measured in six out of nine lambs born from shorn ewes indicating a rapid alteration in thermoregulatory responses to cold during the first few days of life. 4. The levels of GDP binding and mitochondrial protein in perirenal adipose tissue fell by one-third in both groups of lambs during the first 33 days of life whereas lipid content either increased or was unchanged. This indicated that brown adipose tissue (BAT) was developing the characteristics of white adipose tissue.(ABSTRACT TRUNCATED AT 400 WORDS) PMCID: PMC1175656 PMID: 1484361 [PubMed - indexed for MEDLINE] 210. Biochem Biophys Res Commun. 1992 Jun 30;185(3):1078-82. Cold exposure increases glucose utilization and glucose transporter expression in brown adipose tissue. Nikami H(1), Shimizu Y, Endoh D, Yano H, Saito M. Author information: (1)Department of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan. When rats were exposed to a cold environment (4 degrees C) for 10 days, tissue glucose utilization was increased in brown adipose tissue (BAT), a tissue specified for non-shivering thermogenesis, but not in skeletal muscle. Cold exposure also caused an increase in the amount of GLUT4, an isoform of glucose transporters expressed in insulin-sensitive tissues, in parallel with an increased cellular level of GLUT4 mRNA. In contrast to BAT, no significant effect of cold exposure was found in skeletal muscle. The results suggest the cold-induced increase in glucose utilization by BAT is attributable, at least in part, to the increased expression of GLUT4. PMID: 1378263 [PubMed - indexed for MEDLINE] 211. Early Hum Dev. 1992 Jun-Jul;29(1-3):63-73. The placenta, PGE2 and parturition. Thorburn GD(1). Author information: (1)Department of Physiology, Monash University, Clayton, Victoria, Australia. It is proposed that prostaglandin E2 (PGE2), secreted by the fetal placenta of the sheep, acts as a circulating regulator of the physiological function of many fetal organs (tissue) in a way analogous to catecholamines in the adult. The specificity of PGE2 action in different tissues is determined by three different receptor subtypes which regulate intracellular calcium concentrations via the IP3 pathway, or cyclic AMP concentrations via the adenylcyclase system. The placenta, by secreting PGE2 (and possibly other factors such as adenosine), modifies the function of key organ systems allowing the fetus to survive and develop in the aqueous environment of the uterus. During fetal development, fetal organs and metabolic pathways can mature while their function is suppressed by placental PGE2. At birth, by ligating the cord and removing the placenta as the source of these inhibitory substances, the newborn is able to adapt readily to its new environment with fully-functional, mature organ systems. This paper discusses how placental PGE2 may regulate fetal breathing movements, whether the removal of placental PGE2 is involved in the initiation of continuous breathing at birth, and whether it suppresses the activity of the peripheral chemoreceptors during fetal life. The ability of PGE2 to maintain a widely patent ductus arteriosus, to suppress non-shivering thermogenesis, to stimulate fetal insulin secretion and to suppress the hepatic gluconeogenic pathway in the fetus is also discussed. Finally, the ability of PGE2 to activate the fetal hypothalamo-pituitary-adrenal axis is discussed, raising the possibility that the placenta also plays a key role in the initiation of birth in this species. PMID: 1327713 [PubMed - indexed for MEDLINE] 212. Respir Physiol. 1992 Mar;87(3):309-24. Control of metabolic and ventilatory responses to cold in anesthetized cats. Gautier H(1), Bonora M, Lahiri S. Author information: (1)Laboratoire de Physiologie Respiratoire, Faculté de Médecine Saint-Antoine, Paris, France. Interactions between the control of thermogenesis and ventilation were studied during normoxia, hyperoxia, and ambient or CO hypoxia in adult anesthetized intact or carotid-denervated cats. Shivering, metabolic and ventilatory responses to cold stress were studied. In addition, the effects of transient pharmacological stimulation (NaCN) or inhibition (Dopamine) of arterial chemoreceptor activity were studied under different levels of oxygenation. In intact animals, cold exposure provoked increases in VO2 and ventilation which were directly proportional to the intensity of shivering. During ambient or CO hypoxia, VO2 was less than in normoxia for all values of shivering intensity, suggesting that a non-shivering thermogenesis component may also be inhibited by hypoxia. The decrease in VO2 was associated with a smaller decrease in ventilation in ambient than in CO hypoxia because of the presence of the chemoreflex drive during ambient hypoxia. Pharmacological changes in chemoreceptor activity induced transient and opposite changes in ventilation and shivering intensity, confirming their role in the control of thermogenesis. After carotid denervation, when the drug effects were inconsistent or absent, changes in levels of oxygenation were still followed by changes in shivering activity and associated changes in VO2 and ventilation. We conclude that control of thermogenesis and ventilation and their interaction may be mediated by chemoreceptors as well as by direct effects upon central, possibly diencephalic structures. PMID: 1604055 [PubMed - indexed for MEDLINE] 213. Proc Biol Sci. 1992 Feb 22;247(1319):83-7. The ontogeny of peroxisome-proliferator-activated receptor gene expression in the mouse and rat. Beck F(1), Plummer S, Senior PV, Byrne S, Green S, Brammar WJ. Author information: (1)Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Victoria, Australia. The expression of the gene coding for peroxisome-proliferator-activated receptor (PPAR), a novel transacting factor belonging to the steroid superfamily, has been determined in the mouse and rat throughout development using hybridization histochemistry. Messenger RNA is demonstrable in the liver and brown fat from the fetal period onwards and, additionally, in the heart, kidney and gut post-natally. It is proposed that the upregulation of transcription of peroxisomal beta oxidation genes in specific tissues follows binding of the receptor to its natural ligand. Thus PPAR may have an important role in cold adaptation and non-shivering thermogenesis as well as in detoxification. PMID: 1349185 [PubMed - indexed for MEDLINE] 214. Comp Biochem Physiol Comp Physiol. 1992 Feb;101(2):281-93. Localization, cellular morphology and respiratory capacity of "brown" adipose tissue in newborn reindeer. Soppela P(1), Sormunen R, Saarela S, Huttunen P, Nieminen M. Author information: (1)Finnish Game and Fisheries Institute, Reindeer Research, Rovaniemi, Finland. 1. The localization and cellular morphology of adipose tissue was studied by light, fluorescence and electron microscopy in reindeer between 2 weeks pre partum and 4.5 months post partum during calving, and the subsequent growth period. The respiratory capacity of the adipose tissue was examined in terms of morphometric mitochondrial volume and cytochrome-c oxidase or succinate dehydrogenase activity. 2. Adipose tissue was located at specific anatomical sites in the newborn reindeer (from 0 to 2 days of age). The perirenal-abdominal depot was the largest location (32%) followed by the inter(pre)scapular (18%) and sternal (12%) depots. Internal depot dominated over external or peripheral depots (66-34%). The locations of adipose tissue were largely similar in foetal, newborn and young reindeer. 3. The adipose tissue of the newborn reindeer had all the typical cell morphological characteristics of brown adipose tissue: abundant mitochondria, multilocular fat, high vascularization and a dense spot-like sympathetic innervation between the adipocytes. In the young reindeer, however, it resembled white adipose tissue, being almost totally unilocular with few mitochondria. 4. There was a significant correlation between morphometric mitochondrial volume and cytochrome-c oxidase activity (r = 0.848) in the adipose tissue. Mitochondrial volume, cytochrome-c oxidase and succinate dehydrogenase activity were highest after birth and decreased to almost an undetectable level during the first month. A parallel decrease occurred in the amount of brown adipose tissue from birth (1-2%) to the age of about one month (0.3%). 5. It is concluded that the distinct cell morphological features and high respiratory capacity of the adipose tissue indicate the presence of brown adipose tissue at specific anatomical locations in newborn reindeer. A marked progression towards the characteristics of white adipose tissue then takes place at the same locations during the first month. The results suggest the fundamental significance of brown adipose tissue for non-shivering thermogenesis in newborn reindeer. PMID: 1348462 [PubMed - indexed for MEDLINE] 215. J Comp Physiol B. 1992;162(8):740-6. The relative importance of photoperiod and temperature as cues for seasonal acclimation of thermoregulation in pouched mice (Saccostomus campestris: Cricetidae) from southern Africa. Ellison GT(1), Skinner JD, Haim A. Author information: (1)Mammal Research Institute, University of Pretoria, Republic of South Africa. The effect of short photoperiod and cold on metabolism and thermoregulation was investigated in pouched mice (Saccostomus campestris: Cricetidae) from three localities in southern Africa which experience contrasting climatic conditions. Mice were initially acclimated to long photoperiod (14L: 10D) at 25 degrees C, followed first by a decline in photoperiod (to 10L: 14D) and then by a fall in temperature (to 10 degrees C). Minimum observed metabolic rate (identical to basal metabolic rate) was unaffected by the decline in photoperiod but increased significantly following cold acclimation. Because minimal thermal conductance remained constant throughout the study the increase in minimum observed metabolic rate caused a decline in lower critical temperature to around 26 degrees C. In contrast to minimum observed metabolic rate, regulatory non-shivering thermogenesis improved significantly following the decline in both photoperiod and temperature. However, pouched mice from the warmest locality were significantly less responsive to photoperiod than those from the other two localities whose survival might depend upon their ability to accurately predict seasonal changes in temperature. Neither photoperiod nor temperature had any effect on body mass, yet pouched mice from the most arid locality, where food supply might be unpredictable, were significantly smaller and had lower total energy requirements than those from areas experiencing higher annual rainfall. These results indicate that S. campestris displays considerable geographical variation in energy requirements together with differences in the use of photoperiod as an anticipatory cue for predicting the onset of winter. These differences appear to be related to the availability of energy and the relative severity of climatic conditions in each locality. PMID: 1494031 [PubMed - indexed for MEDLINE] 216. Nihon Naibunpi Gakkai Zasshi. 1991 Nov 20;67(11):1252-62. [The influence of the sympathetic nervous system on brown adipose tissue: an experimental and histopathologic study on aging]. [Article in Japanese] Mamiya Y(1), Suzuki M, Namima M, Ouno H. Author information: (1)Department of Pathology, National Defense Medical College, Tokorozawa, Japan. Brown adipose tissue (BAT) is known to be a principal energy source of non-shivering thermogenesis and related diet-induced thermogenesis. These regulate body temperature and body weight and are controlled by the dissipation of excessive dietary caloric intake. We carried out histopathologic, immunohistochemical and biochemical studies of BAT in rats in relation to aging changes. Four groups of Donryu strain male rats (5 each of 1 month, 2 months, 4 months and 20 months of age) were used. They had been given commercial chow and tap water ad libitum and were kept in an air-conditioned room. Body weight (BW), interscapular BAT weight (IBATW) and g IBATW/g BW of rats were measured. Nor-adrenalin (NA), and dopamine-beta-hydroxylase (DBH) of IBAT were determined. To evaluate the catecholaminergic effects of BAT, morphometric quantitation of BAT was carried out based on the cytoplasmic locularity of fat globules in the BAT cells. Distribution of DBH in BAT was assessed immunohistochemically by the avidin biotin peroxidase complex method. With the use of statistical analysis of variance procedure, there were highly significant decreases in the ratio of g IBATW/g BW (p less than 0.0001) and in the concentrations of NA (p less than 0.0001) and DBH (p less than 0.01) between young (weaning at 1 month old) rats and adult (aged from 4 to 20 months) rats. In the morphometric measurement, by the statistical analysis system (SAS) Spearman correlation coefficient method, there was a significant increase of Type 5 cell (monocular brown adipose tissue cell) in 4 month and 20 month rats, compared to 1 month and 2 month rats (p less than 0.05). Immunohistochemical study of BAT showed localization of DBH in perivascular mesenchymal cells which corresponded with the morphologic distribution of catecholamine as reported by Lever. The results suggest that in the processes of aging in the rat there are reductions in the ratio of g IBATW/g BW, NA and the activity in DBH. PMID: 1761139 [PubMed - indexed for MEDLINE] 217. J Physiol. 1991 Oct;442:337-49. Nucleus tractus solitarii lesions alter the metabolic and hyperthermic response to central prostaglandin E1 in the rat. Fyda DM(1), Cooper KE, Veale WL. Author information: (1)Department of Medical Physiology, Faculty of Medicine, University of Calgary, Alberta, Canada. 1. Given that the nucleus tractus solitarii (NTS) may regulate the ability of brown adipose tissue to evoke non-shivering thermogenesis and that brown fat may mediate the rise in whole-body metabolism observed following central pyrogen administration, we assessed whether interruption of baroreceptor afferents coursing though the NTS would interfere with the ability of prostaglandin E1 to evoke a normal fever response profile. 2. Infusion of 150-600 ng of prostaglandin E1 (PGE1) into a lateral cerebral ventricle of the conscious rat resulted in a rise in core temperature, and also an increase in whole-body metabolic rate, brown adipose tissue temperature, arterial blood pressure and heart rate. 3. Following bilateral electrolytic lesions to the NTS, resting core and brown fat temperatures, metabolic rates, blood pressures and heart rates in the NTS-lesioned animals were comparable to control rats. However, the PGE1-evoked increase in metabolic rate, along with the rise in core and brown adipose tissue temperatures and heart rate were attenuated. The pressor response was, however, enhanced, possibly due to the demonstrated interference by the lesions with normal baroreflex control. 4. The findings suggest that the nucleus tractus solitarii region of the rats' brain may be important in mediating the thermogenesis evoked by central PGE1. PMCID: PMC1179892 PMID: 1798032 [PubMed - indexed for MEDLINE] 218. Trans R Soc Trop Med Hyg. 1991 Sep-Oct;85(5):605-7. Accumulation of brown adipose tissue in patients with Chagas heart disease. Soares FA(1), Silveira TC. Author information: (1)Department of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil. Brown adipose tissue (BAT) is an important source of non-shivering thermogenesis. Increased BAT amounts have been reported to occur in association with several diseases, including congestive heart failure. The objective of the present study was to determine whether BAT accumulation occurs in patients with Chagas disease. Histological sections of peri-adrenal tissue obtained at autopsy from 259 patients were examined. Of these patients, 58 had the digestive form of Chagas disease, 50 had the cardiac form without heart failure and 201 had the cardiac form with heart failure. All cases were investigated in terms of nutritional status and classified as malnourished, normotrophic or obese according to the Quetelet index. The results showed no correlation between BAT and the patients' nutritional status, and more BAT accumulation in patients with the cardiac form of Chagas disease compared to patients with the digestive form. Similarly, a history of heart failure was correlated with greater BAT accumulation. On the basis of the present data and of information reported in the literature, we propose that chronic hypoxia may be the cause of BAT accumulation in Chagas disease patients with heart failure. PMID: 1780987 [PubMed - indexed for MEDLINE] 219. Int J Biometeorol. 1991 Sep;35(2):98-102. Seasonal energy requirements and thermoregulation of growing pouched mice, Saccostomus campestris (Cricetidae). Ellison GT(1), Skinner JD. Author information: (1)Mammal Research Institute, University of Pretoria, Republic of South Africa. Pouched mice (Saccostomus campestris) were born in captivity during January and March and subsequently maintained under long photoperiod (14 h light: 10 h dark) at 25 degrees C. During their first winter (July) and the following summer (January) the pouched mice were exposed to natural photoperiod in an unheated laboratory for 3 weeks prior to measurement. The pouched mice continued to grow during the study, and were significantly heavier after summer exposure than after winter exposure 6 months earlier. Although this increase in body mass would result in a decline in their surface area to volume ratio there was no significant decline in minimal thermal conductance (Cm) and winter-exposed pouched mice had a relatively lower Cm than expected. Meanwhile the smaller, winter-exposed animals displayed a significantly higher capacity for non-shivering thermogenesis, together with higher levels of basal metabolism than summer individuals. These differences were not solely attributable to the contrasting body mass of each group and it is therefore clear that S. campestris can increase thermoregulatory heat production, and modify heat loss following exposure to short photoperiod and cold during their first winter. Despite the significant increase in metabolism, the overall energy requirements of small, winter-exposed animals were significantly lower than those for heavier pouched mice following exposure to summer conditions. These results suggest that growing pouched mice can effectively adapt to lower temperature conditions during their first winter, yet accrue considerable overall savings in total energy requirements as a result of their smaller body mass. PMID: 1743777 [PubMed - indexed for MEDLINE] 220. J Dev Physiol. 1991 Apr;15(4):229-35. Fever in young lambs: temperature, metabolic and cardiorespiratory responses to a small dose of bacterial pyrogen. Fewell JE(1), Ricciuti F, Kondo CS, Dascalu V. Author information: (1)Department of Obstetrics and Gynaecology, University of Calgary, Alberta, Canada. Experiments were done on ten lambs ranging in age from 15 to 25 days to define the temperature, metabolic and cardiorespiratory responses to intravenous administration of a small dose of bacterial pyrogen (SAE). Administration of SAE but not normal saline produced a short-lived fever of about 0.7 degrees C. The increase in body-core temperature was preceded by a surge in total body oxygen consumption and the onset of shivering which was influenced by behavioral state (ie, shivering was inhibited during active sleep). The increase in total body oxygen consumption was initially met by an increase in total body oxygen extraction and then by an increase in systemic oxygen delivery. Systemic arterial blood pressure did not change significantly during the febrile response; however, pulmonic arterial blood pressure increased significantly. Thus, our experiments provide new data on oxygen supply and demand during the development of fever and that shivering thermogenesis is inhibited in active sleep following the administration of bacterial pyrogen in young lambs. The influence of active sleep on the overall febrile response, and whether or not there is a shift from shivering thermogenesis to non-shivering thermogenesis remains to be determined. PMID: 1940150 [PubMed - indexed for MEDLINE] 221. Turk J Pediatr. 1991 Apr-Jun;33(2):121-34. Neonatal thermoregulation. Risbourg B(1), Vural M, Kremp O, de Broca A, Leke L, Freville M. Author information: (1)Department of Pediatrics, Picardie University Faculty of Medicine, Amiens, France. The human being is a homeotherm. Homeothermy is a result of thermoregulation which includes many physiological processes. Thermoregulation maintains an equilibrium between heat production (thermogenesis) and heat loss (thermolysis). There are three principal modes of heat production: 1. Voluntary muscle activity. 2. Involuntary tonic or rhythmic muscle activity known as "shivering". 3. Non-shivering thermogenesis (NST) essential for newborns. Heat loss occurs in two stages: 1. The flow of heat from the center of the body to its surface. 2. The flow of heat from the body surface to the environment by conduction, convection, radiation or water evaporation. Even in the very small premature baby, we find that metabolic and vasomotor control responses are developed. To protect the newborn from stress resulting from hypo or hyperthermia, one should take into consideration the concept of the neutral temperature range which is also called the "Thermoneutral Zone" in (TNZ) or "Thermal Neutrality". Curves, proposed in 1971 by Hey are essential for keeping newborns in the TNZ. PMID: 1844181 [PubMed - indexed for MEDLINE] 222. Comp Biochem Physiol A Comp Physiol. 1991;98(3-4):567-74. The effect of experimental overnutrition on nonshivering thermogenesis and obesity in LA/N-cp rats. Tulp OL(1). Author information: (1)Department of Nutrition and Food Sciences, College of Arts and Sciences, Drexel University, Philadelphia, PA 19104. 1. Groups of congenic adult male lean and obese LA/N-cp rats were fed stock chow or the chow diet plus a cafeteria diet supplement from 4 until 6 months of age. 2. Weight gain, adipose cellularity, and adiposity were greater in obese than in lean rats and all three parameters increased more rapidly in obese than in lean rats when fed the cafeteria-supplemented diet. 3. Resting metabolic rates and basal urinary vanilylmandelic acid excretion were greater in lean than in obese rats, while serum triiodothyronine concentrations were similar in both phenotypes. The cafeteria diet was associated with significant increases in all three metabolic parameters in lean but not in obese rats. 4. The results of this study indicate that the obese phenotype of this strain has an impaired capacity for non-shivering thermogenesis (NST), in association with an enhanced propensity for development of obesity when fed stock or cafeteria diets. Moreover, the impairment in NST involves both sympathetic and thyroidal components, and is likely to be contributory if not causative of obesity in this strain. PMID: 1674462 [PubMed - indexed for MEDLINE] 223. Comp Biochem Physiol A Comp Physiol. 1991;98(2):245-51. Seasonal changes in cation transport in red blood cells of grey squirrel (Sciurus carolinensis) in relation to thermogenesis and cellular adaptation to cold. Willis JS(1), Zhao MJ. Author information: (1)Department of Physiology and Biophysics, University of Illinois, Urbana, IL 61801. 1. Unidirectional influx of 42K was measured in red cells of grey squirrels at seasonal intervals over two years. 2. Na/K pump-related (i.e. ouabain-sensitive) K influx at 37 degrees C was maximal in cells collected in January and was more than three times greater than cells collected in summer. Na/K pump activity, maximized by loading the cells with Na, exhibited a similar difference. 3. At 5 degrees C in fresh cells, ouabain-sensitive K influx, expressed as per cent of that at 37 degrees C, was highest in March. In Na-loaded cells it was lowest in summer. 4. Passive "leak" K influx (i.e., the residual influx remaining in presence of ouabain and bumetanide) was highest in October, and declined progressively to the summer months, when it was only 27% of that in October. 5. Cotransport (i.e., bumetanide-sensitive K influx) exhibited the same seasonal pattern as Na/K pump activity in fresh cells. 6. Net gain of Na in cells stored at 5 degrees C for three days in March was less than half of that in January or summer. 7. High transport activity in January may correlate with a requirement for increased non-shivering thermogenesis. However, red cells of grey squirrels exhibit maximum resistance to low temperature in March and at this time resemble the red cells of hibernating mammals. PMID: 1673891 [PubMed - indexed for MEDLINE] 224. Brain Res. 1990 Sep 24;528(1):138-42. Injection of prostaglandin E2 into the anterior hypothalamic preoptic area activates brown adipose tissue thermogenesis in the rat. Amir S(1), Schiavetto A. Author information: (1)Department of Psychology, Concordia University, Montreal, Que, Canada. E series prostaglandins (PGE) are known to elicit potent hyperthermia when injected into the anterior hypothalamic preoptic area (POAH) in rats, but the effector mechanisms mediating the rise in temperature are not well defined. In the present study, microinjection of PGE2 into the POAH dose-dependently increased non-shivering thermogenesis in brown adipose tissue (BAT) in urethananesthetized rats, bringing about a marked and sustained rise in interscapular BAT (IBAT) and core temperatures. The effect of intra-POAH PGE2 injection on IBAT and core temperatures could be blocked by systemic pretreatment with the sympathetic ganglionic blocker chlorisondamine chloride or the beta-adrenergic receptor blocker propranolol, thus implicating the involvement of the sympathetic system. Furthermore, the increase in IBAT and core temperatures induced by intra-POAH PGE2 could be blocked by prior injection of the local anesthetic procaine or the GABA receptor agonist muscimol into the ipsilateral ventromedial hypothalamic nucleus (VMH). Taken together, the results suggest that PGE2 increases body temperature by acting in the POAH to stimulate heat production in BAT via a sympathetic efferent mechanism located in the VMH. PMID: 2245331 [PubMed - indexed for MEDLINE] 225. Arch Int Physiol Biochim. 1990 Aug;98(4):193-9. Non-shivering thermogenesis and brown adipose tissue activity in essential fatty acid deficient rats. Goubern M(1), Yazbeck J, Senault C, Portet R. Author information: (1)Laboratoire d'Adaptation Energétique à l'Environnement, Ecole Pratique des Hautes Etudes, Paris, France. The effects of essential fatty acid (EFA) deficiency on energetic metabolism and interscapular brown adipose tissue (BAT) activity were examined in the cold acclimated rat. Weanling male Long-Evans rats were fed on a low fat semipurified diet (control diet, 2% sunflower oil; EFA deficient diet, 2% hydrogenated coconut oil) for 9 weeks. They were exposed at 5 degrees C for the last 5 weeks. In EFA deficient rats, compared to controls, growth retardation reached 22% at sacrifice. Caloric intake being the same in the two groups, it follows that food efficiency was decreased by 40%. Resting metabolism in relation to body surface area was 25% increased. Calorigenic effect of norepinephrine (NE) in vivo (test of non-shivering thermogenesis) underwent a marked decrease of 34%. BAT weight was 21% decreased but total and mitochondrial protein content showed no variation. A 26% increase in purine nucleotide binding per BAT (taken as an index of thermogenic activity) was observed, suggesting that the enhancement in resting metabolism observed was mainly due to increased BAT thermogenesis. However, BAT mitochondria respiratory studies which are more direct functional tests showed a marked impairment of maximal O2 consumption of about 30% with palmitoyl-carnitine or acetyl-carnitine (both in presence of malate) or with alpha-glycerophosphate as substrate. It is likely that this impaired maximal BAT oxidative capacity may explain the impaired NE calorigenic effect in vivo. A possible increase in mitochondrial basal permeability is also discussed. PMID: 1707615 [PubMed - indexed for MEDLINE] 226. Biochem Biophys Res Commun. 1990 Mar 16;167(2):784-9. Expression of the brown fat mitochondria uncoupling protein in Xenopus oocytes and important into mitochondrial membrane. Klaus S(1), Casteilla L, Bouillaud F, Raimbault S, Ricquier D. Author information: (1)Centre National de la Recherche Scientifique, Centre de Recherches sur la Nutrition, Meudon-Bellevue, France. Non shivering thermogenesis of brown adipose tissue is due to the uncoupling protein (UCP), located in the inner mitochondrial membrane, which functions as a proton translocator and can thus uncouple mitochondrial respiration. We describe here the expression of UCP in Xenopus laevis oocytes after injection of UCP mRNA, which was transcribed in vitro. UCP seems to be correctly transported into mitochondria and integrated into the membrane, but we were not able to establish definitely the functionality of this UCP. We conclude that this expression system could be suitable for the study of the mitochondrial import mechanism but not for the examination of physiological properties of UCP. PMID: 2322252 [PubMed - indexed for MEDLINE] 227. Biochim Biophys Acta. 1990 Feb 2;1015(2):334-40. Variations in energization parameters and proton conductance induced by cold adaptation and essential fatty acid deficiency in mitochondria of brown adipose tissue in the rat. Goubern M(1), Yazbeck J, Chapey MF, Diolez P, Moreau F. Author information: (1)Laboratoire d'Adaptation Energétique à l'Environnement, E.P.H.E., Paris, France. Male weanling Long-Evans rats were fed on a low-fat semipurified diet (control diet, 2% sunflower oil; essential fatty acid (EFA) deficient diet, 2% hydrogenated coconut oil) for 9 weeks. In order to modulate need for non-shivering thermogenesis, groups of rats on each diet were exposed at 28 degrees C (thermoneutrality) and at 5 degrees C (cold acclimation) for the last 5 weeks. In brown adipose tissue (BAT) mitochondria, several parameters of mitochondrial energization, protonmotive force (delta p) and its components delta pH and membrane potential, delta psi, were investigated. Simultaneous measurement of oxygen consumption and delta psi (the main component of delta p) was performed by varying alpha-glycerophosphate concentration and the force/flux relationship of the mitochondria was established by comparison of proton conductance, CmH+, over the whole range of protonmotive force. delta p. In the absence of GDP, at 28 degrees C, EFA deficiency induced a marked increase in CmH+. Cold acclimation led to comparable enhanced CmH+ in control and EFA-deficient mitochondria. In the presence of GDP which binds and inhibits the BAT 32 kDa uncoupling protein, CmH+ was the same in 28 degrees C and 5 degrees C control mitochondria, but EFA deficiency led to an enhanced GDP independent CmH+ at 28 degrees C and to a lesser extent at 5 degrees C. These results are discussed with reference to substantial changes in mitochondrial lipid composition induced by the deficiency. PMID: 2297513 [PubMed - indexed for MEDLINE] 228. Gen Pharmacol. 1990;21(1):141-8. Inhibition by vasodilators of noradrenaline and vasoconstrictor-mediated, but not skeletal muscle contraction-induced oxygen uptake in the perfused rat hindlimb; implications for non-shivering thermogenesis in muscle tissue. Colquhoun EQ(1), Hettiarachchi M, Ye JM, Rattigan S, Clark MG. Author information: (1)Department of Biochemistry, University of Tasmania, Hobart, Australia. 1. The effect of noradrenaline as well as of vasopressin and angiotensin II to increase oxygen uptake and perfusion pressure by the isolated perfused rat hindlimb were completely inhibited by the vasodilators, nitroprusside (0.5 mM), nifedipine (2.5 microM) and isoprenaline (50 nM). 2. Oxygen uptake due to sciatic nerve stimulation of skeletal muscle contraction was not inhibited by 0.5 mM nitroprusside but was found to increase further that produced by a maximum dose of either noradrenaline or angiotensin II. 3. Analysis of high energy phosphates in samples of freeze-clamped hindlimb muscle showed no difference before and after vasoconstrictor addition or with muscle sampled in vivo. 4. It is concluded that norepinephrine mediated increase in oxygen uptake by the perfused rat hindlimb results from its vasoconstrictor action. PMID: 2298385 [PubMed - indexed for MEDLINE] 229. Comp Biochem Physiol B. 1990;97(4):809-13. Liver and brown fat mitochondrial response to cold in the garden dormouse (Eliomys quercinus). Lanni A(1), Martins R, Ambid L, Goglia F. Author information: (1)Department of General and Environmental Physiology, University of Naples, Italy. The involvement of two organs, i.e. the liver and the brown adipose tissue (BAT) in response to cold in a hibernating species such as the garden dormouse has been studied. 2. In animals living in the cold, mitochondrial respiratory rates significantly increased (with respect to those living at 28 degrees C) in both organs with a larger increase in the BAT (+152% in the BAT and 67% in the liver). 3. The increase in BAT activity was obtained by a concomitant increase in: (a) the BAT mass (+30%), (b) the total mitochondrial mass (+20%), and (c) the mitochondrial respiratory rate (+64%). In the liver the increase was due only to an augmentation in mitochondrial mass and activity. 4. These results indicate that: (a) the BAT exerts a pre-eminent role in the physiological response to cold of garden dormouse, (b) a certain non-shivering thermogenesis (NST) is present in the liver of such species. In addition we suggest that a local thermoregulatory response would take place in a metabolically important organ such as the liver. PMID: 2085962 [PubMed - indexed for MEDLINE] 230. Biochem J. 1989 Jul 15;261(2):401-5. The beta-adrenergic radioligand [3H]CGP-12177, generally classified as an antagonist, is a thermogenic agonist in brown adipose tissue. Mohell N(1), Dicker A. Author information: (1)Wenner-Gren Institute, University of Stockholm, Sweden. The effect of CGP-12177, originally developed as a radioligand with antagonist properties for binding studies of beta-adrenergic receptors, was investigated in brown adipose tissue. Contrary to expectations, CGP-12177 showed clear agonist properties in experiments with hamster brown-fat cells, with a maximal effect in stimulating oxygen consumption similar to that of the physiological stimulator noradrenaline, and also with a potency similar to that of noradrenaline [EC50 (50% effective concn.) approx. 70 nM]. This value could be contrasted with the very high affinity of CGP-12177 (KD about 1 nM) for ligand-binding sites on the cells. It is therefore suggested that the high-affinity binding site may not be the one that mediates the CGP-12177-stimulated thermogenesis in isolated cells. Also, when injected into cold-adapted rats, CGP-12177 stimulated non-shivering thermogenesis similarly to noradrenaline. This observation, in conjunction with the reported low general sympathomimetic effect of CGP-12177, may indicate that CGP-12177 could be of interest for the development of anti-obesity drugs. PMCID: PMC1138840 PMID: 2570569 [PubMed - indexed for MEDLINE] 231. Pflugers Arch. 1989 Jul;414(3):317-23. 3H-ouabain binding sites in porcine skeletal muscle as influenced by environmental temperature and energy intake. Dauncey MJ(1), Burton KA. Author information: (1)AFRC Institute of Animal Physiology and Genetics Research, Babraham, Cambridge, Great Britain. The influence of environmental temperature and energy intake on 3H-ouabain binding sites in skeletal muscle has been investigated in young growing pigs at 8 weeks of age. Animals lived for several weeks at 35 or 10 degrees C on a high (H) or low (L) level of energy intake. The four treatment groups were thus: 35H, 35L, 10H and 10L. The total number of 3H-ouabain binding sites (Bmax) in longissimus dorsi muscle (mean values +/- SEM) were 221 +/- 66, 214 +/- 61, 350 +/- 76 and 486 +/- 114 pmol/g wet weight for the 35H, 35L, 10H and 10L groups respectively. Bmax was significantly greater in those living in the cold than the warm (P less than 0.001). Moreover, at 10 degrees C energy intake had a significant effect, with Bmax being greater in the 10L than the 10H group (P less than 0.005). Level of energy intake had no influence on Bmax at 35 degrees C. The apparent dissociation constant was not affected by either temperature or intake. The elevated Bmax and hence the increase in number of Na+,K+-pumping sites in the cold is probably related to increased muscular activity associated with shivering. However, thyroid status also influences the number of Na+,K+-pumping sites and this may have been a contributory factor in the present study. In addition, the elevated Bmax suggests a greater potential for non-shivering thermogenesis associated with increased Na+,K+-ATPase concentration in the cold. Differences in relative stage of development between the four groups may help to explain the results for Bmax in relation to level of energy intake. PMID: 2550882 [PubMed - indexed for MEDLINE] 232. J Dev Physiol. 1989 May;11(5):289-98. The control of thermoregulation in the developing lamb during slow wave sleep. Symonds ME(1), Andrews DC, Johnson P. Author information: (1)Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Headington. This study investigates the mechanisms involved in adjusting metabolic rate in response to acute changes in ambient temperature close to thermoneutrality during postnatal development. Twelve lambs were prepared for sequential studies at 4, 14, 30, 45 and 55 days of age. During each study they were maintained at ambient temperatures of 5, 10, 15, 20, 25 and 30 degrees C for at least 1 h and until a slow wave sleep epoch was established. Eight lambs completed all studies. In these there was a significant fall in oxygen consumption with age which was independent of ambient temperature. This effect was closely related to a decrease in plasma triiodothyronine concentration that was greatest between 4- and 14-days old lambs and was not associated with a change in the plasma concentration of thyrotrophin or thyroxine. In 4-days old lambs oxygen consumption was increased at ambient temperatures of 5 and 10 degrees C by non-shivering thermogenesis, whilst in 14- and 30-days old lambs this effect was achieved by shivering. On the basis of significant changes in oxygen consumption and/or the occurrence of shivering (lower critical temperature) and panting (upper critical temperature) we have shown that there is a fall in both upper and lower critical temperature with age and a widening of the thermoneutral zone. This was associated with a decrease in the plasma cortisol concentration and heart rate as measured at thermoneutrality, whilst rectal temperature increased from 4 to 30 days of age. The other 4 lambs, 3 of which died between 7 and 17 days of age, had low plasma triiodothyronine concentrations when studied at 4 and/or 14 days of age and their oxygen consumption at thermoneutrality was significantly lower than the normal group at 14 days. Shivering thermogenesis occurred at an earlier age and control of body temperature was less effective. It is concluded that triiodothyronine has an important role in the control of metabolic rate in the developing lamb even to meet modest changes in ambient temperature, and possibly directly in survival. PMID: 2614034 [PubMed - indexed for MEDLINE] 233. Br J Nutr. 1989 May;61(3):475-83. Riboflavin deficiency, metabolic rate and brown adipose tissue function in sucking and weanling rats. Patterson BE(1), Bates CJ. Author information: (1)MRC Dunn Nutritional Laboratory, Cambridge. 1. The effects of riboflavin deficiency on growth, whole-body oxygen consumption, cytochrome c oxidase (EC 1.9.3.1) activity and GDP-binding capacity of brown adipose tissue were measured in three groups of rats: sucking pups, weanling rats, and dams. Control groups were weight-matched, pair-fed or fed ad lib. 2. Riboflavin deficiency reduced growth rate and increased the activation coefficient of erythrocyte glutathione reductase (NAD(P)H) (EC 1.6.4.2), as predicted. In sucking pups it also reduced whole-body O2 consumption per unit body-weight, especially after noradrenaline stimulation. In weanling rats, however, it increased O2 consumption both before and after noradrenaline stimulation. 3. Cytochrome c oxidase (EC 1.9.9.1) activity of brown adipose tissue was not consistently affected by riboflavin deficiency. Binding of [3H]GDP to the mitochondria was increased in the deficient weanling rats. 4. Weanling rats therefore, seemed better able to withstand the effects of severe depletion. Their reduced growth and increased non-shivering thermogenesis helped to counteract the unfavourable ratio of riboflavin:other tissue-building materials. The relevance for thermoregulation in riboflavin-deficient children is discussed. PMID: 2547428 [PubMed - indexed for MEDLINE] 234. Comp Biochem Physiol A Comp Physiol. 1989;92(1):37-41. Non-shivering thermogenesis and obesity in adult diabetic Wistar fatty rats. Tulp OL(1), Stevens C, Barbie OA. Author information: (1)Department of Nutrition and Food Sciences, Drexel University, College of Science, Philadelphia, PA 19104. 1. Characteristics of resting and of norepinephrine (NE)-stimulated thermogenesis, and the glycemic response to NE were determined in adult male Wistar Fatty rats. Rats were maintained on Purina chow No. 5001 until 22 weeks of age, and fed semisynthetic diets containing 54% carbohydrate, 20% protein, 16% mixed fats, plus essential vitamins, minerals, and non-nutritive fiber from 22 until 30 weeks of age. 2. Obese rats were 50% heavier than lean throughout the study. Phenotype effects (obese greater than lean) were present for retroperitoneal (RP) and dorsal (DOR) white fat depot weight, adipocyte number per depot, and adipocyte lipid content. Epididymal mass and cellularity were similar in both phenotypes. 3. Interscapular brown adipose tissue (IBAT) mass, adipocyte size, and adipocyte number were greater in obese than in lean. Resting metabolic rates (RMR) of obese rats were lower than in lean, and increased 79% in lean but only 33% in obese animals following NE (200 micrograms/kg BW, s.c.) stimulation. 4. The glycemic response to NE occurred normally in both phenotypes, and resulted in a 3-fold increment in plasma glucose in lean rats and a 5-6-fold increase in plasma glucose in obese rats. 5. The results of this study are consistent with hyperplasia and hypertrophy of IBAT, RP and DOR depots, and indicate that the capacity for non-shivering thermogenesis is impaired in the obese phenotype of this strain in spite of peripheral sensitivity to NE and greater mass and cellularity of brown adipose tissue. PMID: 2567655 [PubMed - indexed for MEDLINE] 235. Med Sci Sports Exerc. 1988 Oct;20(5 Suppl):S193-6. Factors affecting cold acclimation and thermogenesis in man. Leblanc J(1). Author information: (1)Department of Physiology, School of Medicine, Laval University, Quebec City, Canada. Three types of cold exposure are observed in man: systemic moderate cold (SM), systemic severe cold (SS), and local severe cold (LS). Contrary to rat, prolonged exposure to SM cold does not produce non-shivering thermogenesis, as it does in the rat, possibly because of lack of active brown adipose tissue. Instead there is a reduction in heat production, in shivering, and in discomfort through a process known as habituation. No adaptation was found with exposure to SS cold, since shivering and discomfort always prevail and there is indirect evidence of enhanced sympathetic response after repeated exposure to SS cold. Exposure to LS cold leads to adaptive responses in which discomfort and autonomic activity are reduced. It is suggested that LS adaptation is also related to habituation. PMID: 3057321 [PubMed - indexed for MEDLINE] 236. Acta Physiol Pol. 1988 Sep-Dec;39(5-6):380-94. Alterations in thyroid hormone physiology induced by temperature and feeding in newly hatched chickens. Decuypere E(1), Kühn ER. Author information: (1)Laboratory for Physiology of Domestic Animals, Heverlee, Belgium. In the chicken the transition of a poikilotherm to a homeotherm reaction upon cold exposure takes place in the perinatal period between pipping and hatching. However, newly hatched chicks cannot maintain their body temperature within narrow limits after cold exposure. The fact that relatively little attention was payed on the role of thyroid hormones in the thermoregulatory reaction to cold of young chicks was probably due to the hypothetically long latention time that was thought to be necessary to bring about changes in secretory activity by cold stimulation. However, more recently, rapid changes (within hours) of thyroid hormone concentrations upon cold exposure were described in the chickens and the quail. In this study, changes in circulating T3 and T4 concentrations upon cold exposure of young chicks during the first two weeks were followed, that means during the period wherein NST (non-shivering thermogenesis), if it exists at all, should be progressively replaced by ST (shivering thermogenesis). Because of the importance of feeding condition on thyroid hormone levels, the experiments were carried out with and without a preceeding fasting period. In all experiments a short-term cold exposure of young chickens (1-11 days) fed ad lib decreased T3 but increased T4 levels while a reversed picture was found after short cold exposure of the fasted animals. However, after prolonged cold stimulus (15 degrees C) of young chickens fed ad lib, plasma T3 was also significantly elevated over that of controls whereas T4 levels returned to normal values. A prolonged warm treatment (37 degrees C) of young chickens fed ad lib resulted in significantly lower T3 and higher T4 concentrations. After a prolonged cold treatment no differences in T4 or T3 response upon TRH were found whereas the warm treatment abolished these responses upon TRH. However, a cold treatment at the stage of incubation during which the hypothalamo-hypophyseal control of thyroid function is established (dag 10-14) enhanced the T4 response to TRH with a long lasting effect extending to the posthatch period. Since T3 is thought to be the active form of thyroid hormones with regard to thermopoiesis we have studied more specifically the effect of blocking peripheral conversion of T4 on thermoregulatory abilities in young chicks and the influence of temperature treatment on monodeiodination capacity. The lower rectal temperatures following the interference with the peripheral monodeiodination of T4, the effect being more pronounced at the lower ambient temperature, are indicative for a preponderant role of T3 on thermogenesis.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 3257053 [PubMed - indexed for MEDLINE] 237. Acta Physiol Pol. 1988 Sep-Dec;39(5-6):364-79. Hyperiodothyroninaemia of neonates, its significance for thermogenesis. Slebodziński AB(1). Author information: (1)Polish Academy of Sciences, Department of Experimental Pathology of Animals, Poznan. Danowski et al. (1951) were probably the first who showed an increase of PBI in infants shortly after birth. Later a number of investigators presented further evidence on the increased thyroid gland function in newborns. This condition named "neonatal thyroid hyperactivity" [Fisher and Oddie, 1964] was described also in animals. The available data indicate that all the newborn mammals till now studied, independently of the maturation stage of development they reach at birth, display some features of thyroid hyperactivity, but in some it does not lead to hyperiodothyroninaemia. Interspecies differences coincide well with significance of the thyroid hormones for neonatal thermogenesis. There are few sequential studies of the three principal iodothyronines: T4, T3 and rT3 available at present. The most comprehensive data concern infants, newborn lambs and pigs. Immediately after birth, there is a sudden rise in serum thyroid hormone concentrations, with some species differences related to the degree of the increase and to the iodothyronines involved. The course of the postnatal hyperiodothyroninaemia is dependent on the maturation level reached at birth, food intake, and cooling relative to extrauterine environment. At least five main factors contribute to the immediate postnatal hyperiodothyroninaemia: 1) abrupt depletion of the preformed fetal hormonal iodine stores; 2) preferential T3 secretion; 3) increase in the T4 to T3 monodeiodination in the peripheral tissues; 4) a release of thyroid hormone content from peripheral reservoirs to plasma, and 5) action of other hormone(s) concomitantly released at birth. From the point of view of the thermal adaptability, the newborn mammals fall into two distinct groups: first, in which immediately after birth the metabolic rate decreases, and second, in which the metabolic rate increases, after cooling. Our understanding of the role and significance of hormonal factors involved in mechanisms of the postnatal thermogenesis is incomplete. However, some similarities in adaptation to cold in adults and in newborns seem to be relevant. Cold adaptation is accomplished by development of nonshivering thermogenesis (NST) depending on NA. The presence of brown adipose tissue (BAT) is essential for NA thermogenic action. According to the common opinion, based on data from laboratory animals and human baby, non-shivering thermogenesis, but not shivering, predominates in newborns. However, data from domestic animals indicate that shivering thermogenesis may be of comparable or greater thermogenic capacity than NST at birth. Besides, there are some newborns which have little or no BAT and associated NST.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 3257052 [PubMed - indexed for MEDLINE] 238. Anesthesiology. 1988 Jun;68(6):836-42. The thermoregulatory threshold in humans during halothane anesthesia. Sessler DI(1), Olofsson CI, Rubinstein EH, Beebe JJ. Author information: (1)Department of Anesthesia, University of California, San Francisco 94143-0648. Comment in Anesthesiology. 2013 Jan;118(1):181-6. Although suppression of thermoregulatory mechanisms by anesthetics is generally assumed, the extent to which thermoregulation is active during general anesthesia is not known. The only thermoregulatory responses available to anesthetized, hypothermic patients are vasoconstriction and non-shivering thermogenesis. To test anesthetic effects on thermoregulation, the authors measured skin-surface temperature gradients (forearm temperature--finger-tip temperature) as an index of cutaneous vasoconstriction in unpremedicated patients anesthetized with 1% halothane and paralyzed with vecuronium during elective, donor nephrectomy. Patients were randomly assigned to undergo maximal warming (warm room, humidified respiratory gases, and warm intravenous fluids; n = 5) or standard temperature management (no special warming measures; n = 5). Skin-surface temperature gradients greater than or equal to 4 degrees C were prospectively defined as significant vasoconstriction. Normothermic patients [average minimum esophageal temperature = 36.4 +/- 0.3 degrees C (SD)] did not demonstrate significant vasoconstriction. However, each hypothermic patient displayed significant vasoconstriction at esophageal temperatures ranging from 34.0 to 34.8 degrees C (average temperature = 34.4 +/- 0.2 degrees C). These data indicate that active thermoregulation occurs during halothane anesthesia, but that it does not occur until core temperature is approximately equal to 2.5 degrees C lower than normal. In two additional hypothermic patients, increased skin-temperature gradients correlated with decreased perfusion as measured by a laser Doppler technique. Measuring skin-surface temperature gradients is a simple, non-invasive, and quantitative method of determining the thermoregulatory threshold during anesthesia. PMID: 3377230 [PubMed - indexed for MEDLINE] 239. Clin Endocrinol (Oxf). 1988 Jun;28(6):665-73. Metabolic and thyroidal responses to mild cold are abnormal in obese diabetic women. Lean ME(1), Murgatroyd PR, Rothnie I, Reid IW, Harvey R. Author information: (1)MRC Dunn Nutrition Laboratory, Cambridge, UK. Mild cold exposure (22 degrees C, with reference to 28 degrees C, thermoneutral) was studied by overnight whole-body indirect calorimetry in euthyroid women. Basal, sleeping, energy expenditure (EE) was significantly increased (+3.8%, P less than 0.05) in six normal weight women but reduced (-3.5%, P less than 0.05) in five obese type II diabetic women. Mixed responses were found in five women with simple obesity. Biochemical measurements were made on fasting blood samples taken at 0900 h after 12 h exposure to the two temperatures. Serum T4, free T3 and TSH were within the normal reference range in all subjects. Serum T4 did not show any differences between the groups, nor any effect from temperature. There was a significant increase in free T3 (P less than 0.05) at 22 degrees C in the control subjects, but no differences in the obese diabetic women. Serum thyroglobulin fell significantly in the diabetic group. Both TSH and free T3 responses to mild cold were significantly different between the groups, but both correlated positively (P less than 0.05) with the changes in sleeping energy expenditure at 22 degrees C with reference to 28 degrees C. Changes in TSH and free T3 were themselves significantly correlated within individuals (P less than 0.01). The normal physiological non-shivering thermogenesis of adult humans on exposure to a cool environment may thus be mediated by a pituitary-thyroid mechanism. The abnormal response of obese diabetic women was associated with impaired TSH and thyroid hormone responses, and may be a factor contributing to weight gain. PMID: 3254262 [PubMed - indexed for MEDLINE] 240. Clin Exp Pharmacol Physiol. 1988 May;15(5):391-400. Thermogenesis and the effect of injected catecholamines on the oxygen consumption of cafeteria-fed rats. Maxwell GM(1), Nobbs S, Fourie F, Bates DJ. Author information: (1)Department of Paediatrics, University of Adelaide, Adelaide Children's Hospital, South Australia. 1. The oxygen consumption (VO2) of unrestrained rats given a 'cafeteria' (high energy, high fat) or control diet was studied. The resting values of VO2 were the same in each dietary group, whether maintained at 26 degrees C or 6 degrees C. This negative finding suggests that cafeteria feeding is not an important cause of diet-induced thermogenesis (DIT). 2. The response of each group of rats to injected noradrenaline or dopamine was also studied. Each catecholamine could increase VO2 values but the response was much less in cold-adapted rats measured at 6 degrees C. In all experimental circumstances the dopamine response exceeded that of noradrenaline. There was no evidence that the cafeteria diet consistently increased the response to either catecholamine. 3. These results suggest that DIT cannot be equated with non-shivering thermogenesis (NST). Furthermore, it is suggested that dopamine would be a better agent for measuring the oxygen equivalent of NST, since it would stimulate the dopamine receptors as well as the alpha- and beta-adrenoreceptors of brown fat. PMID: 3271615 [PubMed - indexed for MEDLINE] 241. Hokkaido Igaku Zasshi. 1988 Jan;63(1):85-96. [Effects of cold acclimation and repetitive stress on stress-induced neuroendocrine response]. [Article in Japanese] Murazumi K(1). Author information: (1)Department of Physiology, Asahikawa Medical College, Japan. In order to elucidate the mechanism (S) involved in improved cold tolerance by means of enhanced non-shivering thermogenesis of the repetitively stressed rats, noradrenaline (NA) turnover of brown adipose tissue (BAT) and adrenocortical responses were investigated. (1) NA turnover of BAT in the cold-acclimated rats was greater than that in the resting controls. NA level of BAT in the cold-acclimated rats decreased to about 40% of the control level. It was thus inferred that this lower NA levels was induced by accelerated NA turnover. (2) NA turnover of BAT in the stressed rats after repetitive immobilization stress was higher than that of the non-stressed controls. Therefore, increased sympathetic activity of BAT would be one of the mechanisms of cross adaptation between cold and stress. (3) NA turnovers of BAT in the controls, the cold-acclimated rats and stressed ones were increased by acute cold exposure (-5 degrees C). NA turnovers of BAT in the controls and the stressed rats were increased by acute immobilization stress. (4) Plasma corticoids (corticosterone and deoxycorticosterone) in the cold-acclimated rats were higher than that of controls. Plasma corticoids in the controls, the cold-acclimated rats and stressed ones were increased by acute cold exposure (-5 degrees C, 15 min) and acute immobilization stress (30 min). The extents of increases in plasma corticoids in the stressed rats, but not in the cold-acclimated ones, were greater than those in the controls. It was suggested that repetitive immobilization stress could enhance nonshivering thermogenesis via an enhanced responsiveness of adrenocortical secretion to acute stress and cold. It would be concluded from these results that enhanced responses of corticoid secretion and accelerated sympathetic activity were associated with the establishment of cross adaptation between cold and stress. It was suggested that the extent of participation of these factors was not necessarily the same between the cold-acclimated and the stressed organisms. PMID: 3360402 [PubMed - indexed for MEDLINE] 242. Braz J Med Biol Res. 1988;21(2):171-6. Thermogenic mechanisms in cold-acclimated animals. Griggio MA(1). Author information: (1)Departamento de Fisiologia, Escola Paulista de Medicina, São Paulo, Brasil. 1. This paper reviews the mechanisms of thermogenesis after cold-acclimation. 2. Upon exposure to cold, the oxygen consumption of animals increases by means of shivering and non-shivering thermogenesis. As cold exposure progresses, shivering decreases while non-shivering thermogenesis increases, so that the cold-acclimated animal produces heat mostly by non-shivering thermogenesis. 3. Brown adipose tissue in several species, including man, is an essentially thermogenic organ that produces heat by uncoupling mechanisms in mitochondria. 4. The activity of brown adipose tissue can be assessed by physiological and biochemical methods. 5. After cold acclimation, the activity and mass of brown adipose tissue are higher than in control animals. Brown adipose tissue is considered the main factor responsible for non-shivering thermogenesis. PMID: 3060204 [PubMed - indexed for MEDLINE] 243. Comp Biochem Physiol A Comp Physiol. 1988;89(1):85-91. Thermogenic capabilities of the opossum Monodelphis domestica when warm and cold acclimated: similarities between American and Australian marsupials. Dawson TJ(1), Olson JM. Author information: (1)Museum of Zoology, University of Michigan, Ann Arbor 48109. 1. Monodelphis domestica is a small marsupial mammal from South America. Its thermogenic abilities in the cold were determined when the opossums were both warm (WA) and cold (CA) acclimated. Maximum heat production of M. domestica was obtained at low temperatures in helium-oxygen. 2. Basal metabolic rate (BMR) in the WA animals was 3.2 W/kg and mean body temperature was 32.6 degrees C at 30 degrees C. These values were lower than those generally reported for marsupials. Nevertheless, these M. domestica showed considerable metabolic expansibility in response to cold. Sustained (summit) metabolism was 8-9 times BMR, while peak metabolism was 11-13 times BMR. These maximum values were equal to, or above, those expected in small placentals. 3. Cold acclimation altered the thermal responses of M. domestica, particularly in warm TaS. However, summit metabolism was not significantly increased; nor did M. domestica show a significant thermogenic response to noradrenaline, which in many small placentals elicits non-shivering thermogenesis. The thermoregulatory responses of this American marsupial were, in most aspects, similar to those of Australian marsupials. This suggests that the considerable thermoregulatory abilities of marsupials are of some antiquity. PMID: 2450718 [PubMed - indexed for MEDLINE] 244. Brain Res. 1987 Dec 15;436(2):273-82. Hyperthermia induced by pre-pontine knife-cut: evidence for a tonic inhibition of non-shivering thermogenesis in anaesthetized rat. Shibata M(1), Benzi RH, Seydoux J, Girardier L. Author information: (1)Département de Physiologie, Faculté de Médicine, Centre Médical Universitaire, Genève, Switzerland. Temperature of colon, interscapular brown adipose tissue (IBAT) and paw skin (index of vasomotor activity) were monitored before and after microwire knife lesions at the pre-pontine or/and the post-mammillary levels in the urethane-anaesthetized rats at room temperature of 23-24 degrees C. Following the pre-pontine, but not the post-mammillary cut, colonic and IBAT temperatures increased by 3-4 degrees C within 90-240 min. IBAT temperature rose faster with a shorter latency and attained a higher steady-state value than colonic temperature; skin temperature, however rose by only 0.8 degrees C. A procaine microinjection into the pre-pontine area transiently increased by more than 1 degree C both colonic and IBAT temperatures, with similar kinetics as for the knife cut. Cardiac output distribution was measured using radiolabelled microspheres. Brown adipose tissue (BAT) was found to be the only organ to which the fractional blood flow increased dramatically (12 times over baseline value) during the development of hyperthermia. Propanolol, injected after the hyperthermia had fully developed, decreased IBAT and then colonic temperatures. Hexamethonium decreased both colonic and IBAT temperatures with a concomitant rise in skin temperature while tubocurarine was without effect. It is concluded that the hyperthermia observed after the pre-pontine lesion results from an increased sympathetic stimulation of BAT thermogenesis triggered by the release of a tonic inhibitory control on its heat production. Such an inhibitory system would be located somewhere between the lower midbrain and the upper pons. PMID: 3435828 [PubMed - indexed for MEDLINE] 245. Pflugers Arch. 1987 Nov;410(4-5):376-84. Fetal sheep temperatures in utero during cooling and application of triiodothyronine, norepinephrine, propranolol and suxamethonium. Schröder HJ(1), Hüneke B, Klug A, Stegner H, Carstensen M, Leichtweiss HP. Author information: (1)Universitäts-Frauenklinik, Abt. experimentelle Medizin, Hamburg, Federal Republic of Germany. Fetal sheep (n = 13) were chronically instrumented to measure temperatures in the maternal femoral artery (MAT), the amniotic fluid (AFT), the fetal brown adipose tissue (BFT) and the fetal arterial blood (DAT). Cooling loops were inserted into the amniotic cavity. In 4 fetuses osmotic minipumps delivering triiodothyronine (T3) were implanted subcutaneously. One to seven days after surgery the following results were obtained: 1) During control DAT was 0.59 +/- 0.2 degrees C (SD), BFT 0.60 +/- 0.24 degrees C and AFT 0.38 +/- 0.31 degrees C higher than MAT. T3 levels in treated fetuses were 3.4 +/- 1.5 micrograms/l. 2) Infusion of norepinephrine (NE) (5.2 +/- 0.9 micrograms/min per kg fetal body weight) with phentolamine (26.1 +/- 4.3 micrograms/min per kg) into a fetal vein did not change temperatures. 3) During cooling (-53 +/- 15 W) MAT decreased 0.45 +/- 0.3 degrees C, DAT 1.9 +/- 0.39 degrees C, BFT 1.61 +/- 0.52 degrees C and AFT 4.2 +/- 1.8 degrees C. 4) The amniotic fluid was cooled until steady state temperatures were achieved. Then propranolol (26.1 +/- 4.3 micrograms/min per kg) or suxamethonium (3 +/- 1 mg/kg) were introduced into the fetal vein. No consistent and significant changes of temperatures could be detected. It is concluded that 1) lowering the fetal core temperature by 1.6 - 1.9 degrees C and its ambient temperature (AFT) by 4.2 degrees C does not induce shivering or non-shivering thermogenesis suppressible by pharmacologic agents, 2) thermogenesis in fetal brown adipose tissue cannot be induced by NE (with or without supplemention of T3).(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 3124078 [PubMed - indexed for MEDLINE] 246. Brain Res Bull. 1987 Jan;18(1):7-11. Brown adipose tissue thermogenesis induced by low level electrical stimulation of hypothalamus in rats. Freeman PH, Wellman PJ. Brown adipose tissue (BAT) is an energy dissipating form of adipose tissue implicated in non-shivering thermogenesis as well as diet-induced thermogenesis. In the present study, in vivo interscapular BAT (IBAT) temperature was recorded prior to and following low level electrical stimulation (a 30 sec train of 60 Hz, 100 microA 0.5 msec isolated pulses) of various hypothalamic regions in rats. Significant increases in IBAT temperature were observed after stimulation of the anterior, medial preoptic, paraventricular and dorsomedial hypothalamus but not after stimulation of either ventromedial or caudal hypothalamus. For positive sites, IBAT temperature typically increased at 3-4 minutes following stimulation, peaked at 7-8 minutes after stimulation and declined at 20 minutes after stimulation. Although alterations in diet-induced thermogenesis have been reported after ventromedial hypothalamic lesions, the increases in BAT temperature noted in the present study suggest that inhibitory fibers that course through the paraventricular hypothalamus may form part of the central nervous system control of brown adipose tissue thermogenesis induced by overfeeding. PMID: 3828843 [PubMed - indexed for MEDLINE] 247. J Comp Physiol B. 1987;157(5):625-33. Effect of photoperiod and melatonin on cold resistance, thermoregulation and shivering/nonshivering thermogenesis in Japanese quail. Saarela S(1), Heldmaier G. Author information: (1)Department of Zoology, University of Oulu, Finland. The effect of photoperiod and melatonin treatment on cold resistance and thermogenesis of quails was studied. The birds were acclimated for 8 weeks to short day (8L:16D) or long day (16L:8D) conditions, and 8 of 16 quails in each group were implanted with melatonin capsules. One group of quails was maintained outside in an aviary during winter. Oxygen consumption (VO2), body temperature (Tb, recorded with temperature transmitters) and shivering (integrated pectoral EMG) were recorded continuously, and samples of heart rate and breathing rate were picked up when ambient temperature was decreased stepwise from 27 down to -75 degrees C. Heat production maximum (HPmax), cold limit, lower critical temperature, basal metabolic rate (BMR) and thermal conductance were determined. The results show that short day, cold and melatonin treatment improved cold resistance and thermal insulation of quails when compared with quails acclimated to long day conditions. An increase in HPmax was induced only by melatonin treatment. The results suggest that the acclimatization of quails is under control of the pineal gland. The linear increase of shivering intensity with VO2 at moderate cold load shows that shivering is the primary source for thermoregulatory heat production in the quail. At Ta's below -40 degrees C shivering remained constant although VO2, heart rate and breathing rate continued to increase with increasing cold load. This could indicate the existence of a nonshivering thermogenesis in birds. Unlike to mammals, this non-shivering thermogenesis in birds would serve as secondary source of heat supporting shivering thermogenesis in severe cold. PMID: 3693622 [PubMed - indexed for MEDLINE] 248. Comp Biochem Physiol A Comp Physiol. 1987;87(1):31-3. Cold acclimation in food-restricted rats. Puerta ML, Abelenda M. Food intake, body weight and brown adipose tissue (BAT) mass and composition of rats exposed at 6 degrees C either with food ad libitum or food-restricted were compared with those of rats in the thermoneutral zone, with food ad libitum. Cold acclimation with food ad libitum increases food intake and prevents body weight gains. IBAT (interscapular BAT) increases its mass and changes its composition after 3 weeks of cold exposure. Cold acclimation with food restriction produces a progressive decrease in body weight. IBAT mass increases after 3 weeks but changes in composition occur sooner. It is concluded that the overfeeding that accompanies cold acclimation is not necessary for non-shivering thermogenesis in BAT. PMID: 2886258 [PubMed - indexed for MEDLINE] 249. Comp Biochem Physiol B. 1987;88(2):519-22. Increased oxidative capacity in skeletal muscles from cold-acclimated ducklings: a comparison with rats. Barré H(1), Bailly L, Rouanet JL. Author information: (1)Laboratoire de Thermorégulation et Métabolisme Energétique (U.A. 181, C.N.R.S.), Faculté de Médecine Lyon-nord, France. 1. The effects of prolonged cold exposure on cytochrome oxidase activity were investigated in skeletal muscles, liver and adipose tissues from cold-acclimated (CA) and control (TN) ducklings and rats. 2. Cold acclimation increased the oxidative capacity of skeletal muscles (+33% in gastrocnemius and +195% in pectoral) and liver (+47%) from CA ducklings, but decreased the oxidative capacity of gastrocnemius muscle (-22%) from CA rats. On the other hand, in these CA rats it increased the oxidative capacity of liver by 88% and, above all, brown adipose tissue by 544%. 3. The significance of these changes due to acclimation to cold in ducklings and rats is discussed. Such an increase in oxidative capacity of CA duckling muscles may explain the non-shivering thermogenesis observed in these birds. PMID: 2827948 [PubMed - indexed for MEDLINE] 250. Br J Nutr. 1986 Nov;56(3):615-23. Effects of preweaning nutritional deprivation on basal metabolism and thermoregulatory thermogenesis in the rat. Muralidhara DV(1), Shetty PS. Author information: (1)Nutrition Research Centre (ICMR), Department of Physiology, St. John's Medical College, Bangalore, India. 1. Nutritional deprivation was induced preweaning in Wistar rats by increasing the litter size to sixteen, while paired litters with only five pups served as controls. The nutritionally deprived pups were rehabilitated after weaning by ad lib. access to an adequate diet. 2. The body-weights and body lengths were significantly lower in the nutritionally deprived group and significant differences persisted even after 9 weeks of rehabilitation. 3. The body temperature of the nutritionally deprived animals was significantly lower than that of their paired controls, both before and following nutritional rehabilitation, except for a short period after weaning when the nutritionally deprived animals were initially given the diet ad lib. 4. The resting oxygen consumption of the nutritionally deprived animals was comparable to that of the controls when corrected for metabolic body size, both before and after weaning. Noradrenaline-stimulated increase in O2 consumption (non-shivering thermogenesis; NST) was reduced by 50% at weaning in the nutritionally deprived animals and returned to levels comparable to those of controls within a short period of rehabilitation. 5. The decrease in NST capacity seen in the nutritionally deprived animals was associated with an inability to thermoregulate when exposed to cold (5 degrees), resulting in death. Cold-induced thermogenesis (CIT) also reappeared soon after nutritional rehabilitation. 6. Reduction in metabolic rate, NST and CIT seen in the animals nutritionally deprived preweaning was short-lived and disappeared soon after nutritional rehabilitation. Rapid reversal of these physiological changes indicates that they do not confer any long-term benefit or change in metabolic efficiency and are unlike the changes in body size and growth which do not completely recover following nutritional rehabilitation. PMID: 3676236 [PubMed - indexed for MEDLINE] 251. J Physiol. 1986 Nov;380:541-9. Suppression of non-shivering thermogenesis in the rat by heat-seeking behaviour during cold exposure. Morimoto A, Murakami N, Nakamori T, Watanabe T. Changes in rectal temperature (Tre) during cold exposure (0 +/- 1 degrees C) were observed in three groups of rats: heat-seeking, no-behaviour and semi-restrained groups. Significant increases in Tre were observed in the no-behaviour and the semi-restrained groups during cold exposure. In the heat-seeking behaviour group Tre remained constant during cold exposure. The increased Tre in the semi-restrained group during cold exposure was markedly attenuated by the systemic injection of beta-blocker (propranolol: 10 mg/kg, I.P.), indicating that this increase of Tre was caused by activation of non-shivering thermogenesis (n.s.t.). Furthermore, the rise in Tre in the semi-restrained group was preceded by a greater increase in the temperature of the interscapular brown adipose tissue. Using the autoradiographic [14C]deoxyglucose technique, it was revealed that the enhanced n.s.t. in the no-behaviour and the semi-restrained groups was accompanied by a significant increase of metabolic activity in the anterior part of the ventromedial hypothalamus. We conclude that during cold exposure motionlessness of slightly restrained animals increase n.s.t. when thermoregulatory behaviour to gain heat is not available. This increased n.s.t. is mediated by activation of hypothalamic function. PMCID: PMC1182953 PMID: 3612575 [PubMed - indexed for MEDLINE] 252. Biochem Biophys Res Commun. 1986 Oct 15;140(1):134-42. Triiodothyronine (T3) neogenesis in lean and obese LA/N-cp rats. Tulp OL, McKee ST. Pre-obese LA/N-cp rats consumed more food and gained weight more rapidly than their lean littermates, and measures of adipose tissue depots indicated that the excess weight was deposited principally as carcass fat. Serum T3 concentrations and resting metabolic rates were lower in corpulent than in lean animals, consistent with a greater efficiency of weight gain in those animals. In vitro measures of T3 neogenesis from T4 were lower in corpulent than in lean animals in liver, kidney, and skeletal muscle and greater in interscapular brown adipose tissue. The intracellular generation of T3 from T4 is a fundamental component of the normal adaptive response to alterations in diet and environment, and is an essential prerequisite for the expression of non-shivering thermogenesis. These results are consistent with a functional impairment in the activity of the enzyme T4-5'-deiodinase in peripheral tissues, and suggest that this impairment is contributory if not causative of obesity in this strain of rat. PMID: 3778441 [PubMed - indexed for MEDLINE] 253. Pol J Pharmacol Pharm. 1986 Sep-Dec;38(5-6):417-23. Effects of prazosin on metabolism and body temperature in normothermic rabbits. Matuszek M, Szreder Z, Korolkiewicz Z. An attempt was made to study the influence of prazosin on thermoregulatory parameters. Two sets of experiments were carried out in rabbits. In the first set of experiments prazosin was given as 3 h infusion intravenously, (iv) (0.1, 0.25 and 0.5 mg/kg/h) or intracerebroventricularly, (icv) (20, 50 and 100 micrograms/animal) at an ambient temperature of 22 degrees C. Iv infusion caused a fall while icv administration a rise in body temperature. In the second set of experiments at different ambient temperatures (Ta = 4, 22, 28 degrees C) the following thermoregulatory parameters were recorded: rectal (Tre) and ear skin (Te) temperatures, metabolic rate (M), respiratory heat loss (Eres). The most evident result of iv infusion of prazosin in a dose of 0.25 mg/kg/h was a fall in Tre accompanied by a decrease in metabolic rate at ambient temperature of 4 degrees C. At Ta of 22 degrees C and 28 degrees C prazosin iv (0.25 mg/kg/h) induced only minimal changes in measured parameters. The results of the experiments may suggest that prazosin given peripherally induced hypothermia at Ta of 4 degrees C by inhibition of non-shivering thermogenesis. PMID: 3575162 [PubMed - indexed for MEDLINE] 254. Clin Endocrinol (Oxf). 1986 Jul;25(1):55-65. Alterations in the hypothalamic-pituitary-thyroid axis after prolonged residence in Antarctica. Reed HL, Burman KD, Shakir KM, O'Brian JT. The human population which lives and works in polar environments has been increasing steadily over the last 15 years. Very little is known about how these residents adjust to their environment. Cold adaptation in man is a poorly understood phenomenon. Euthermic mammals maintain body temperature during cold exposure via non-shivering thermogenesis, a process which is hormonally mediated. We studied prospectively the response of the hypothalamic-pituitary-thyroid axis in 17 euthyroid men before, during and after assignment to duty in the Antarctic. Serum total and free T4 levels fell slightly but not significantly after very prolonged Antarctic residence. Serum total and free T3 decreased significantly from basal levels of 170 +/- 3 ng/dl and 388 +/- 19 pg/dl to 155 +/- 5 ng/dl and 319 +/- 14 pg/dl respectively after Antarctic duty. Serum T3 levels increased after 42 weeks of polar living, the end of the observation period, but the change did not attain statistical significance. The integrated TSH response to TRH administration increased by 50% to 734 +/- 58 microIU.min/ml over warm climate basal response levels of 456 +/- 33 microIU.min/ml by the end of the study. The daily circadian rhythm of serum cortisol was maintained throughout the study period. The alterations in thyroid hormones which we describe, are apparently related to the chronic cold exposure which our subjects experienced in this polar environment. PMID: 3098460 [PubMed - indexed for MEDLINE] 255. J Physiol. 1986 Jun;375:27-38. Multilocular adipocytes from muscovy ducklings differentiated in response to cold acclimation. Barré H, Cohen-Adad F, Duchamp C, Rouanet JL. Morphological and functional aspects of adipose tissue from 6-week-old cold-acclimated muscovy ducklings reared at 4 degrees C ambient temperature (Ta) from the age of 1 week were examined for the occurrence of brown adipose tissue (b.a.t.) in order to explain non-shivering thermogenesis (n.s.t.) observed at this age. Metabolic rate and integrated muscle electrical activity (e.m.g.) were measured at different Ta (from -10 to +28 degrees C) in cold-acclimated and in control ducklings reared at thermoneutrality. The results confirm the existence of n.s.t. in 6-week-old cold-acclimated muscovy ducklings. In cold-acclimated ducklings, typical multilocular adipocytes were found in subcutaneous adipose deposits instead of the unilocular white adipocytes as in control ducklings. Mitochondria isolated from this differentiated tissue were less abundant than in b.a.t. of mammals. Their respiration rate was similar to the respiration rate of white adipose tissue mitochondria from control rats and much lower than the b.a.t. mitochondria rate from cold-acclimated rats. It is therefore unlikely that this differentiated adipose tissue contributes to the n.s.t. observed, an n.s.t. whose capacity reached 5.26 W/kg (+73.5% above resting metabolic rate) in cold-acclimated ducklings. The role of this differentiated adipose tissue in the metabolic adaptation to cold is discussed. PMCID: PMC1182745 PMID: 3795059 [PubMed - indexed for MEDLINE] 256. Reprod Nutr Dev. 1986;26(2B):637-42. [Thermogenesis induced by diet in the 2- and 7-day-old Zucker rat]. [Article in French] Planche E, Joliff M. Gas exchanges were measured at the thermoneutral temperature of 35 degrees C on "fasted" (3 h 30 min) and then "refed" (75 min) fa/fa and Fa/fa rats aged 2 and 7 days. The CO2 production, O2 consumption and respiratory quotient increased significantly after refeeding in all pups. The percentage of increase in the gas exchanges was similar in both genotypes at 2 days. At 7 days, the percentage of increase was significantly higher in Fa/fa than in fa/fa pups. This demonstrated a defect in diet-induced thermogenesis in 7-day old pups. However, since this defect (unlike non-shivering thermogenesis) was absent in 2-day old pups, it is concluded that it is probably not a primary factor but rather a consequence of the obesity already present in fa/fa pups at 7 days of age. PMID: 3726271 [PubMed - indexed for MEDLINE] 257. J Perinat Med. 1986;14(1):27-33. Temperature regulation in healthy and resuscitated newborns immediately after birth. Schubring C. Oxygen consumption (VO2) is a sensitive and reliable indicator of any disturbances of thermoregulatory adaptation in the newborn. This study has been carried out in a attempt to find out, if there is any difference between the thermoregulatory processes of healthy and resuscitated neonates. To this end, both VO2 and rectal temperature (RT) were continuously measured in 31 healthy and 13 resuscitated neonates respectively, within the first 140 postnatal minutes and during 30 minutes from the second until the fifth day of their lives. In the healthy neonates, the VO2 used to decrease over the study period. The high initial VO2 observed postnatally is due to mechanisms of thermoregulation beginning immediately after delivery as soon as the newborn child is exposed to chilly environmental temperatures. The brown adipose tissue (BAT) is supposed to be the essential site of non-shivering thermogenesis (NST). The thermogenetic function of this tissue may be shown by local measuring of temperature. In the resuscitated neonates, VO2 was lower than in the healthy children. Hypoxia results in an ineffective capillary blood supply of the BAT owing to a redistribution of circulating blood volume, thus leading to a disturbance of thermoregulation. Since the activity of the BAT is dependent on oxygen supply hypoxia might be regarded as the limiting factor. In the presence of an isothermal environment, the RT measured in the healthy children differed from those determined in the resuscitated neonates. This clearly shows that thermoregulatory processes may be impaired by a difficult birth.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 3701561 [PubMed - indexed for MEDLINE] 258. Biochim Biophys Acta. 1986;853(3-4):187-204. Evidence for the existence of an inner membrane anion channel in mitochondria. Garlid KD, Beavis AD. Mitochondria normally exhibit very low electrophoretic permeabilities to physiologically important anions such as chloride, bicarbonate, phosphate, succinate, citrate, etc. Nevertheless, considerable evidence has accumulated which suggests that heart and liver mitochondria contain a specific anion-conducting channel. In this review, a postulated inner membrane anion channel is discussed in the context of other known pathways for anion transport in mitochondria. This anion channel exhibits the following properties. It is anion-selective and inhibited physiologically by protons and magnesium ions. It is inhibited reversibly by quinine and irreversibly by dicyclohexylcarbodiimide. We propose that the inner membrane anion channel is formed by inner membrane proteins and that this pathway is normally latent due to regulation by matrix Mg2+. The physiological role of the anion channel is unknown; however, this pathway is well designed to enable mitochondria to restore their normal volume following pathological swelling. In addition, the inner membrane anion channel provides a potential futile cycle for regulated non-shivering thermogenesis and may be important in controlled energy dissipation. PMID: 2441746 [PubMed - indexed for MEDLINE] 259. J Auton Nerv Syst. 1985 Dec;14(4):377-86. Fluorescent histochemical demonstration of catecholamines in brown adipose tissue from obese (ob/ob) and lean mice acclimated at different temperatures. Ashwell M, Dunnett SB. Fluorescent histochemistry was used to visualize catecholamines in brown adipose tissue (BAT) of lean and genetically obese mice after they had been acclimated at different temperatures. At all temperatures, strong catecholamine-dependent fluorescence, attributable to the sympathetic innervation, was seen around the blood vessels of BAT from both lean and obese animals. Additionally, catecholamine-dependent fluorescent varicosities, in direct contact with the adipocytes were seen in abundance in lean mice acclimated at 23 degrees, 13 degrees or 4 degrees C and in obese mice acclimated at 13 degrees C. This latter compartment was greatly reduced in lean mice acclimated at 33 degrees C and in obese mice acclimated at 23 degrees and 33 degrees C. Three acute treatments (pretreatment with a monoamine oxidase inhibitor; 24 h food deprivation; and short-term cold exposure followed by short-term warm exposure) all increased the varicose fluorescence associated with adipocytes in obese mice housed at 23 degrees C, which suggests that the low resting level in these animals is attributable, at least in part, to subthreshold concentrations of catecholamines in existing varicosities rather than the absence of sympathetic varicosities per se. These results are in accordance with the results from noradrenaline turnover studies which suggest that the difference in sympathetic nervous system (SNS) activity in BAT from lean and obese (ob/ob) mice is best demonstrated at normal environmental temperatures. The reduced SNS activity in BAT of obese mice (which our studies show to be at the 'cellular' level) is likely to be a major factor in their reduced non-shivering thermogenesis and resultant high efficiency of energy storage as previously suggested by other workers. PMID: 4086726 [PubMed - indexed for MEDLINE] 260. Physiol Behav. 1985 Jul;35(1):15-20. Hypothalamic modulation of energy expenditure. Atrens DM, Sinden JD, Pénicaud L, Devos M, Le Magnen J. The acute effects of electrical stimulation of the hypothalamus on energy expenditure as measured by indirect calorimetry were investigated in 20 unanaesthetized rats. Thirty sec of stimulation increased both O2 consumption and respiratory quotient (R.Q.). The largest magnitude hypermetabolic response (39% mean peak increase in O2 consumption) was produced by stimulation of the ventromedial hypothalamic nucleus. Stimulation of the lateral hypothalamus produced hypermetabolic effects similar to but smaller than those produced by medial stimulation. A number of considerations suggest that the hypermetabolism is not secondary to changes in motor activity, carbohydrate utilization or blood glucose levels. Consequently, these data suggest that the hypothalamus modulates energy expenditure through changes in non-shivering thermogenesis. These metabolic changes may modulate the effects of various hypothalamic manipulations on body weight. PMID: 4059396 [PubMed - indexed for MEDLINE] 261. Brain Res Bull. 1985 Jun;14(6):585-93. Impaired diet-induced thermogenesis in brown adipose tissue from rats made obese with parasagittal hypothalamic knife-cuts. Coscina DV, Chambers JW, Park I, Hogan S, Himms-Hagen J. Two experiments were performed to determine if bilateral parasagittal hypothalamic knife-cuts (KCs), which produce long-term overeating and obesity, after biochemical indices of brown adipose tissue (BAT) reactivity to thermogenic stimuli. In the first study, responses to environmental cold were tested. Four weeks after surgery, KC rats had gained 4-5 times more weight than controls and were obese (increased Lee Obesity Index and weight of gonadal white fat). Before being sacrificed, groups of KC and control rats were exposed to 4 degrees C for 21 hr or remained at 28 degrees C. Interscapular BAT weighed 300% more in KC rats, due largely to increased white fat content. Functional indices of BAT thermogenic capacity (protein content, DNA content, cytochrome oxidase activity and mitochondrial guanosine diphosphate (GDP) binding) were normal at 28 degrees C. Exposure to 4 degrees C produced greatly enhanced responses but these were equivalent for both groups. This suggested an intact capacity for non-shivering thermogenesis in obese KC rats. In the second study, the same BAT responses were examined in other rats fed a palatable "cafeteria" diet (CAFE). One week after surgery, KC and control rats were subdivided into groups that received chow alone or chow plus four different palatable foods daily. Before sacrificing 4-5 weeks later, KC rats had gained 3-4 times more weight than controls and were obese. Interscapular BAT weighed 200-300% more in KC rats. CAFE feeding produced larger increments in all variables for KC vs. control rats. Most importantly, GDP binding was reduced in both KC groups, and significantly more so after CAFE feeding.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 4027698 [PubMed - indexed for MEDLINE] 262. Life Sci. 1985 May 27;36(21):2025-32. Improving cold tolerance in elderly rats by aminophylline. Lee TF, Wang LC. During severe cold exposure, old rats (23-26 months) were less capable in maintaining normal body temperature as compared to young rats (6-9 months) due to lower rate of heat production (HP). Single injection of optimal doses of aminophylline (AMPY; 10 and 18.7 mg/kg, i.p.), a phosphodiesterase inhibitor which enhances the intracellular cyclic AMP concentration, significantly increased the rate of HP in old rats to levels beyond the control values observed in young rats. Consequently, cold tolerance of the old rats was significantly improved. This AMPY-improved cold tolerance is apparently not due to increased non-shivering thermogenesis (NST) since AMPY failed to enhance norepinephrine-stimulated NST in the old rats. It is likely that AMPY increased substrate mobilization and/or conversion, thereby circumventing the limiting role of substrate availability for shivering thermogenesis. Thus, the age-dependent decrease in cold tolerance may be due to a reduced capacity for substrate mobilization when challenged by cold. PMID: 3999913 [PubMed - indexed for MEDLINE] 263. Arch Toxicol. 1985 Feb;56(4):279-82. Hypothermia produced by tributyl S,S,S-phosphorotrithioate (DEF). Ray DE, Cunningham VJ. Tributyl S,S,S-phosphorotrithioate (DEF) produces profound hypothermia in rats, mice and guinea pigs by inhibition of thermogenesis. Its actions on heat conservation and motor control are, however, minimal. It is effective against both shivering and non-shivering thermogenesis and completely blocks the increase in body temperature evoked by anterior hypothalamic stimulation. A number of other measures indicated that this is unlikely to be due to a lack of peripheral thermogenic capacity: thus plasma concentrations of glucose, free fatty acids, and ketone bodies remained normal or rose after DEF, and in vitro noradrenaline-stimulated lipolysis was normal in the presence of DEF. The metabolic response to the uncoupler, 2,4-dinitrophenol was unchanged by DEF, and the increase in temperature of brown fat evoked in vivo by nerve stimulation or noradrenaline was also unaffected. It is suggested that DEF (or more likely a DEF metabolite) acts selectively on a central thermogenic control process. PMID: 3994512 [PubMed - indexed for MEDLINE] 264. Acta Physiol Scand. 1985 Feb;123(2):215-20. Some aspects of thermoregulation in newborn reindeer calves (Rangifer tarandus tarandus). Markussen KA, Rognmo A, Blix AS. At birth reindeer calves often are exposed to sub-zero ambient temperatures (Ta) sometimes even combined with wind and precipitation. The resting metabolism was measured in three different age groups (1, 7 and 14 days old) at Ta's of -20, -5, 10 and 20 degrees C. Resting metabolism in the thermoneutral zone decreased from 5.1 W X kg-1 at day 1 and 7 to 4.8 W X kg-1 at day 14. At day 1 apparent lower critical temperature (Tlc) was 11 degrees C, while at day 7 it was 7.7 degrees C and at day 14 7.3 degrees C, but total body conductance continued to decrease below apparent Tlc. At Ta's of -5 and -20 degrees C total body conductance was: 0.77 and 0.72 W X degrees C-1 at day 1, 0.98 and 0.92 W X degrees C-1 at day 7, 1.08 and 0.91 W X degrees C-1 at day 14, respectively. Thermal conductance of pelt samples from the trunk was determined in vitro at different combinations of windspeed, Ta and wetness. The conductance of dry fur increased from 5.9 to 11.8 W X m-2 X degrees C-1 at a windspeed of 0 and 10 m X s-1, respectively, as compared to 28.7 W X m-2 X degrees C-1 when wetted without wind. Newborn reindeer calves seem to be heavily dependent on non-shivering thermogenesis in brown adipose tissue for their cold defence since deep body temperature in a calf subjected to propranolol infusion when exposed to a Ta of -25 degrees C in combination with a 10 m X s-1 windspeed increased its cooling rate five times. PMID: 2858960 [PubMed - indexed for MEDLINE] 265. Acta Paediatr Hung. 1985;26(3):227-31. Absence of responses in energy metabolism and respiratory quotient to carnitine infusion in premature infants. Rubecz I, Sándor A, Hamar A, Vincellér M, Mestyán J. Plasma levels of total, free and acylcarnitine, as well as oxygen consumption and respiratory quotient were determined in premature infants maintained at neutral temperature. The effects on these parameters of intravenous infusion of 24 mg/kg/day carnitine were studied. Total, free and acylcarnitine increased and the acyl/free carnitine ratio decreased significantly during the four-hour study period. Resting heat production and respiratory quotient remained practically unchanged throughout the study period, indicating that in the face of carnitine sufficiency exogenous carnitine did not influence whole body heat production and substrate utilization pattern in premature infants. Further examinations in carnitine depleted infants will be required to clarify the regulatory role of carnitine in neonatal fatty acid metabolism and non-shivering thermogenesis. PMID: 4084411 [PubMed - indexed for MEDLINE] 266. Reprod Nutr Dev. 1985;25(1B):175-81. Factors controlling brown adipose tissue development. Ricquier D, Mory G, Bouillaud F, Combes-George M, Thibault J. Brown adipose tissue (BAT) is a site of non-shivering thermogenesis in mammals. Thermogenesis in brown adipocytes is related to the presence of a specific mitochondrial component called "uncoupling protein". When animals are chronically exposed to cold, their BAT is enlarged and exhibits several changes such as cellular differentiation, hyperplasia, mitochondriogenesis and marked synthesis of uncoupling protein. The hormonal and neural factors controlling this adaptive response have been studied. It is concluded that sympathetic innervation of BAT and released noradrenaline play an essential role in the development of BAT. PMID: 3887525 [PubMed - indexed for MEDLINE] 267. Sports Med. 1985 Jan-Feb;2(1):59-71. Adaptation to exercise in the cold. Shephard RJ. The winter athlete has several potential tactics for sustaining body temperature in the face of severe cold. An increase in the intensity of physical activity may be counter-productive because of increased respiratory heat loss, increased air or water movement over the body surface, and a pumping of air or water beneath the clothing. Shivering can generate heat at a rate of 10 to 15 kJ/min, but it impairs skilled performance, while the resultant glycogen usage hastens the onset of fatigue and mental confusion. Non-shivering thermogenesis could arise in either brown adipose tissue or white fat. Brown adipose tissue generates heat by the action of free fatty acids in uncoupling mitochondrial electron transport, and by noradrenaline-induced membrane depolarisation and sodium pumping. The existence of brown adipose tissue in human adults is controversial, and although there are theoretical mechanisms of heat production in white fat, their contribution to the maintenance of body temperature is small. Acclimatisation to cold develops over the course of about 10 days, and in humans the primary change is an insulative, hypothermic type of response; this reflects the intermittent nature of most occupational and athletic exposures to cold. Nevertheless, with more sustained exposure to cold air or water, humans can apparently develop the humoral type of acclimatisation described in small mammals, with an increased output of noradrenaline and/or thyroxine. The associated mobilisation of free fatty acids suggests the possibility of using winter sport as a pleasant method of treating obesity. In men, a combination of moderate exercise and facial cooling induces a substantial fat loss over a 1- to 2-week period, with an associated ketonuria, proteinuria, and increase of body mass. Possible factors contributing to this fat loss include: (a) a small energy deficit; (b) the energy cost of synthesising new lean tissue; (c) energy loss through the storage and excretion of ketone bodies; (d) catecholamine-induced 'futile' metabolic cycles with increased resting metabolism; and (e) a specific reaction to cold dehydration. Current limitations for the clinical application of such treatment include uncertainty regarding optimal environmental conditions, concern over possible pathological reactions to cold, and suggestions of a less satisfactory fat mobilisation in female patients. Possible interactions between physical fitness and metabolic reactions to cold remain controversial.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 3883460 [PubMed - indexed for MEDLINE] 268. Int J Obes. 1985;9(6):423-32. The thermogenic role of adipose tissue in the dog. Holloway BR, Stribling D, Freeman S, Jamieson L. Brown adipose tissue was clearly present in neonatal dogs. In the adult the tissue was superseded by a tissue with the gross characteristics of white adipose. However despite their appearance adult adipose tissue depots may contribute to non-shivering thermogenesis. Regional blood flow measurements using injected radioactive microspheres indicated large increases in blood flow to adipose depots during infusion of noradrenaline. Coupled with blood flow estimations, measurement of arteriovenous differences in dissolved oxygen across the bladder fat depot demonstrated a quantitative increase in oxygen extraction by the depot during noradrenaline infusion. Acute activation of non-shivering thermogenesis in the dog was not associated with increased mitochondrial GDP-binding in adipose tissue. However chronic treatment with a beta-stimulant (LY79730) which increased capacity for non-shivering thermogenesis was associated with increased mitochondrial GDP-binding and cytochrome oxidase activity in peri-renal adipose tissue. PMID: 3007382 [PubMed - indexed for MEDLINE] 269. Int J Obes. 1985;9 Suppl 2:81-8. Brown adipose tissue thermogenesis and the energetics of lactation in rodents. Trayhurn P. Brown adipose tissue thermogenesis has been shown to be suppressed during lactation in rats and mice. In parallel with this suppression there is a reduction in the capacity for non-shivering thermogenesis in the whole animal. The extent to which thermogenesis is reduced in lactation is related to litter size, the larger the litter the greater being the reduction. It is argued that the suppression of brown adipose tissue thermogenesis during lactation results in a substantial economy in the non-lactational component of maternal energy expenditure. PMID: 2999015 [PubMed - indexed for MEDLINE] 270. Jpn J Physiol. 1985;35(3):423-42. Lasting consistency of cold adaptability in rats reared in cold for many generations. Moriya K, Yahata T, Kuroshima A. Wistar rats were successively reared in cold at 5 degrees C from 1969 to 1984. The historical changes observed in these rats were reported. The cold-adapted rats reared in cold for 8 to 11 successive generations (C8-11G) were examined on their cold tolerance and non-shivering thermogenesis. C8-11G rats showed greater nonshivering thermogenesis than that of the warm-adapted control group (W), and rats exposed to cold for periods of 2 to 8 weeks (C). The nonshivering thermogenesis of C8-11G rats was diminished to a similar level to that of W and C rats by administration of a ganglion blocker, of reserpine, or of beta-adrenoceptor blocker. The de-adapted rats reared in warm at 25 degrees C for 3 generations after being reared for many generations in cold (DA-3G) showed much more nonshivering thermogenesis as compared to W rats. Cold tolerance of DA-3G rats was at a level of intermediate between that of W and C rats. Brown adipose tissue (BAT) weight of DA-3G rats was similar to that of C rats, while chemical composition of BAT in DA-3G rats differed from that of C and W rats. PMID: 2865387 [PubMed - indexed for MEDLINE] 271. Acta Physiol Scand. 1984 Dec;122(4):443-53. Modes of thermal protection in newborn muskoxen (Ovibos moschatus). Blix AS, Grav HJ, Markussen KA, White RG. The muskoxen (Ovibos moschatus), a native of Greenland and the Canadian North West Territories, give birth in late April, and the newborn calves are known to tolerate an ambient temperature (Ta) of -35 degrees C. At birth the calves weigh about 8 kg, increasing in weight with 0.6 kg . day-1 for the first 30 days. With a deep body temperature (DBT) of 39.5 degrees C (range 37.7-41.3 degrees C) the newborn calves are consequently able to maintain a thermogradient of at least 70 degrees C between body core and the environment. The calves use primarily two modes of thermal protection: High metabolic heat production and prime fur insulation. Metabolic rate was about 3.5 W . kg-1 at thermoneutrality in calves aged from 8 h to 7 days. Lower critical temperature at this age was about -7 degrees C and a drop in Ta to -30 degrees C increased metabolism to about 5.3 W . kg-1. Upper critical temperature at age 4-7 days is as low as 20 degrees C, while it in calves aged only 18-24 h appears to be even lower. The calves possess great amounts of brown adipose tissue (BAT) at birth. Mitochondria from the BAT deposits were isolated and found to be in an extremely loose-coupled state with a great capacity for thermogenesis. Skeletal muscle contained very few mitochondria and is hardly employed in aerobic non-shivering thermogenesis. Calves shiver visibly while drying just after birth, but are normally not seen shivering thereafter. The conductance value for the dry pelt of newborn calves averaged 3.2 W . m-2 . 0 degrees C-1 (n = 4). Wetting of the pelt with ice-water at a Ta of 3 degrees C increased conductance to 8.8 W . m-2 . 0 degrees C-1. The conductance of the pelt was also influenced by wind, being 10 W . m-2 . C-1 at a wind-speed of 10 m . sec-1. The legs of the newborn calves are heavily furred and countercurrent circulation is not present, subcutaneous temperature just above the hooves being +29.8 degrees C at Ta of -24 degrees C as compared to 37.5 degrees C on the back. The newborn calves could cope with a Ta of -30 degrees C without apparent problems under experimental conditions, but they suffered hypothermia when exposed to a Ta of -33 degrees C in combination with wind of 10 m . sec-1.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 6524390 [PubMed - indexed for MEDLINE] 272. Life Sci. 1984 Oct 15;35(16):1699-704. Impaired activation of thermogenesis in the corpulent rat. Tulp OL. The capacity for non-shivering thermogenesis was measured in groups of 12 week-old congenic lean and corpulent LA/N-cp rats of both sexes to determine if their obese state might be associated with an impairment in energy expenditure via non-shivering thermogenesis. Body weights of the corpulent phenotypes were 1.6 to 1.8 times greater than those of the lean phenotype. Measurements of resting oxygen consumption were similar in lean and in corpulent rats, and were greater in female than in male rats. Isoproterenol stimulation resulted in a significant increase in oxygen consumption in lean rats, while the rates of oxygen consumption of isoproterenol-stimulated corpulent rats were unchanged. Acute exposure of male rats to a 5 degrees C cold environment resulted in significant decreases in colonic and in rectal temperature in both phenotypes, but body temperatures recovered more rapidly in lean than in corpulent rats. Urinary VMA excretion was greater in lean than in corpulent rats and increased following cafeteria-feeding in lean but not in corpulent rats. These observations are consistent with an impaired mechanism of sympathetically-mediated thermogenesis in the corpulent phenotype of the LA/N-cp rat, and which may be a contributing factor in the development of their obese state via a decreased capacity for energy expenditure. PMID: 6482675 [PubMed - indexed for MEDLINE] 273. Life Sci. 1984 Mar 19;34(12):1101-9. Effects of fasting and aminophylline on norepinephrine-stimulated non-shivering thermogenesis. Jourdan ML, Wang LC, Christopherson RJ. In an attempt to further elucidate the mechanisms of fasting-depressed maximum thermogenesis and cold tolerance, norepinephrine (NE)-stimulated non-shivering thermogenesis (NST) in cold-acclimated rats was used as a functional index of possible alterations in adrenergic efficacy after fasting. Fasting decreased the magnitude of maximum NE-Stimulated NST by 18.2% [6.87 +/- 0.47 Kcal (Kg X 75 X min)-1 well-fed vs. 5.81 +/- 0.39 Kcal (Kg X 75 X min)-1 fasted], but the apparent adrenergic binding affinity was not affected [Ke = 0.43 micrograms NE min-1 well-fed vs. 0.55 micrograms NE min-1 fasted]. Pretreatment with aminophylline [15 mg Kg-1, i.p.], a phosphodiesterase inhibitor, restored the fasting-depressed NE-stimulated NST to the fed level. The results suggest that the depression of maximum thermogenesis after fasting is not due to changes in adrenergic binding characteristics but to alteration in cAMP production/degradation, resulting in decreased substrate mobilization for thermogenesis. PMID: 6323899 [PubMed - indexed for MEDLINE] 274. Pflugers Arch. 1984 Feb;400(2):171-7. Brown adipose tissue and thermogenesis in hypophysectomized rats in relation to temperature acclimation. Laury MC, Azma F, Zizine L, Portet R. The aim of this work was to test the role of pituitary dependent hormones in cold-induced non-shivering thermogenesis. In the 28 degrees C-acclimated rat, hypophysectomy inhibited body growth and led to an atrophy of thyroid and adrenals. In brown adipose tissue (BAT) some alterations were induced which are usually observed after cold acclimation of the animal: increase in relative weight, decreases in the relative amount of lipids, increases in the amounts of protein and DNA and modification of the proportions of several phospholipid fatty acids; moreover, basal lipolysis, in vitro, was enhanced to the same extent as that following cold acclimation of the normal rat. The in vivo stimulation by norepinephrine (NE) of O2 consumption (test for nonshivering thermogenesis) and of fatty acid release into blood were suppressed. Progressive cold acclimation of the hypophysectomized rats at 15 degrees C led to a hypertrophy of BAT to the same extent as in the sham-operated animals. The in vivo sensitivity to NE was partially restored. The results suggest that hypophysectomy does not suppress the ability to acclimate to moderate cold by means of BAT dependent non-shivering thermogenesis. However, the low ability to produce heat seems to indicate that pituitary or pituitary-dependent hormones are necessary to optimize the cold stimulation of brown fat thermogenesis. PMID: 6718222 [PubMed - indexed for MEDLINE] 275. Pflugers Arch. 1983 Aug;398(3):264-5. Decreased capacity for non-shivering thermogenesis during lactation in mice. Trayhurn P. The capacity for non-shivering thermogenesis (NST) has been measured during and after lactation in mice. NST was found to be reduced in early and mid-lactation and at the time of weaning, the reduction being greatest at mid-lactation. By one week after weaning, however, the capacity for NST had returned to the level in virgin animals. PMID: 6634385 [PubMed - indexed for MEDLINE] 276. Arch Int Physiol Biochim. 1983 Apr;91(1):35-42. Effect of cold adaptation on liver peroxisomes and peroxisomal oxidative activities of rat. A morphometric/stereologic and biochemical study. Pollera M, Locci-Cubeddu T, Bergamini E. The variations in liver peroxisomes and in peroxisomal enzymes were studied in the rat during adaptation to cold (5 degrees C). An increase in the number and in the volume and surface fractions of peroxisomes was detected by day 7. Qualitative ultrastructural changes of the peroxisome compartment were observed. Several peroxisomal enzyme activities were found to exhibit a significant increase with different temporal patterns. These results are discussed with regard to the possible contribution of liver peroxisomes to non-shivering thermogenesis. PMID: 6192781 [PubMed - indexed for MEDLINE] 277. Biosci Rep. 1983 Mar;3(3):217-24. Reduced lipogenesis in cafeteria-fed rats exhibiting diet-induced thermogenesis. Rothwell NJ, Stock MJ, Trayhurn P. Fatty-acid synthesis has been measured in vivo with 3H2O in cafeteria-fed rats exhibiting diet-induced thermogenesis. Synthesis was decreased in brown adipose tissue, the liver, white adipose tissue, and the carcass of the cafeteria-fed animals compared to rats fed the normal stock diet. Whole-body synthesis was also decreased in the cafeteria-fed group. Diet-induced thermogenesis, in contrast to cold-induced non-shivering thermogenesis, does not lead to increased fatty-acid synthesis and this is presumably due to the inhibitory effects on lipogenesis of the high dietary fat intake characteristic of cafeteria diets. The results also indicate that the energy cost of body fat deposition in cafeteria-fed rats is lower than in animals fed a low-fat/high-carbohydrate stock diet. PMID: 6860780 [PubMed - indexed for MEDLINE] 278. Exp Gerontol. 1983;18(3):199-210. Age-related changes in thermoregulation in male albino rats. Balmagiya T, Rozovski SJ. Male Sprague Dawley rats were followed longitudinally from 3 to 24 months of age. Resting oxygen consumption (VO2), measured in the thermal neutral zone (29 +/- 1.0 degrees C) decreased 47% between 3 and 24 months of age with a stable period from 6 to 9 months. Changes in rectal temperature in general followed changes in VO2. On the average the decline in rectal temperature from 3 to 24 months was 0.8 degrees C. Thermal conductance dropped initially from 3 to 6 months and remained stable during further age periods. Thermal circulation index rose slightly from 3 to 13 months, and dropped thereafter from 13 to 24 months. When animals were exposed to a mild cold challenge (18-19 degrees C for 90 min.), the increase in VO2 was the same from 3 to 13 months of age. At 24 months this increase was significantly higher. The capacity for non-shivering thermogenesis (NST) measured after norepinephrine stimulation declined from 3 to 6 months, remained stable from 6 to 9 months and declined to 13 months. The capacity for NST after a mild cold challenge was significantly decreased at 24 months of age. These results suggest that shivering thermogenesis (ST) may be the main source of heat production in the old organism when faced with a mild cold challenge. Since ST is more energy consuming than NST it may explain the accidental hypothermia which occurs often in the elderly. PMID: 6641822 [PubMed - indexed for MEDLINE] 279. Experientia Suppl. 1983;44:26-44. Thermogenic responses induced by nutrients in man: their importance in energy balance regulation. Jequier E. The regulation of body weight depends upon the control of food intake and the regulation of energy expenditure. In man, the control system for food intake may be overwhelmed by psychological or social influences and the thermogenic response to a variable energy input may play an important role in the energy regulatory system. Energy expenditure can be divided into 3 components: basal metabolic rate, thermogenesis and physical activity. Of these 3 components, thermogenesis, (i.e. the energy expended above the metabolic rate in the resting state) is the expenditure. The two main factors which contribute to thermogenesis, i.e food intake and cold exposure, elicit diet-induced thermogenesis (DIT) and non-shivering thermogenesis (NST), respectively. It is of interest to study thermogenesis in individuals who present a tendency to gain weight, in order to assess whether the thermogenic responses may be lower in these subjects than in lean controls. It has recently been shown that DIT consists of two separate components which can be described as "obligatory" and "regulatory" thermogenesis. The former is due to the energy costs of digesting, absorbing and converting the nutrients to their respective storage forms. The latter is an energy dissipative mechanism, mainly studied in animals. There is good experimental evidence showing that brown adipose tissue (BAT) is involved in the adaptive thermogenesis observed in rats fed a varied and palatable "cafeteria" diet. In addition, a thermogenic defect in BAT has been demonstrated in adult as well as young genetically obese animals, and this defect is present not only in adult, but also in young (12 day old) ob/ob mice, i.e. before the development of obesity. Thus, a defective thermogenesis seems to be a cause, rather than a consequence, of obesity in these animals. In man, the role of thermogenesis in energy balance regulation is not yet understood. Some conflicting results may have arisen from inadequate techniques to measure energy expenditure. In our laboratory, we have developed three different techniques to measure energy expenditure in man, namely direct calorimetry, indirect calorimetry using an open-circuit ventilated hood system, and a respiratory chamber. Data from recent studies on DIT in man support the concept that a defect in thermogenesis may contribute to energy imbalance and weight gain in obese individuals.(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 6357848 [PubMed - indexed for MEDLINE] 280. Comp Biochem Physiol A Comp Physiol. 1983;74(4):855-60. Effects of cold acclimation on the feeding pattern and energetic metabolism of genetically obese Zucker rats. Bertin R, Razanamaniraka I, De Marco F, Portet R. 1. The feeding pattern, growth rate and energetic metabolism were studied in obese Zucker rats of 5-12 weeks of age kept at ambient temperatures of 22 or 10 degrees C. 2. During this period, the increment in obesity of the 22 degrees C-exposed animal was found to be due to diurnal hyperphagia and not to a lowered resting metabolism. 3. In the 10 degrees C-exposed rat the development of non-shivering thermogenesis associated with a lack of enhancement of food intake leads to prevent the obesity. PMID: 6132732 [PubMed - indexed for MEDLINE] 281. Eur J Biochem. 1982 Dec 15;129(2):373-80. Fatty acids as acute regulators of the proton conductance of hamster brown-fat mitochondria. Locke RM, Rial E, Scott ID, Nicholls DG. Possible mechanisms are evaluated for the acute regulation of the hamster brown-fat mitochondrial proton-conductance pathway which is active during non-shivering thermogenesis. Isolated mitochondria are incubated under conditions designed to approximate to the non-thermogenic state, and the effect of the steady infusion of fatty acids or acyl derivatives upon respiration, membrane potential and membrane proton conductance is monitored continuously. Fatty acids increase the proton conductance with no detectable threshold concentration, allowing the generated acyl carnitine to be rapidly oxidized. The extent of depolarization and of respiratory increase is a function of the rate of infusion. Immediately infusion is terminated the conductance decreases, the mitochondria repolarize and respiration returns to the initial rate. Infusion of acyl-CoA and acylcarnitine cause only a slight depolarization or respiratory increase after high concentrations of these derivatives have accumulated. Any factor which decreases the rate of conversion of fatty acid to acyl-CoA potentiates the conductance increase. An effect of acyl-CoA upon chloride permeability is not specific to brown-fat mitochondria. Fatty acids infused into rat liver mitochondrial incubations produced a small conductance increase, comparable to that of acyl-CoA or acylcarnitine. It is concluded that fatty acids are the most plausible acute regulators of the proton conductance. The relation to the brown-fat-specific 32000-Mr protein is discussed. PMID: 6295765 [PubMed - indexed for MEDLINE] 282. Eur J Pharmacol. 1982 Oct 15;84(1-2):87-91. Cold acclimation and resistance to ethanol-induced hypothermia. Lomax P, Lee RJ. The fall in core temperature induced by a fixed dose of ethanol (1 g x kg-1 i.p.) was an exponential function of the ambient temperature over the range 0-18 degrees C. In rats acclimated to 4 degrees C for 7 days the dose response curve relating the fall in body temperature to ethanol was markedly attenuated. The hypothermic effect of ethanol declined exponentially over 20 days of exposure to 4 degrees C and by the 20th day the fall was no greater than in saline injected controls. Blood ethanol concentrations were similar in acclimated and non-acclimated rats indicating that pharmacokinetic factors do not account for the altered responses. Although the time course of the development of resistance to the hypothermic effect of ethanol parallels that of cold acclimation to 4 degrees C, and the development of non-shivering thermogenesis, the attenuated drug effect does not appear to be due to the altered metabolic activity of brown adipose tissue. It is suggested that the modulation of the effect of ethanol in lowering the thermoregulatory set point results from central nervous system adaptation to the environmental thermal stress. PMID: 7140822 [PubMed - indexed for MEDLINE] 283. J Auton Nerv Syst. 1982 Sep;6(2):225-35. Hypothalamic regulation of lipid metabolism in the rat: effect of hypothalamic stimulation on lipogenesis. Takahashi A, Shimazu T. The rates of fatty acid synthesis and syntheses of other lipids were measured in vivo by determining 3H-incorporation from tritiated water or 14C-incorporation from [U-14C]glucose into white adipose tissues (WAT), brown adipose tissue (BAT) and liver, during electrical stimulation of the ventromedial hypothalamic nucleus (VMH) and the lateral hypothalamic nucleus (LH) of female rats. Electrical stimulation of the VMH markedly increased the rate of fatty acid synthesis and the conversion of glucose to total lipids, glyceride glycerol and phospholipids in interscapular BAT, but not in parametrial or retroperitoneal WAT. Conversely, on VMH stimulation, the syntheses of total lipids, glyceride glycerol and phospholipids from glucose in the liver decreased slightly, though not significantly. Electrical stimulation of the LH had no such effect. Administration of insulin increased the rate of fatty acid synthesis in both brown and white adipose tissues and in the liver. The rate of disappearance of [14C]glucose and the concentration of insulin in the blood were not changed significantly by stimulation of the VMH. These data indicate that electrical stimulation of the VMH, but not the LH, enhances lipogenesis in BAT preferentially through a mechanism not involving insulin, but probably through activation of sympathetic innervation of BAT. The physiological significance of the findings is discussed in relation to hypothalamic function in controlling non-shivering thermogenesis and obesity. PMID: 6757306 [PubMed - indexed for MEDLINE] 284. Boll Soc Ital Biol Sper. 1982 Aug 30;58(16):1032-6. [Cold adaptation and changes in peroxisome enzyme in various organs of the rat]. [Article in Italian] Locci-Cubeddu T, Cizza G, Formichi R, Marcassa C, Bergamini E. In the rat brown fat peroxisomes - thermogenetic organules - an peroxisomal enzyme activities undergo remarkable changes during the adaptation to cold of the animals (see 3). In this paper was show that changes of peroxisomal enzyme activities occur also in liver and kidney during cold-adaptation. Catalase, L-hydroxyacid oxidase, uricase and D-aminoacid oxidase (DAO) were assayed as in (6). During cold-adaptation, the activity of the former three enzymes (Table 2) increases with the weight of the organs (Table 1) whereas that of DAO exhibits a much larger increase (Table 3). Results are discussed with regard to the contribution of the liver to non-shivering thermogenesis. PMID: 6128006 [PubMed - indexed for MEDLINE] 285. Life Sci. 1982 May 3;30(18):1525-30. Characteristics of diet-induced brown adipose tissue growth and thermogenesis in rats. Tulp OL, Gregory MH, Danforth E Jr. The characteristics of regional brown (BAT) and white adipose tissue (WAT) growth and of thermogenesis following experimental overfeeding were studied in groups of male Sprague-Dawley rats fed lab chow or cafeteria diets for 8 weeks postweaning. Regional BAT and WAT growth was determined by dissection and weighing, and thermogenesis was characterized by measurements of resting and norepinephrine (NE)-stimulated oxygen consumption, of serum thyroid hormone concentrations, and of 24-hour urinary NE excretion levels. Cafeteria feeding resulted in a 113% increase in total BAT, with the most prominent increases in the interscapular, thoracic, and perirenal regions. Retroperitoneal, epididymal, and omental WAT were significantly greater in cafeteria than in chow-fed rats. Resting oxygen consumption of cafeteria-fed rads increased by 10% and NE excretion by 64% compared to chow-fed controls, while serum T3 concentrations were nearly doubled in the cafeteria-fed rats. The thermogenic response to NE injection in cafeteria-fed rats was 102% of their resting levels, compared to a 51% increase in the chow-fed controls. The results indicate that increased BAT growth occurs in all primary BAT depots following cafeteria-feeding in rats, and that the greater BAT mass is qualitatively proportional to their greater capacity for non-shivering thermogenesis. Also, the increased NE excretion and greater serum T3 concentration are consistent with increased sympathetic and thyroidal activity and may in part explain the thermogenic response to diet in the rat. PMID: 7078352 [PubMed - indexed for MEDLINE] 286. Res Vet Sci. 1981 Jul;31(1):76-81. Evidence for the presence of brown adipose tissue in the pig. Dauncey MJ, Wooding FB, Ingram DL. Small quantities of tissue closely resembling brown adipose tissue have been found in pigs aged two to three months. The tissue, which was taken post mortem from near the great veins in the neck, in the subscapular area and close to the adrenal and thyroid glands, was embedded in connective tissue or white adipose tissue. Examination under the light microscope and electron microscope revealed the following features characteristic of brown adipocytes: multilocular fat: large, round nucleus; numerous mitochondria with cristae; the presence of large amounts of glycogen, and the close proximity of numerous unmyelinated nerve cells with synaptic vesicle filled varicosities. No mitochondrial inclusions were seen. It is suggested that this finding of brown adipose tissue could lead to a better understanding of the control of non-shivering thermogenesis. PMID: 7313324 [PubMed - indexed for MEDLINE] 287. Biochim Biophys Acta. 1981 Jun 23;664(3):549-60. Fatty acid synthesis in mouse brown adipose tissue. The influence of environmental temperature on the proportion of whole-body fatty acid synthesis in brown adipose tissue and the liver. Trayhurn P. Fatty acid synthesis has been measured in vivo with 3H2O in mice acclimated at different environmental temperatures (33, 22, 4 degrees C), and the importance of brown adipose tissue and the liver to whole-body fatty acid synthesis at each temperature assessed. At 33 degrees C, when non-shivering thermogenesis is minimal, the rate of fatty acid synthesis in interscapular brown adipose tissue was lower than in the liver, but higher than in white adipose tissue and the carcass. At 4 degrees C, when non-shivering thermogenesis is maximal, the fatty acid synthesis rate in interscapular brown adipose tissue was many times greater than in any other tissue. High fatty acid synthesis rates were also found in other brown adipose tissue depots--subscapular, dorsocervical and axillary--of cold-acclimated mice. In mice maintained at 22 degrees C the rate of fatty acid synthesis was also higher in brown adipose tissue than in other tissues. Overall, the relative importance of brown adipose tissue as a site of fatty acid synthesis increased with lower environmental temperatures, while that of the liver decreased. It was calculated that brown adipose tissue in total accounted for approx. 5% of whole-body fatty acid synthesis at 33 degrees C, 10% at 22 degrees C and 30% at 4 degrees C. In contrast, hepatic synthesis amounted to 32% of whole-body fatty acid synthesis at 33 degrees C, 16% at 22 degrees C and only 11% at 4 degrees C. An estimate of the contribution that de novo synthesis makes to total fatty acid utilization by interscapular brown adipose tissue suggests that fatty acid synthesis and breakdown constitutes a significant heat-dissipating 'cycle' in brown adipose tissue of cold-acclimated mice. Such a cycle is not evident in suckling animals since fatty acid synthesis in brown adipose tissue is very low during early development. PMID: 7272321 [PubMed - indexed for MEDLINE] 288. Acta Anaesthesiol Scand. 1981 Jun;25(3):215-8. Human body temperature and controlled cold exposure during moderate and severe experimental alcohol-intoxication. Risbo A, Hagelsten JO, Jessen K. In an attempt to obtain more conclusive data, especially concerning the condition in many cases of very high alcohol concentration, two groups of healthy volunteers were exposed to controlled cold surroundings in a climate chamber after i.v. infusion of 96% ethyl alcohol, 1-2 1/2 ml per kg bodyweight, supplemented with alcohol perorally; the maximum blood alcohol concentration measured was 57 mmol/l, corresponding to 2.62%. One group was not habituated to drinking; the other group was habituated to heavy drinking, but functioned well socially. During the stay in a neutral environment, the alcohol infusion caused a rapid elevation of skin temperature with a short, but significant delay in temperature elevation in the alcohol-habituated group. After controlled exposure to cold, a rapid fall in surface temperature back to pre-alcoholic infusion values was seen in both groups. During cold exposure, core temperature remained unchanged in both groups. No changes in plasma catecholamines were found. A 12-18% increase in metabolic rate was seen in both groups during cold exposure, probably as an expression of the specific dynamic effect of alcohol. That the observed vasoconstriction was sufficient to prevent an undue fall in core temperature is further supported by the fact that neither shivering, nor non-shivering thermogenesis was activated, as no visible shivering occurred and no rise in plasma catecholamines was seen. PMID: 7324838 [PubMed - indexed for MEDLINE] 289. Pflugers Arch. 1981 Jun;390(3):224-9. Contribution of skeletal muscle to the regulatory non-shivering thermogenesis in small mammals. Dubois-Ferrière R, Chinet AE. Energy dissipation (E) was measured by direct microcalorimetry in perifused resting soleus muscles from cold adapted, euthyroid, hypothyroid and hyperthyroid mice, before and during exposure to noradrenaline (NA), lipid substrates or ouabain. The thermogenic effect of NA on the muscle was transitory and it did not exceed 5% of basal E, in all groups of preparations. The substrate effects were larger than that of NA and were sustained. They were the largest in hypothyroid animals and were not potentiated by NA. Basal E and the thermogenic effects of NA and the lipid substrates were identical in preparations from mice adapted to 23 degrees C and to 8 degrees C. The inhibitory effect of ouabain in resting muscles was very small, but it was increased by adaptation to the lower temperature. Experiments performed on rat muscles perfused in situ showed much larger thermogenic effects of NA than that observed in perifused mouse muscles. It is suggested that the NA thermogenic effect in resting muscles from small mammals is essentially mediated by hemodynamic changes which tend to suppress a hypoxic and acidotic restriction of the metabolic rate, rather than by any direct effect of NA on skeletal muscle cells. PMID: 7196021 [PubMed - indexed for MEDLINE] 290. Pflugers Arch. 1981 Mar;389(3):237-42. Influence of noradrenaline on blood flow to brown adipose tissue in rats exhibiting diet-induced thermogenesis. Rothwell NJ, Stock MJ. 1. The influence of noradrenaline on regional blood flow was determined using radioactive microspheres in rats maintained on either stock diet or a palatable cafeteria diet. 2. Cardiac output and blood flow to brain, lungs, liver and skeletal muscle were similar for rats on the two diets. 3. Blood flow to total dissectable brown adipose tissue in control and cafeteria rats represented 1 and 2% of cardiac output respectively but these values rose to 7 and 15.5% during infusion of noradrenaline. 4. Arterial oxygen content was similar for all groups but the oxygen content of venous blood draining the interscapular brown adipose tissue fell to 6 ml O2/100 ml blood in control rats and 1 ml/100 ml in cafeteria rats after noradrenaline. 5. The total oxygen consumption of brown adipose tissue was calculated and found to account for 42% of the response to noradrenaline in control rats and 74% in cafeteria animals. The increments in the oxygen consumption of other tissues were almost identical in both groups and so all the diet-induced changes in thermogenic capacity can be attributed to increases in brown adipose tissue metabolism. 6. These findings demonstrate the quantitative importance of brown adipose tissue in diet-induced thermogenesis and confirm the similarities between diet and non-shivering thermogenesis. PMID: 7195009 [PubMed - indexed for MEDLINE] 291. Biochem J. 1981 Feb 15;194(2):653-6. Changes in mitochondrial components of hamster brown adipose tissue in response to cold acclimation. Yacoe ME. Cold acclimation of hamsters was found to result in an increase in cytochrome concentration relative to ATPase activity in brown adipose tissue mitochondria, but not in liver mitochondria. These data lend support to the hypothesis that the uncoupled respiration characteristic of non-shivering thermogenesis is the result of an adaptive change in the composition of brown adipose tissue mitochondria in response to cold acclimation. PMCID: PMC1162793 PMID: 6458282 [PubMed - indexed for MEDLINE] 292. Biochim Biophys Acta. 1980 Oct 6;620(1):10-7. Fatty acid synthesis in brown adipose tissue in relation to whole body synthesis in the cold-acclimated golden hamster (Mesocricetus auratus). Trayhurn P. The synthesis of fatty acids has been measured in vivo with 3H2O in brown adipose tissue, the liver, white adipose tissue and the 'carcass' of cold-acclimated (4 degrees C) golden hamsters (Mesocricetus auratus), and the results compared with those of warm-acclimated (30 degrees C) animals. In warm-acclimated hamsters the highest rate of synthesis was found in the liver, which accounted for more than a quarter of the total body synthesis. Cold-acclimation led to an almost 3-fold increase in whole-body fatty acid synthesis, compared to warm-acclimated animals, and this resulted from increases in all the individual tissues examined, particularly in brown adipose tissue. In cold-acclimated hamsters the rate of synthesis appeared to be similar in brown adipose tissue and the liver. However, studies with Triton WR 1339 suggested that at least one-half of the apparent synthesis in brown adipose tissue resulted from the rapid incorporation into the tissue of fatty acids synthesised elsewhere. On a whole-body basis, the liver made a much greater contribution than brown adipose tissue to total fatty acid synthesis in cold-acclimated hamsters; this is in marked contrast to the relative importance of these two tissues in cold-acclimated rats and mice. It is concluded that in the hamster, an animal widely used for studying the mechanisms of non-shivering thermogenesis in brown adipose tissue, the fatty acids utilised for generating thermoregulatory heat are synthesised principally in tissues other than brown adipose tissue. PMID: 7417474 [PubMed - indexed for MEDLINE] 293. Nature. 1980 Jul 17;286(5770):274-6. Increased proton conductance pathway in brown adipose tissue mitochondria of rats exhibiting diet-induced thermogenesis. Brooks SL, Rothwell NJ, Stock MJ, Goodbody AE, Trayhurn P. It has recently been demonstrated that in rats induced to overeat by being fed a varied and palatable diet (the 'cafeteria diet') there is a marked increase in heat production which serves to reduce, or prevent, the development of obesity. This diet-induced thermogenesis is associated with increases in sympathetic activity, and with changes in brown adipose tissue. Following cafeteria feeding, brown adipose tissue hypertrophies and and exhibits increased lipolysis and an apparently greater thermogenesis in response to noradrenaline. These metabolic changes resemble those seen during non-shivering thermogenesis in cold-adapted rats, and it was proposed that non-shivering thermogenesis and diet-induced thermogenesis have a similar metabolic origin which depends on the unique capacity of brown adipose tissue for thermogenesis. During non-shivering thermogenesis heat is produced in brown adipose tissue through a proton conductance pathway across the inner mitochondrial membrane that dissipates the proton gradient generated by respiration. The activity of the proton conductance pathway can be modulated by purine nucleotides, and changes in the pathway seem to be related to the level of purine nucleotide binding to brown adipose tissue mitochondria. We now report results which indicate that the proton conductance pathway is augmented in cafeteria-fed rats, and suggest that it operates to dissipate their excess energy intake through diet-induced thermogenesis PMID: 6250051 [PubMed - indexed for MEDLINE] 294. J Physiol. 1980 Jul;304:193-202. Thermoregulatory noradrenergic and serotonergic pathways to hypothalamic units. Brück K, Hinckel P. 1. In guinea-pigs hypothalamic single units were extracellularly tested for their response to thermal stimulation of the skin and to electrical stimulation of two different pontine areas, the nucleus raphé magnus and the dorsomedial reticular formation. Furthermore, thermoregulatory control actions were measured during the stimulations.2. Electrical stimulation of those reticular formation areas containing noradrenaline cells caused an increase of oxygen uptake, electrical muscle activity and body temperature, while stimulation of the nucleus raphé magnus, known to contain serotonin cells, brought about inhibition or had no effect.3. The recorded units could be subdivided into three groups. Cell type a. Neurones on the boundary of preoptic and anterior hypothalamic regions which increased their firing rate when the skin was cooled and decreased it when the nucleus raphé magnus was stimulated. Cell type b. Neurones in the anterior hypothalamus which did not respond to brain-stem stimulation. Cell type c. More posterior neurones which increased their firing rate when the skin was warmed or when the nucleus raphé magnus was stimulated and decreased their firing rate when the reticular formation was stimulated.4. Cell type a seems to represent interneurones which are connected to the ascending serotonergic thermoregulatory pathway. As for cell type c, it is inferred that it could represent interneurones which control the threshold for shivering and non-shivering thermogenesis. PMCID: PMC1282925 PMID: 7441533 [PubMed - indexed for MEDLINE] 295. J Dev Physiol. 1980 Jun;2(3):119-37. Sympathetic innervation and the development of structure and function of brown adipose tissue: studies on lambs chemically sympathectomized in utero with 6-hydroxydopamine. Alexander G, Stevens D. Fetal sheep were injected intramuscularly with 25-100 mg/kg of 6-hydroxydopamine HBr on 3-4 occasions between the 94th and 136th day of pregnancy. Following birth, which took place normally, the metabolic response to cold (summit metabolism) was found to be lower in treated than in control lambs, by an amount that approximated the thermogenic potential of brown fat. Under thermo-neutral conditions, the dose of infused noradrenaline (10 microgram kg-1 min-1) that stimulates maximum non-shivering thermogenesis in control lambs failed to stimulate thermogenesis in treated lambs unless accompanied by a dose of the alpha-blocker, phentolamine. This failure was apparently due to vasoconstriction induced by hypersensitivity to noradrenaline; hypersensitivity was also indicated when one-tenth of this dose was found to be fully effective in stimulating metabolism and substrate mobilization of the treated lambs. Examination of the perirenal adipose tissue of treated lambs with the electron microscope and by a monoamine fluorescence technique that visualizes catecholamine-containing structures, revealed that the tissue possessed the histological characteristics of brown fat, but there was little or no evidence of sympathetic innervation, in contrast with profuse innervation in control lambs. This is consistent with the observed hypersensitivity to noradrenaline. Similar histological findings were made in lambs that had received weekly intraperitoneal injections of 6-hydroxydopamine from day 70 of gestation, after which time sympathetic innervation normally begins to appear. It is probable that an intact sympathetic innervation is unnecessary for normal development of brown adipose tissue. This chemical sympathectomy appears to be long-lasting since treated lambs 8-months old were unable to vasoconstrict their extremities effectively in response to cold, and significant monoamine fluorescence could not be demonstrated in the various tissues examined. PMID: 7204907 [PubMed - indexed for MEDLINE] 296. Pflugers Arch. 1980 Jun;385(3):193-201. Regional blood flow in genetically obese (ob/ob) mice. The importance of brown adipose tissue to the reduced energy expenditure on non-shivering thermogenesis. Thurlby PL, Trayhurn P. PMID: 7190682 [PubMed - indexed for MEDLINE] 297. Pflugers Arch. 1980 May;385(1):25-8. Effect of the adrenocorticostatic agent, metopirone, on thermoregulatory heat production in the European hedgehog*. Werner R, Wünnenberg W. 1. Non-shivering thermogenesis (NST) was studied in 8 hedgehogs before and after a single injection of metopirone ditartrate (150-450 mg/kg, i.p.) at a thermoneutral chamber temperature (Ta) of 28C and during cold exposure (Ta = 8 degrees C for 20 min). 2. An average metabolic increase of 149% of the standard metabolic rate (SMR) was observed 12-26 min after an injection of metopirone ditartrate at thermoneutral chamber temperature. Average temperatures simultaneously increased by 2.1C in the brown adipose tissue (BAT) and 2.0C in the deep colon. This initial effect lasted for 40 plus or minus 8 min. 3. In a period of 3-48 h after injection of metopirone ditartrate, cold-induced NST was reduced by 89% of SMR (av.). Concomitant exposure to cold caused average temperatures to decrease by 1.0C in the BAT and 1.1 C in the colon relative to control experiments. 4. Our results suggest the participation of corticosteroids in the control of NST in the hedgehog. As metopirone blocks enzymatic 11 beta-hydroxylation in the steroid ring, there is a pronounced increase of endogenous 11-deoxycorticosteroids, such as deoxycorticoterone (DOC). An injection of DOC (3 mg/kg, i.m.) increases NST at hermoneutrality similar to the initial metabolic effect elicited by metopirone ditartrate. The reduced response to cold exposure after several hours may be explained by competitive inhibition of glucocorticoid receptors since there is also an increased production of other 11-deoxycorticosteroids. PMID: 7191094 [PubMed - indexed for MEDLINE] 298. Eur J Biochem. 1979 Dec;102(1):203-10. High number of high-affinity binding sites for (-)-[3H]dihydroalprenolol on isolated hamster brown-fat cells. A study of the beta-adrenergic receptors. Svoboda P, Svartengren J, Snochowski M, Houstĕk J, Cannon B. The beta-adrenergic receptors of hamster brown adipocytes have been characterised by binding of the radioactive ligand (-)-[3H]dihydroalprenolol, directly to isolated intact cells in suspension. The brown fat cell contains 57,000 specific and saturable binding sites which have a dissociation constant (Kd) for [3H]dihydroalprenolol of 1.4 nM as determined by Scatchard analysis. The kinetically derived Kd, determined from forward and reverse rate constants, is 5 nM. Both of these values are in agreement with the dissociation constant (Kd = 2.2 nM) for alprenolol, determined from competition studies with [3H]dihydroalprenolol in these cells. Beta-adrenergic agonists competed for the specific binding sites with a typical beta 1-adrenergic specificity. The order of potency of agonists agrees well with the ability of these agents to stimulate respiration in isolated brown adipocytes: 50% stimulation of respiration occurs with apparently less than 10% occupancy of binding sites. Both the high affinity and high number of specific binding sites of [3H]dihydroalprenolol in brown fat cells presumably reflect the generally accepted dominating role of catecholamines in the regulation of brown fat metabolism and non-shivering thermogenesis. PMID: 230037 [PubMed - indexed for MEDLINE] 299. Pflugers Arch. 1979 Jul;380(3):227-32. Thermoregulation in the diabetic-obese (db/db) mouse. The role of non-shivering thermogenesis in energy balance. Trayhurn P. 1. Thermoregulation and non-shivering thermogenesis have been studied in the genetically diabetic obese (db/db) mouse. 2. At all environmental temperatures between 33 and 10 degrees C the body temperature of the diabetic mice was lower than that of the normal littermates, the difference varying from 1.1 degrees C at 33 degrees C to 4.5 degrees C at 10 degrees C. 3. At 4 degrees C the diabetic mice rapidly died (3.2h) of hypothermia while the normal mice maintained their body temperature within the normal range. 4. At 23 degrees C the diabetic animals exhibited a diurnal rhythm in body temperature which was similar in both phase and amplitude to the controls, but at every point throughout the 24h cycle the temperature of the mutants was lower by 1--2 degrees C. 5. The resting metabolic rate at thermoneutrality (33 degrees C) was higher per whole animal for the diabetics than for the normals. However, at temperatures below thermoneutrality the converse was observed; between 30 and 4 degrees C the RMR of the mutants was lower than the controls by approximately 25%. 6. The capacity for non-shivering thermogenesis in diabetic mice was only one-half that found in normal animals. 7. The diabetic mouse has abnormalities in thermoregulation and non-shivering thermogenesis which are similar to those found in the genetically obese (ob/ob) mouse. It is concluded that the high metabolic efficiency of the diabetic mouse, like that of the ob/ob mouse, can be explained by a reduced energy expenditure on thermoregulatory thermogenesis; this may represent a primary mechanism for the operation of the "thirfty genotype" associated with obesity and diabetes. PMID: 573463 [PubMed - indexed for MEDLINE] 300. Br J Nutr. 1979 Mar;41(2):361-70. Effect of dietary composition and cold exposure on non-shivering thermogenesis in young pigs and its alteration by the beta-blocker propranolol. Dauncey MJ, Ingram DL. 1. Young pigs were fed on three diets consecutively, each diet being given for 1 week. The diets were given in random order as (g pig feed/kg body-weight): (a) 20, (b) 60, (c) 20 plus a supplement with the energy equivalent of 40 g pig feed/kg. The supplements included desiccated coconut, fish meal and glucose. 2. At the end of each week resting metabolic rate, beginning 12--14 h after feeding, was measured overnight using an open-circuit respiration chamber at thermoneutrality. 3. The oxygen consumption of pigs on the 60 g/kg diet was always higher than on the 20 g/kg diet. The addition of desiccated coconut, or fish meal also increased metabolic rate; whereas with added glucose, O2 consumption tended to be even lower than on 20 g/kg alone. 4. The administration of the beta-blocker propranolol to pigs on ad lib, food intake reduced the rate of overnight resting O2 consumption, measured from 10 until 20 h after feeding, by 12%, but it had no effect on O2 consumption when the intake was 20 g feed/kg. Exposure to mild cold (15 degrees) caused an increase in O2 consumption and this was reduced by 14% after injection of propranolol. PMID: 427088 [PubMed - indexed for MEDLINE] 301. Fiziol Zh SSSR Im I M Sechenova. 1979 Jan;65(1):61-6. [Changes in muscular thermogenesis in cold adapted rats following beta-adrenoreceptor blockade]. [Article in Russian] Pastukhov IuF, Valov RP, Sazonov VS. The administration of beta-adrenergic blocking agent propranolol to cold adapted rats entailed some decrease of the total metabolic reaction and body temperature as well as an additive (compensatory) increase of electrical muscle activity. The compensatory effect was more obvious in postural-tonic groups of muscles (m. trapezius, m. masseter) and in deeper portions of muscles (m. tibialis ant., m. trapezius), mainly presented by the red fibers. An adaptive increase of non-shivering thermogenesis and temperature effect of muscular contraction seem to be mainly controlled by beta-adrenergic mechanisms. PMID: 220103 [PubMed - indexed for MEDLINE] 302. Comp Biochem Physiol C. 1979;63C(1):31-4. The interaction of shivering and non-shivering thermogenesis in deer mice (Peromyscus maniculatus). Lilly FB, Wunder BA. PMID: 37038 [PubMed - indexed for MEDLINE] 303. J Physiol. 1978 Oct;283:569-84. The central control of shivering and non-shivering thermogenesis in the rat. Banet M, Hensel H, Liebermann H. 1. To test whether the preoptic area controls only non-shivering and the spinal cord only shivering thermogenesis, ten rats were chronically implanted with a preoptic and a spinal cord thermode each. The following were then studied: (a) the effect of propranolol (8 mg/kg.hr) on the metabolic response to cooling the preoptic area, and the spinal cord, (b) the effect of exogenous noradrenaline (0.5 mg/kg) on the metabolic response to cooling the preoptic area, and the spinal cord, and (c) the effect of warming the preoptic area on the metabolic response to cooling the spinal cord, and vice versa. 2. Administration of propranolol inhibited the metabolic response to cooling each of the thermosensitive areas, but the response to cooling the preoptic area was more strongly inhibited than that to cooling the spinal cord. 3. Administration of exogenous noradrenaline did not prevent the metabolic response to cooling either the preoptic area or the spinal cord. 4. Warming the spinal cord completely inhibited the metabolic response to cooling the preoptic area, and warming the preoptic area fully inhibited the metabolic response to cooling the spinal cord. 5. It is concluded that exogenous noradrenaline underestimates the capacity for non-shivering thermogenesis, and that both thermosensitive areas can control both forms of thermogenesis, but that the preoptic area threshold of non-shivering thermogenesis is probably lower than that of shivering, while the spinal cord threshold of shivering is probably lower than that of non-shivering thermogenesis. PMCID: PMC1282796 PMID: 722590 [PubMed - indexed for MEDLINE] 304. Pflugers Arch. 1978 Feb 22;373(2):189-93. Thermoregulation and non-shivering thermogenesis in the genetically obese (ob/ob) mouse. Trayhurn P, James WP. 1. The capacity ofr thermoregulation and thermogenesis in lean and genetically obese (ob/ob) mice has been investigated. 2. At 4 degrees C ob/ob mice rapidly die of hypothermia, because of a reduced capacity for cold-induced thermogenesis, but the animals are able to survive if previously adapted to 12 degrees C. 3. At all environmental temperatures between 30 degrees C and 10 degrees C the body temperature of ob/ob mice is 2.0-2.5 degrees C below that of lean animals. This may be due to a lower "setting" for body temperature. 4. At 34 degrees C the oxygen consumption of obese mice is greater than that of the lean animals while at 30 degrees C it is similar. When the environmental temperature is below 30 degrees C the oxygen consumption of the lean mice is greater. The obese animals therefore expend less energy on thermoregulatory thermogenesis. 5. The capacity for non-shivering thermogenesis was measured in lean and obese mice by investigating the effect of an injection of L-nor-adrenaline (1000 microgram/kg body weight) on the metabolic rate at 31 degrees C. Non-shivering thermogenesis was reduced by one-half in the obese animals. 6. One cause of the obesity of the ob/ob mouse is its high metabolic efficiency. We suggest that this high metabolic efficiency is due, at least in part, to less energy being expended on thermoregulatory thermogenesis. PMID: 565045 [PubMed - indexed for MEDLINE] 305. Biochim Biophys Acta. 1978 Feb 9;501(2):286-95. On the rate-limiting step in the transfer of long-chain acyl groups across the inner membrane of brown adipose tissue mitochondria. Normann PT, Ingebretsen OC, Flatmark T. Brown adipose tissue mitochondria predominantly oxidize fatty acids in order to generate heat for non-shivering thermogenesis, and have an unusually high capacity for net transfer of long-chain fatty acyl groups from the outer to the inner (matrix) compartment. The activities of the "outer" and "inner" carnitine long-chain acyltransferases have been estimated in isolated mitochondria of cold-acclimated guinea pits by the continuous spectrophotometric recording of the redox level of flavoproteins in the acyl-CoA dehydrogenase pathway. This redox level is determined by the intramitochondrial content of acyl-CoA under the selected experimental conditions. The apparent initial rate of the "inner" acyltransferase (palmitoyl-L-carnitine added) is three order of magnitudes higher than the "outer" acyltransferase (palmitoyl-CoA added), and this difference is not influenced by the substrate concentration, pH and reaction temperature. Thus, the "outer" acyltransferase reaction is rate limiting in the transfer of long-chain acyl groups across the inner membrane of these mitochondria and catalyzes a non-equilibrium reaction in the intact organelle. Estimates of the absolute rate of the "outer" long-chain acyltransferase indicate that it exceeds that of rat liver mitochondria by a factor of 20. PMID: 620016 [PubMed - indexed for MEDLINE] 306. Arch Int Physiol Biochim. 1978 Feb;86(1):145-52. Post-natal development of brown adipose tissue in the rat bred at 23 degrees C or 28 degrees C. Beauvallet M, Portet R, Blancher G, Solier M. In view to study the effects of thermal environment on the development and the thermogenic activity of interscapular brown adipose tissue (BAT), young rats born at 23 degrees C or 28 degrees C were sacrificed at 1, 3, 7, 11, 14 or 21 days after birth. The rate of increase in animal weight was quite the same at both temperatures up to the 14th day. The development of BAT and its contents in lipids, in water and in noradrenaline indicate that the energetic activity of the tissue is greatly stimulated in rats kept at 23 degrees C up to the 11th day. It is concluded that in rats bred in the habitual thermal conditions (23 degrees C), the occurrence of non shivering thermogenesis (NST) is important during the period of ten days after birth; in the following period NST could be progressively replaced by other thermoregulatory processes. PMID: 80171 [PubMed - indexed for MEDLINE] 307. Experientia Suppl. 1978;32:89-93. The identification of the component in the inner membrane of brown adipose tissue mitochondria responsible for regulating energy dissipation. Nicholls DG, Bernson VS, Heaton GM. The proton conductance of the inner membrane of hamster brown adipose tissue mitochondria can be regulated in vitro by exogenous purine nucleotides, which bind to a component on the outer face of the inner membrane. This unique mechanism has been proposed to represent the molecular site of non-shivering thermogenesis in this tissue. Using a photo-affinity analogue of ATP, we have identified the nucleotide binding component as a protein of 32,000 daltons. PMID: 348493 [PubMed - indexed for MEDLINE] 308. Experientia Suppl. 1978;32:219-27. Non shivering thermogenesis and implication of the thyroid in cold labile and cold resistant populations of the golden spiny mouse (Acomys russatus). Borut A, Haim A, Castel M. The golden spiny mouse is dependent on non shivering thermogenesis (N.S.T.) for thermoregulation at cool ambient temperatures. Mice from the shores of the Dead Sea (Ein-Gedi, EG-mice) lose body heat when exposed to 6 degrees C. Their rate of cooling is linearly correlated to the magnitude of N.S.T. This is true for mice acclimated to 28 degrees C, born in the laboratory or freshly captured. Mice from the high mountains of South Sinai (S-mice) resist cooling under the same conditions and their N.S.T. is about twice that of EG-mice. EG-mice did not acclimate to cold. However thyroxine injections made them cold resistant and their N.S.T. rose to values close to that of S-mice. Light and electronmicroscopy of the thyroids in mice acclimated to 28 degrees C and exposed to 6 degrees C, or injected with TRH suggested intense activity in S-mice and little activity in EG-mice. PMID: 274309 [PubMed - indexed for MEDLINE] 309. Experientia Suppl. 1978;32:177-83. "Cascade" principle of the control of non-shivering thermogenesis by intravenously infused noradrenaline. Mejsnar JA. A hypothesis is presented according to which noradrenaline (NA) infused into the blood reaches the biophase of thermogenic cells through three "cascade" steps, namely the blood volume, extravascular space and biophase. The influx rate of the NA entering the system is given by a forcing function and multiplied by cardiac output. Distribution of the NA at each step is identically described by three differential equations. PMID: 274306 [PubMed - indexed for MEDLINE] 310. Comp Biochem Physiol C. 1978;61C(1):189-201. The sympathico-adrenomedullary system and non-shivering thermogenesis in Perodicticus potto (Prosimii, Lorisidae, Lorisinae). Goffart M, Canguilhem B, Hildwein G, Juchmès J. PMID: 30577 [PubMed - indexed for MEDLINE] 311. Experientia Suppl. 1978;32:315-9. Control of non-shivering thermogenesis in a hibernator. Wünnenberg W, Merker G. Present experiments indicate that in hedgehogs two different control mechanisms of non-shivering thermogenesis (NST) exist. During arousal from hibernation catecholamines control heat production in the interscapular brown adipose tissue. In a non-hibernating state, cold-induced NST is controlled by a desoxycorticosterone-like acting compound. The effector system of this second mode of NST is obviously not the interscapular brown fat but a layer of brown adipose tissue which covers the whole back of the hedgehog. PMID: 25783 [PubMed - indexed for MEDLINE] 312. Comp Biochem Physiol C. 1978;59(1):33-7. Non-shivering thermogenesis in the potoroo, Potorous tridactylus (Kerr). Nicol SC. PMID: 24519 [PubMed - indexed for MEDLINE] 313. J Physiol. 1977 Aug;269(3):669-76. The control of shivering and non-shivering thermogenesis in the rat. Banet M, Hensel H. 1. The effect of intraperitoneal administration of propranolol (4, 8 and 12 mg/kg) on colonic temperature was studied in twelve rats during exposure to ambient temperatures of 30, 15 and 5 degrees C. 2. At 30 degrees C, propranolol had no effect on colonic temperature; at 15 and 5 degrees C, however, 4 mg propanolol/kg induced a fall in colonic temperature of about 0-8 degrees C, whereas 8 and 12 mg propanolol/kg induced a fall of about 1-5-2-0 degrees C. 3. Assuming that the temperature regulations system of the rat has a proportional controller and that the effect of propranolol was due to the blockade of non-shivering thermogenesis, the results are interpreted as showing that shivering is activated only when heat loss exceeds the capacity for non-shivering thermogenesis. PMCID: PMC1283732 PMID: 894609 [PubMed - indexed for MEDLINE] 314. Nurs Mirror Midwives J. 1976 Dec 2;143(23):75. Non-shivering thermogenesis. Stokes TM. PMID: 1050708 [PubMed - indexed for MEDLINE] 315. Eur J Biochem. 1976 Aug 16;67(2):511-7. Hamster brown-adipose-tissue mitochondria. The role of fatty acids in the control of the proton conductance of the inner membrane. Heaton GM, Nicholis DG. The specific ability of fatty acids to increase the proton conductance of the inner membrane of mitochondria from the liver and brown adipose tissue of cold-adapted hamsters was compared. The liver and brown-adipose-tissue mitochondria had their effective proton conductances increased by respectively 0.028 and 0.94 nmol H+- min-1. (mV of proton electrochemical gradient)-1 for each nmol of palmitate bound. No difference could be detected between the abilities of liver and brown-adipose-tissue mitochondria to bind fatty acids. Purine nucleotides did not displace farry acids from the brown-adipase-tissue mitochondria. The endogenous fatty acid content of hamster brown-adipose-tissue mitochondria prepared in the absence of album was found to be equivalent to 17 +/- 7 nmol of palmitate/mg protein. The fatty acid content was reduced to 1 nmol/mg after preincubation of the mitochondria with CoA, ATP and carnitine. No inert pool of fatty acids could be detected. The endogenous fatty acids of hamster liver mitochondria were less than 4 nmol of palmitate equivalent/mg protein. Some of the fatty acid associated with the brown-adipose-tissue mitochondria originates during preparation of the mitochondria. In the light of these results, the physiological role of the fatty acids in controlling the proton conductance of the brown-adipose-tissue mitochondrial inner membrane, and hence- non-shivering thermogenesis, is re-evaluated. PMID: 964256 [PubMed - indexed for MEDLINE] 316. Pflugers Arch. 1976 May 12;363(2):125-33. Cold-adaptive modifications in man induced by repeated short-term cold-exposures and during a 10-day and-night cold-exposure. Brück K, Baum E, Schwennicke HP. Two types of cold exposures were carried out in humans. A. Fourteen subjects were exposed 4-7 times within 2 weeks to the following conditions: ambient temperature was decreased from 28 degrees C to between plus and minus 5 degrees C; the subjects wore a bathing suit and remained in a resting position during the exposure which lasted for 1h. B. Nine conscripts were studied before and after a 10-day exercise, during which they were exposed to moderately cold conditions during day and night. The exercise did not require increased physical activity. In two thirds of the subjects A, metabolic reactions and shivering threshold were shifted to a lower weighted mean body temperature as well as a lower esophageal temperature ("hypothermic" type of adaptation). This modification in the thermoregulatory system was linked with a reduction in thermal discomfort and cold sensation. No change was found in the resting metabolic rate nor was there any indication of the development of non-shivering thermogenesis. Similar modifications were found in 4 of the 9 soldiers (study B). These 4, however, had particularly high shivering thresholds before the 10-day exercise and the values found thereafter were no lower than those found in the remaining five and in the subjects of group A before the cold-exposure regimen. PMID: 945546 [PubMed - indexed for MEDLINE] 317. J Physiol (Paris). 1976 Mar;72(1):59-77. [Fetal and neo-natal development of brown adipose tissue in guinea pigs and rats. Feto-maternal or milk transfer of essential fatty acids : lipogenesis and morphology (author's transl)]. [Article in French] Loriette C, Lapous D, Raulin J. Brown adipose tissue (BAT) lipogenesis (fatty acid, glycerol and CO2 synthesis) and its morphology determined by optical microscopy, were studied in guinea pigs and rats during intra-uterine life and during the suckling period. Following the receptor induction and after the commencement of the hormone sensitive adenylate-cyclase/lipase system (i.e. on the 60th day in guinea pigs, on the 20th day in rats), the fetal BAT releases fatty acids (NEFA) and is capable of allowing the non-shivering thermogenesis. When the maternal diet and, consequently, the fetal or neonatal BAT are supplied with considerable linoleic acid, NEFA contain a large proportion of essential fatty acids. In vitro, the greater the linoleic acid concentration in these NEFA, the less inhibited is the lipogenesis from (2-14C) pyruvate. Thus, in periods just preceding or succeeding birth, fatty acid and glycerol synthesis are higher when the feto-maternal and/or the milk supply are enriched in linoleic acid than when they contain a large proportion of endogenous fatty acids. Morphological studies indicate that the adipose cell evolution could be nonidentical in BAT more or less enriched in essential fatty acids. Linoleic enriched BAT (of animals born to females kept on a sunflower oil diet) seemed to be in a healthy physiological state at birth, perhaps due to rapid lipid renewal and synthesis in their membranes. The control BAT (of animals born to females kept on a lard diet) appeared loaded with fats and in a worse conservation state at the same age. PMID: 180283 [PubMed - indexed for MEDLINE] 318. Eur J Biochem. 1976 Feb 16;62(2):223-8. Hamster brown-adipose-tissue mitochondria. Purine nucleotide control of the ion conductance of the inner membrane, the nature of the nucleotide binding site. Nicholls DG. The inner membrane of hamster brown adipose tissue mitochondria possesses a mechanism for the conductance of protons (or hydroxyl ions) and halide anions which may be specifically inhibited by exogenous purine nucleoside di- or triphosphates. The mechanism of the nucleotide interaction is examined. The added nucleotides can inhibit the ion conductances without equilibrating with the matrix pools of purine nucleotides. ADP translocation is completely sensitive to atractylate, and no mechanism for GDP translocation could be detected. The nucleotides act on the conductance mechanism without covalent modification. A purine nucleotide binding site is described which is distinct from the adenine nucleotide translocase, does not bind atractylate, has a capacity of 0.7 nmol - mg-1, and affinities, specificities and a pH dependency closely corresponding to the conditions required for the inhibition of the ion conductances. The binding site is not apparent in rat liver mitochondria. A causal relationship is suggested between the occupation of this site by added purine nucleotides, and the inhibition of the ion conductance pathway. The role of the pathway in the physiological control of non-shivering thermogenesis by the tissue is discussed. PMID: 1253787 [PubMed - indexed for MEDLINE] 319. Arch Int Physiol Biochim. 1976 Feb;84(1):89-98. Variations of rat brown adipose tissue composition during cold acclimatization. Portet R, Beauvallet M, Solier M. The modifications in weight and composition (lipids, proteins, water) of rat interscapular brown adipose tissue (BAT) were studied along the six first weeks of cold exposure and acclimatization. The variations of noreponephrine content was also investigated. During the first day of cold exposure, the major part of tissue lipids was released. During the following two days there was a fall in lipid and norepinehprine contents and uptake of water. Then, until the end of the first week a rapid repletion occurred. At that moment the relative pass of the tissue and the amounts of its principal components reached values which are not changed during the following weeks. We can conclude that the adaptative changes in the levels of BAT essential components are carried out at the end of the first week of cold exposure, long time before the non shivering thermogenesis is entirely effective. PMID: 60978 [PubMed - indexed for MEDLINE] 320. Am J Phys Anthropol. 1976 Jan;44(1):91-3. Skin temperatures at the nape in infants at high altitude. Dufour DL, Little MA, Thomas RB. Skin temperatures were measured on three Quechua Indian infants resident at 4,000 meters above sea level in Peru. Nape temperatures were warmer than other skin sites, suggesting that the brown adipose tissue associated with non-shivering thermogenesis is metabolically active despite the reduced oxygen availability at high altitude. The question of the role of non-shivering thermogenesis in infant thermoregulation under the covariant stresses of hypoxia and cold is still open. PMID: 1247116 [PubMed - indexed for MEDLINE] 321. Mol Cell Biochem. 1975 Apr 30;7(1):45-50. The regulation of glycerol 3-phosphate oxidase of rate brownadipose tissue mitochondria by long-chain free fatty acids. Houstĕk J, Drahota Z. Added free fatty acids inhibit oxidation of glycerol 3-phosphate, succinate and NADH in brown-adipose tissue mitochondria from 10-day-old rats. The most pronounced is the inhibitory effect of glycerol 3-phosphate cytochrome c reductase (GP-cyto. c reductase). Contrary to other reductases, GP-cyto. c reductase activity of freshly isolated mitochondria is already inhibited by the fraction of endogenous free fatty acids. Both added and endogenous free fatty acids inhibition of GP-cyto. c reductase is fully reversible by the removal of free fatty acids by bovine serum albumine treatment. The inhibition of GP-cyto. c reductase is of strictly non-competitive type. The most inhibitory are unsaturated long-chain free fatty acids-oleic and linoleic acid. Results are discussed with regards to the regulatory importance of free fatty acids in brown-adiposetissue during intensive non-shivering thermogenesis. PMID: 166298 [PubMed - indexed for MEDLINE] 322. Eur J Pharmacol. 1975 Feb;30(2):352-5. Norepinephrine-induced depolarization of skeletal muscle cells. Teskey N, Horwitz B, Horowitz J. I.v. administration of norepinephrine to anesthetized hamsters was followed by a significant depolarization of the cell membranes of skeletal muscle (gracilis anticus and sartorius). The occurrence of this depolarization in consistent with the suggestion that changes in ionic distribution across the cell membrane are associated with activation of non-shivering thermogenesis in muscle cells as has been proposed for brown adipocytes. PMID: 1126368 [PubMed - indexed for MEDLINE] 323. Acta Anat (Basel). 1975;93(1):88-99. The harp seal, Pagophilus groenlandicus (Erxleben, 1777). XVII. Structure and metabolic adaption of the caval sphincter muscle with some observations on the diaphragm. George JC, Ronald K. Three types of fibre, dark (type 1), light (type 2) and intermediate, were distinguished in the caval sphincter muscle of the diaphragm in the harp seal (Pagophilus groenlandicus) using histochemical and electron-microscopic techniques. The dark fibre contained large peripheral aggregations of mitochondria, numerous lipid droplets and dense aggregates of glycogen granules. The same features were observed in the dark fibre of the diaphragm muscle too. In the light of the low oxidative enzyme activity and high lipase activity observed in the diaphragm and other skeletal muscles of the harp seal in previous studies, it is postulated that these mitochondrial aggregations and lipid droplets represent an adaptation for the generation of heat through non-shivering thermogenesis comparable to that in the brown adipose tissue. Such ability to generate and maintain heat by uncoupling the oxidative phosphorylation process should enable the caval sphincter muscle to function efficiently in regulating the cardiac return of blood from the inferior vena cava during a dive when the body temperature as a whole drops. The lack of the regional differences in the fibre composition of the harp seal diaphragm, as were reported in the rat diaphragm, is attributed to the seal's large body size, lower metabolic rate and diving habit. PMID: 1189903 [PubMed - indexed for MEDLINE] 324. Acta Paediatr Scand. 1975 Jan;64(1):57-68. The influence of different environmental temperatures on pulmonary gas exchange and blood gas changes after birth. Tunell R. The oxygen uptake (VO2) and respiratory exchange ratio (R) was determined during the first 20 min and at one and at 2 hours after birth in 16 healthy full-term newborn infants studied in different environmental temperatures. Arterial blood gases and acid-base balance were determined on repeated blood samples from the abdominal aorta. The infants were grouped in a "warm" group (n equal to 10) where efforts were made to avoid cooling after birth, and a "cold" group (n equal to 6) where a decrease in rectal temperature to a mean value of 35.4 degrees C at 2 hours occurred. Irrespective of environmental temperature, VO2 was approximately 10 ml/kg min during the first 8 min after birth, thereafter decreasing to about 6-7 ml/kg min. During the first 8 min the main increase in PaO2 occurred and about 2 ml/kg min of the VO2 was accounted for by changes in oxygen stores after birth. At 16-20 min and at 60 min after birth a negative relationship was found between VO2 and PaO2. During the period 8-120 min after birth a close relationship was found between VO2 and the degree of muscular activity. Within 4-16 min after birth, R values above 1.0 were regularly found simultaneously with the main decrease in PaO2. In infants kept "cold" a tendency to hyperventilate was found, probably elicited by cold stimuli. The rapid drop in deep body temperature regularly seen after birth could thus not be explained by a limited ability to increase pulmonary gas exchange. A high degree of evaporative heat loss, a relatively low "basal" metabolic rate and a limited response in "non-shivering thermogenesis" seem to be the main reasons for the heat loss after birth. PMID: 1167727 [PubMed - indexed for MEDLINE] 325. J Physiol. 1974 May;238(3):657-70. Inhibition of thermoregulatory non-shivering thermogenesis by trauma in cold-acclimated rats. Stoner HB. 1. Heat production and blood flow in the interscapular brown adipose tissue of 3 degrees C acclimated rats have been measured by the heated thermo-couple technique.2. When the environmental temperature (T(a)) was reduced from 30 to 3 degrees C heat production by the brown adipose tissue began to increase at the lower limit of the thermoneutral zone and then increased linearly.3. Blood flow also increased when T(a) was reduced but was not so well correlated with T(a). There was however a good positive correlation between blood flow and heat production.4. During the first hour after a 4 hr period of bilateral hind-limb ischaemia in a 20 degrees C environment the percentage of rats not producing heat in the interscapular brown adipose tissue increased and the tissue blood flow fell.5. By varying the T(a) of the injured rat it was found that the T(a) at which heat transfer from the interscapular brown adipose tissue commenced was significantly lower than in the controls although the slope of the regression lines relating heat production and T(a) was unaltered.6. Blood flow also increased in the injured rat when T(a) was lowered but the increase in the tissue blood flow per unit increase in heat production was less than in the controls.7. In a 5 degrees C environment heat production in the interscapular brown adipose tissue of the injured rat was further increased by the S. C. injection of L-isoprenaline or L-noradrenaline.8. It is concluded that the central control of thermoregulatory non-shivering thermogenesis is inhibited after injury in the rat. PMCID: PMC1330908 PMID: 4852486 [PubMed - indexed for MEDLINE] 326. Physiol Bohemoslov. 1974;23(3):235-43. Non-shivering thermogenesis in the golden hamster. Vybíral S, Janský L. PMID: 4280590 [PubMed - indexed for MEDLINE] 327. Nihon Seirigaku Zasshi. 1974;36(2):62-71. [Role of sympathetic nerve system and skeletal muscles in theophylline-induced thermogenesis. Studies on non-shivering thermogenesis. 2 (author's transl)]. [Article in Japanese] Kurahashi M. PMID: 4152719 [PubMed - indexed for MEDLINE] 328. Nihon Seirigaku Zasshi. 1973 Aug-Sep;35(8):456-7. [Proceedings: 177. Mechanisms of non-shivering thermogenesis of rats reared in cold for successive generations (author's transl)]. [Article in Japanese] Moriya K, Kuroshima K, Ito S. PMID: 4799367 [PubMed - indexed for MEDLINE] 329. Nihon Seirigaku Zasshi. 1973 Aug-Sep;35(8):433-4. [Proceedings: 123. Studies on a model of non-shivering thermogenesis in vivo (author's transl)]. [Article in Japanese] Kurahashi M. PMID: 4799319 [PubMed - indexed for MEDLINE] 330. J Physiol. 1973 Jul;232(2):285-96. The role of the liver in non-shivering thermogenesis in the rat. Stoner HB. 1. The temperatures of the liver and afferent aortic and portal blood were measured in 20 degrees C acclimated rats at different environmental temperatures (T(a)) between 20 and 37 degrees C. The heated-thermocouple technique was used to measure the metabolic heat production of the liver, its blood flow, and to correct the temperature difference between it and the reference junction for blood flow.2. The temperature of the liver was higher than that of the afferent blood. On raising T(a) from 20 to 30 degrees C the liver temperature fell and the temperature difference between the liver and the aortic blood was reduced despite the decrease in the thermal gradient between the liver and the exterior and a small reduction in hepatic blood flow. A further rise in T(a) to 37 degrees C led to an increase in the liver and blood temperatures. The same pattern was seen when the temperature differences were corrected for blood flow.3. Metabolic heat production in the liver decreased when T(a) was raised from 20 to 30 degrees C.4. In a 20 degrees C environment inhibition of non-shivering thermogenesis with propranolol HCl (10 mg/kg body wt. I.V.) led to a fall in the temperature of the liver and its metabolic heat production towards levels found in untreated rats at T(a) = 30 degrees C. Consequently, in treated rats the change in metabolic heat production on raising T(a) to 30 degrees C was less than in untreated ones.5. These results are interpreted as evidence for the participation of the liver in thermoregulatory non-shivering thermogenesis. PMCID: PMC1350455 PMID: 4727083 [PubMed - indexed for MEDLINE] 331. Nihon Seirigaku Zasshi. 1973 Feb;35(2):65-76. [Studies on non-shivering thermogenesis]. [Article in Japanese] Kurahashi M. PMID: 4738948 [PubMed - indexed for MEDLINE] 332. Biol Rev Camb Philos Soc. 1973 Feb;48(1):85-132. Non-shivering thermogenesis and its thermoregulatory significance. Janský L. PMID: 4578360 [PubMed - indexed for MEDLINE] 333. J Physiol. 1972 Dec;227(1):51-70. Habituation and acclimatization of sheep to cold following exposures of varying length and severity. Slee J. 1. Male and female Scottish Blackface sheep were shorn and exposed for 2 weeks either to a thermoneutral temperature (+30 degrees C), to chronic cold (+8 degrees C) or to +30 degrees C interrupted by daily short cold shocks (-10 degrees C). During and at the end of these conditioning treatments, the sheep also received two acute cold exposures (-20 degrees C, 4 m.p.h. wind for 2-8 hr) 1 week apart. Some of these sheep and a fourth (control) group, were subsequently re-shorn and slowly cooled to +8 degrees C.2. Resting metabolism and the metabolic response to cooling (both inferred from heart rates) were increased by previous chronic cold treatment. Resistance to body cooling (measured during acute cold exposure) was generally increased by both chronic and acute cold, and non-shivering thermogenesis was probably induced in the female sheep. These effects were defined as acclimatization.3. In contrast, cold shocks reduced the subsequent metabolic response to cold and encouraged facultative body cooling. This pattern of response (defined as habituation) therefore caused greater thermolability.4. Habituation and acclimatization were antagonistic. Habituation was removed by acute cold exposure and, conversely, acclimatization was inhibited by short cold shocks.5. There were sex differences in response but these were confounded by probable differences in insulation and in body condition (males thinner).6. It was concluded that the induction of different forms of adaptation depended on the length, severity and frequency of cold exposures. Habituation to whole body cold exposure apparently involved central nervous system centres normally receiving peripheral cold stimuli. PMCID: PMC1331262 PMID: 4646585 [PubMed - indexed for MEDLINE] 334. J Physiol. 1972 Feb;220(3):511-28. Regional distribution of cardiac output in young lambs: effect of cold exposure and treatment with catecholamines. Alexander G, Bell AW, Setchell BP. 1. Lambs less than 3 days old, exposed to thermoneutral or intensely cold conditions in a respiration chamber, were infused with adrenaline or noradrenaline, 1 or 10 mug/kg.min; and the effects on oxygen consumption, cardiac output and its distribution to skin, skeletal and cardiac muscle, liver, spleen, kidney, gut, brown adipose tissue and brain were determined. Cardiac output was estimated by the Fick and dye dilution methods and the distribution of cardiac output by Sapirstein's method of fractional distribution of indicators.2. Under thermoneutral conditions, metabolic rate was stimulated by both doses of noradrenaline and by the low, but not the high dose of adrenaline. Under cold conditions, the low dose of catecholamines had little effect on the already elevated metabolic rate, but the high doses depressed the metabolic response to cold.3. The low dose of adrenaline increased cardiac output under thermoneutral conditions whereas the high dose decreased cardiac output; the effects of noradrenaline were less marked, in contrast to reported effects in new-born rabbits. The low doses of catecholamine given under cold conditions had little effect on the already elevated cardiac output, but the high doses, particularly of adrenaline, decreased cardiac output.4. Blood flow through the skin of the extremities was markedly reduced by cold exposure, while flow through the peri-renal fat was doubled, flow through the skeletal muscle was quadrupled and flow through the cardiac muscle was trebled. These increases, particularly in skeletal muscle, were due to increased cardiac output and to vasodilation, as indicated by the reduced ratio of blood pressure to blood flow. Results are contrasted with published reports that blood flow through brown fat in new-born rabbits was greatly increased by cold, but muscle flow was scarcely altered.5. In almost all organs examined the high doses of adrenaline infused in either environment markedly reduced blood flow, presumably by generalized vasoconstriction. Changes due to noradrenaline were small under thermoneutral conditions and flow through brown fat was increased by only 60% during infusion of 10 mug/kg.min. Much greater increases have been reported in new-born rabbits. Under cold conditions the high doses of noradrenaline tended to decrease flow in most organs including brown fat and muscle.6. The results provide likely explanations for published reports that adrenaline failed to stimulate non-shivering thermogenesis or suppressed the mobilization of metabolites and the metabolic response to cold. PMCID: PMC1331667 PMID: 5016035 [PubMed - indexed for MEDLINE] 335. Int J Biometeorol. 1971 Dec;15(2):321-4. Means of noradrenalin action during non-shivering thermogenesis in a single muscle. Mejsnar J, Jansky L. PMID: 5146828 [PubMed - indexed for MEDLINE] 336. Int J Biometeorol. 1971 Dec;15(2):305-8. Comparison of the effects of local hypothalamic acetylcholine and RF-heating on non-shivering thermogenesis in the guinea pig. Zeisberger E, Bruck K. PMID: 5146824 [PubMed - indexed for MEDLINE] 337. Int J Biometeorol. 1971 Dec;15(2):156-61. Interaction of superficial and hypothalamic thermosensitive structures in the control of non-shivering thermogenesis. Brück K, Schwennicke HP. PMID: 5146802 [PubMed - indexed for MEDLINE] 338. Cesk Fysiol. 1971;20(4):309-50. [Non-shivering thermogenesis and its role in body temperature regulation]. [Article in Czech] Fanský L. PMID: 5003936 [PubMed - indexed for MEDLINE] 339. Fiziol Zh SSSR Im I M Sechenova. 1968 Dec;54(12):1475-80. [Shivering and non-shivering thermogenesis in skeletal muscles]. [Article in Russian] Tkachenko EIa. PMID: 5737058 [PubMed - indexed for MEDLINE] 340. J Physiol. 1968 Sep;198(2):251-76. Shivering and non-shivering therogenesis during summit metabolism in young lambs. Alexander G, Williams D. 1. Summit metabolism of lambs declined steadily from about 3.5 l. O(2)/kg.hr during the first day of life, to about 2.0 l. O(2)/kg.hr at 2 months of age.2. The contributions of shivering and non-shivering thermogenesis to these changes were estimated by three independent methods; non-shivering thermogenesis was stimulated by catecholamines in a thermoneutral environment, shivering was suppressed by curariform drugs during summit metabolism, and an attempt was made to suppress non-shivering thermogenesis during summit metabolism by use of the sympatholytic drugs phentolamine and propranolol. Drugs were given by intravenous infusion during measurement of oxygen consumption in a closed circuit respiration chamber.3. ;Resting' metabolic rate of lambs during the first day of life was increased two to three-fold, from 1 l. O(2)/kg.hr, by either adrenaline or noradrenaline infused at 1-10 mug/kg.min. The increase declined with increasing age of lamb and was virtually absent by 3 weeks. The response to catecholamines appeared maximal at the dose levels used.4. Muscular paralysis induced by suxamethonium or gallamine reduced summit metabolism by about 2 l. O(2)/kg.hr in all lambs examined within the first 2 months of life. The residual metabolic rate, and the metabolic response to catecholamines under thermoneutral conditions, declined with age in the same manner, and their magnitudes were similar.5. Summit metabolism in lambs aged up to 2 months was depressed to varying degrees by the sympathetic inhibitors phentolamine, propranolol and hexamethonium. The depression with propranolol was greater, and the decline with age clearer, than with phentolamine. Hexamethonium and phentolamine depressed blood pressure, propranolol decreased heart rate and phentolamine and propranolol each suppressed shivering in some experiments.6. In 1 day-old lambs estimates of non-shivering thermogenesis, by the various methods, ranged from 0.8 to 1.4 l. O(2)/kg.hr (mean 1.1 l. or 31% of summit metabolism), and the estimates of shivering ranged from 1.3 to 1.9 l. O(2)/kg.hr (mean 1.6 l. or 46% of summit metabolism). However, in lambs 1-month old, estimates of non-shivering thermogenesis from sympathetic inhibition (0.6 and 0.8 l. O(2)/kg.hr) were considerably higher than estimates from muscular paralysis or stimulation by catecholamines (0.2 and 0.1 l. O(2)/kg.hr). It is suggested that the depression of summit metabolism by the sympathetic inhibitors is not solely due to specific inhibition of non-shivering thermogenesis, at least in the older lambs.7. The possession of a non-shivering thermogenic mechanism in addition to shivering is of clear survival value to new-born lambs. PMCID: PMC1365322 PMID: 5698273 [PubMed - indexed for MEDLINE] 341. J Physiol. 1968 Apr;195(3):639-46. Adipose tissue and heat production in the new-born ox (Bos taurus). Jenkinson DM, Noble RC, Thompson GE. 1. A histological examination of adipose tissue from 1- and 6-day-old calves showed a structure typical of white adipose tissue and no evidence of brown adipose tissue.2. Infusion of noradrenaline (1.0 mug/kg.min I.V.) into 1-to 6-day-old calves affected heart rate and respiratory rate but did not increase heat production, rectal temperature, skin temperature or skin evaporative loss.3. Cold exposure led to shivering and an increased oxygen consumption in the 6-day-old calf.4. Blood samples taken from 6-day-old calves in the cold (-1 degrees C) appeared to have a higher proportion of unesterified fatty acids in the total blood lipid than samples taken in an environment of 20 degrees C, but no change in fatty acid composition was found.5. It has been concluded that there is no non-shivering thermogenesis in the young calf. PMCID: PMC1351691 PMID: 5649639 [PubMed - indexed for MEDLINE] 342. Pflugers Arch Gesamte Physiol Menschen Tiere. 1967;296(4):276-88. [Age-dependent extent of non-shivering thermogenesis in the guinea pig]. [Article in German] Zeisberger E, Brück K, Wünnenberg W, Wietasch C. PMID: 4384706 [PubMed - indexed for MEDLINE] 343. Pflugers Arch Gesamte Physiol Menschen Tiere. 1967;296(4):263-75. [Quantitative relation between noradrenaline effect and extent of non-shivering thermogenesis in the guinea pig]. [Article in German] Zeisberger E, Brück K. PMID: 4384705 [PubMed - indexed for MEDLINE] 344. Nature. 1966 Apr 23;210(5034):426. Adrenergic beta-receptors and non-shivering thermogenesis. Schönbaum E, Johnson GE, Sellers EA, Gill MJ. PMID: 5963242 [PubMed - indexed for MEDLINE] 345. Nature. 1965 Apr 10;206(980):201-2. Non-shivering thermogenesis and brown adipose tissue in the human new-born infant. Dawkins MJ, Scopes JW. PMID: 5830159 [PubMed - indexed for MEDLINE] 346. Maandschr Kindergeneeskd. 1964 Sep;32:641-52. BROWN ADIPOSE TISSUE AND NON-SHIVERING THERMOGENESIS IN NEWBORN ANIMALS. DAWKINS MJ, HULL D. PMID: 14210935 [PubMed - indexed for MEDLINE]