1. Cell Metab. 2010 Jul 7;12(1):53-64. doi: 10.1016/j.cmet.2010.05.012. Adipose acyl-CoA synthetase-1 directs fatty acids toward beta-oxidation and is required for cold thermogenesis. Ellis JM(1), Li LO, Wu PC, Koves TR, Ilkayeva O, Stevens RD, Watkins SM, Muoio DM, Coleman RA. Author information: (1)Department of Nutrition, 2301 MHRC, Dauer Drive, University of North Carolina, Chapel Hill, NC 27599, USA. Long-chain acyl-CoA synthetase-1 (ACSL1) contributes 80% of total ACSL activity in adipose tissue and was believed to be essential for the synthesis of triacylglycerol. We predicted that an adipose-specific knockout of ACSL1 (Acsl1(A-/-)) would be lipodystrophic, but compared to controls, Acsl1(A-/-) mice had 30% greater fat mass when fed a low-fat diet and gained weight normally when fed a high-fat diet. Acsl1(A-/-) adipocytes incorporated [(14)C]oleate into glycerolipids normally, but fatty acid (FA) oxidation rates were 50%-90% lower than in control adipocytes and mitochondria. Acsl1(A-/-) mice were markedly cold intolerant, and beta(3)-adrenergic agonists did not increase oxygen consumption, despite normal adrenergic signaling in brown adipose tissue. The reduced adipose FA oxidation and marked cold intolerance of Acsl1(A-/-) mice indicate that normal activation of FA for oxidation in adipose tissue in vivo requires ACSL1. Thus, ACSL1 has a specific function in directing the metabolic partitioning of FAs toward beta-oxidation in adipocytes. Copyright 2010 Elsevier Inc. All rights reserved. PMCID: PMC2910420 PMID: 20620995 [PubMed - indexed for MEDLINE] 2. J Biol Rhythms. 2010 Jun;25(3):166-75. doi: 10.1177/0748730410368621. Is the torpor-arousal cycle of hibernation controlled by a non-temperature-compensated circadian clock? Malan A(1). Author information: (1)Institute of Cellular and Integrative Neurosciences, CNRS (National Center for Scientific Research) and University of Strasbourg, France. malan@inci-cnrs.unistra.fr During the hibernation season, mammalian hibernators alternate between prolonged bouts of torpor with a reduced body temperature (Tb) and short arousals with a return to euthermy. Evidence is presented here to show that this metabolic-and also physiological and neuroanatomical-rhythm is controlled by a clock, the torpor-arousal (TA) clock. The temperature dependence of torpor bout duration in 3 species of Spermophilus (published data) may be described by assuming that the TA clock is a circadian clock (probably not the suprachiasmatic clock) that has lost its temperature compensation. This loss might result either from a permanent deletion, or more likely from a seasonal epigenetic control at the level of the clock gene machinery. This hypothesis was verified over the full Tb range on published data from 5 other species (a monotreme, a marsupial, and 3 placental mammals). In a hibernation season, instantaneous subjective time of the putative TA clock was summated over each torpor bout. For each animal, torpor bout length (TBL) was accurately predicted as a constant fraction of a subjective day, for actual durations in astronomical time varying between 4 and 13 to 20 days. The resulting temperature dependence of the interval between arousals predicts that energy expenditure over the hibernation season will be minimal when Tb is as low as possible without eliciting cold thermogenesis. PMID: 20484688 [PubMed - indexed for MEDLINE] 3. Physiol Res. 2006;55(5):543-9. Epub 2005 Dec 12. Thermal, cardiac and adrenergic responses to repeated local cooling. Janský L(1), Matousková E, Vávra V, Vybíral S, Janský P, Jandová D, Knízková I, Kunc P. Author information: (1)Department of Animal Physiology, Faculty of Biology, Southbohemian University, Branisovská, Ceské Budejovice, Czech Republic. The aim of this study was to ascertain whether repeated local cooling induces the same or different adaptational responses as repeated whole body cooling. Repeated cooling of the legs (immersion into 12 degrees C water up to the knees for 30 min, 20 times during 4 weeks = local cold adaptation - LCA) attenuated the initial increase in heart rate and blood pressure currently observed in control subjects immersed in cold water up to the knees. After LCA the initial skin temperature decrease tended to be lower, indicating reduced vasoconstriction. Heart rate and systolic blood pressure appeared to be generally lower during rest and during the time course of cooling in LCA humans, when compared to controls. All these changes seem to indicate attenuation of the sympathetic tone. In contrast, the sustained skin temperature in different areas of the body (finger, palm, forearm, thigh, chest) appeared to be generally lower in LCA subjects than in controls (except for temperatures on the forehead). Plasma levels of catecholamines (measured 20 and 40 min after the onset of cooling) were also not influenced by local cold adaptation. Locally cold adapted subjects, when exposed to whole body cold water immersion test, showed no change in the threshold temperature for induction of cold thermogenesis. This indicates that the hypothermic type of cold adaptation, typically occurring after systemic cold adaptation, does not appear after local cold adaptation of the intensity used. It is concluded that in humans the cold adaptation due to repeated local cooling of legs induces different physiological changes than systemic cold adaptation. PMID: 16343045 [PubMed - indexed for MEDLINE] 4. Front Biosci. 2004 Sep 1;9:3068-84. Thermal homeostasis in systemic inflammation: modulation of neuronal mechanisms. Jansky L(1), Vybiral S. Author information: (1)Faculty of Biology, University of South Bohemia, Budweis, Czech Republic. JanskyL@seznam.cz Fever can be defined as a specific model of body temperature control, modified by action of humoral substances released due to bacterial infection. Under laboratory conditions exogenous and endogenous pyrogens affect nervous endings in the body periphery, as well as thermosensitive neurons in the hypothalamus, which first manifests as a shock reaction and then as shifts of temperature thresholds for activation of thermoregulatory effectors (cold thermogenesis, vasomotion, sweating or panting) to higher body temperatures. During the later phase of fever, the temperature threshold for cold thermogenesis starts to move downwards, while the thresholds for other thermoregulatory outputs remain elevated, the result being enlarging of the interthreshold zone. This creates conditions for cooling of the body and for termination of the fever. During different phases of fever cytokines, prostaglandins, neuropeptides and catecholamines participate in modulation of mechanisms regulating thermoregulatory functions. This paper aims to specify the role of individual cytokines in induction of fever, as well as in activation of thermoregulatory centers as well as individual thermoregulatory effectors and to define differences in their mode of action. The paper further attempts to summarize our knowledge on humoral modulation of the cytokine release. It is concluded that cytokines are not the primary factors responsible for setting of the body thermostat during fever. PMID: 15353338 [PubMed - indexed for MEDLINE] 5. Cesk Fysiol. 2003 Aug;52(3):107-17. [Physiologic basis of human adaptation to cold]. [Article in Czech] Janský L(1). Author information: (1)Katedra fyziologie zivocichů, Biologická fakulta, Jihoceská univerzita, Ceské Budĕjovice. janskyl@seznam.cz Intermittent exposures to cold (15 head out immersions into 14 degrees C water, for 1 h, within 3 weeks) induce physiological changes leading to the restriction of heat loss from the body, due to hypothermia and vasoconstriction. These adaptational changes may save more than 25% of energy during 1 hour cold test. Insulative adaptation due to increased amount of the subcutaneous fat is less prominent. Winter swimmers show similar mechanisms of cold adaptationn as humans adapted by intermittent cold exposures in the laboratory. Additionally, winter swimmers exert a greater capacity of nonshivering thermogenesis than nonadapted controls. Thus, adaptation of humans to cold involves hypothermic, metabolic and insulative mechanisms. Time courses of development of individual mechanisms of adaptation differ. Intermittent local cold exposures (20 immersions of legs into 12 degrees C water, for 45 min, within 4 weeks lower sympathetic tone and induce redistribution of cardiac output, in order to ensure preferential warming of central parts of the body. Basal metabolism and cold induced thermogenesis are increased, but the threshold for induction of cold thermogenesis is not influenced. In contrast to changes induced by repeated whole body immersions, these changes may not ensure greater resistance to the cold stress. PMID: 12931541 [PubMed - indexed for MEDLINE] 6. J Therm Biol. 2000 Dec 1;25(6):437-442. Role of beta adrenoceptors in metabolic and cardiovascular responses of cold exposed humans. Simecková M(1), Janský L, Lesná I I, Vybíral S, Srámek P. Author information: (1)Faculty of Physical Education and Sports, Charles University, Prague, Czech Republic Effect of a nonspecific beta adrenergic blocker - propranolol (40 mg per os) on thermoregulatory responses of cold water immersed (12.5 degrees C) humans was studied. Propranolol attenuates resting and cold induced thermogenesis, rectal temperature, heart rate and systolic blood pressure, but increases production of adrenaline and cortisol. Propranolol has no effect on the threshold body temperature for induction of cold thermogenesis and on central thermosensitivity. The following conclusions are drawn from consideration of the data presented: During the early phase of cooling (20 min after the start of cooling) the thermogenesis mediated by beta adrenergic receptors may cover about 80% of the total metabolic increase induced by cold. After about 30 min of cooling the relative proportion of beta adrenergic thermogenesis starts to decline, reaching 20% of the total cold thermogenesis at the end of cooling.It can be suggested from consideration of the data that, in man, the beta adrenergic receptors in the heart, blood vessels, adipocytes and muscles participate in mediating effect of cold on cardiovascular and thermoregulatory responses. Furthermore, these data imply that human adrenergic thermogenesis is produced outside of the brown adipose tissue. Thus, physiological mechanisms mediating adrenergic thermogenesis in humans appear to be different from those in small mammals. PMID: 10880867 [PubMed - as supplied by publisher] 7. 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] 8. Am J Physiol. 1998 Sep;275(3 Pt 2):R683-90. Increased in vitro fatty acid supply and cellular transport capacities in cold-acclimated ducklings (Cairina moschata). Bénistant C(1), Duchamp C, Cohen-Adad F, Rouanet JL, Barré H. Author information: (1)Unité Mixte de Recherches 5578 Centre National de la Recherche Scientifique-Université Claude Bernard Lyon I, Laboratoire Associé Institut National de la Recherche Agronomique, Villeurbanne, France. In cold-acclimated (CA) birds, lipids play a crucial role in regulatory thermogenesis by acting both as substrates for and activators of thermogenic processes. The capacity to supply lipids to thermogenic tissues, which could limit cold thermogenesis, was assessed in CA ducklings (5 wk old, 4 degrees C) and compared with thermoneutral controls (TN, 25 degrees C). In CA ducklings, basal lipolytic activity of adipose tissue fragments was higher (202 +/- 9 vs. 130 +/- 14 nmol glycerol released . 100 mg tissue-1 . h-1, +55%) than in TN controls, while glucagon had a much higher stimulatory effect (+140 to +500% depending on dose). This was consistent with increased plasma levels of nonesterified fatty acids (FA, +57%) and glycerol (+31%) in vivo. In vitro endothelial lipase activity per organ was higher in CA than in TN ducklings in red gastrocnemius muscle (6.3 +/- 0.6 vs. 3.5 +/- 0.3 microeq nonesterified FA released per hour, +80%) and liver (+55%). The intracellular FA-binding capacity of (12-18 kDa) proteins was higher in gastrocnemius muscle (+43%) and liver (+74%) from CA ducklings. In gastrocnemius, it was linked to a higher content (21 +/- 2 vs. 15 +/- 2 microg/mg protein, +37%) of an intracellular 15.4-kDa FA-binding protein. These in vitro results indicate that coordinated increases in FA supply from adipose tissue, cellular uptake of lipoprotein-derived FA, and intracellular FA transport capacity occur in CA ducklings endowed with higher thermogenic capacity and cold endurance. PMID: 9728063 [PubMed - indexed for MEDLINE] 9. Ann N Y Acad Sci. 1997 Mar 15;813:733-7. Endotoxin shock-associated hypothermia. How and why does it occur? Romanovsky AA(1), Shido O, Sakurada S, Sugimoto N, Nagasaka T. Author information: (1)Department of Physiology, University of Kanazawa Medical School, Japan. romanovs@ohsu.edu In sum, our results indicate that LPS shock-associated hypothermia involves the following major mechanisms: 1) a decrease in the threshold Tb for activation of cold thermogenesis; 2) the resultant widening of the interthreshold zone; and 3) cold-seeking behavior. We speculate that, in severe systemic inflammation, this hypothermia constitutes an adaptive response. PMID: 9100963 [PubMed - indexed for MEDLINE] 10. Pflugers Arch. 1996 Jul;432(3):368-72. Changes in thermal homeostasis in humans due to repeated cold water immersions. Janský L(1), Janáková H, Ulicný B, Srámek P, Hosek V, Heller J, Parízková J. Author information: (1)Department of Comparative Physiology, Faculty of Science, Charles University, Vinicná 7, CZ-12800 Prague 2, Czech Republic. The purpose of this study was to monitor changes in body and skin temperatures, heat production, subjective shivering, cold sensation and body fat content in humans after intermittent cold water immersion. Repeated exposures of young sportsmen to cold water (head out, 14 degrees C, 1 h, 3 times per week for 4-6 weeks) induced changes in regulation of thermal homeostasis. "Cold acclimated" subjects exhibited an hypothermic type of adaptation. Central and peripheral body temperatures at rest and during cold immersion were lowered. The metabolic response to cold was delayed and subjective shivering was attenuated. The observed hypothermia was due to the shift of the threshold for induction of cold thermogenesis to lower body temperatures. "Cold acclimated" subjects also showed a lowered cold sensation. Because of the observed physiological changes, about 20% of the total heat production was saved during one cold water immersion of "cold acclimated" subjects. Maximal aerobic and anaerobic performances were not altered. No change in the thermosensitivity of the body temperature controller, as assessed from the unchanged slope of the relation between the deep body temperature and total heat production, was observed. Changes in cold sensation and regulation of cold thermogenesis were noticed first after four cold water immersions and persisted for at least 2 weeks after termination of the adaptation procedure. A trend towards a small increase in the body fat content was also observed. This finding, as well as the increased vasoconstriction, evidenced by the lowered skin temperature, indicate that slight changes in body insulation may also occur after "cold acclimation" in humans. PMID: 8765994 [PubMed - indexed for MEDLINE] 11. Pharmacol Biochem Behav. 1996 Jul;54(3):555-64. Ethanol effect on activation and maintenance of cold stress response in immature rats. Spiers DE(1), Kelleher SA, Eichen PA. Author information: (1)Animal Sciences Department, University of Missouri, Columbia 65211, USA. Rats at thermoneutral ambient temperature (Ta) exhibit change in thermoregulatory response to ethanol (EtOH) from 2 to 15 days of age. In the present study, rats at 2-3, 8-9, and 14-15 days of age were administered either saline or EtOH (4 g/kg b.wt.;IP) using two different routines to determine EtOH effect on specific cold defense mechanisms. Injection of EtOH in the first routine occurred after exposure to cold Ta, to determine effect on maintenance of cold thermogenesis. EtOH-induced metabolic depression increased from 3 to 8 days of age, with little change after this time. Injection of EtOH in the second routine was at thermoneutral Ta, followed at 20 min postinjection by rapid exposure to cold Ta to determine effect on activation of cold thermogenesis. EtOH-treatment delayed onset of cold thermogenesis at 2-3 and 14-15 days of age, and completely eliminated 8-9-day-old response to cold Ta. Rats exposed to cold Ta at 2-3 days of age exhibited a slower rate of EtOH absorption and lower blood EtOH concentration than rats in the older groups, to explain some age differences in EtOH response. PMID: 8743629 [PubMed - indexed for MEDLINE] 12. Arctic Med Res. 1995;54 Suppl 2:70-5. Enhancing tolerance to cold exposure--how successful have we been? Mercer JB(1). Author information: (1)Department of Medical Physiology, University of Tromsø, Norway. The risk of accidental hypothermia is always present in persons living at high latitudes, with cold water immersion representing the most extreme challenge. While most of the effort concerned with protection against cold exposure has involved finding ways of decreasing heat loss by improving insulation some attempts have been made in finding ways of improving cold tolerance by modifying the thermoregulatory response to cold. The main strategies that have been used are: - thermal acclimation, physical exercise, dietary enhancement of thermogenesis, pharmacological enhancement of thermogenesis and manipulation of thermoregulatory set-point. This paper briefly reviews the success of these strategies. While none of the strategies examined have resulted in concrete methods which are routinely used to improve cold tolerance, it is concluded that the pharmacological enhancement of cold thermogenesis using ephedrine in combination with methylxanthine represents the most promising method for delaying the onset of hypothermia in humans. PMID: 8900836 [PubMed - indexed for MEDLINE] 13. Obes Res. 1994 May;2(3):246-54. Influence of opioids in hypothalamic nuclei on cold thermogenesis of lean and obese LA/N-cp rats. Rodd DW(1), Loomis JL, Farrell PA. Author information: (1)Noll Laboratory for Human Performance Research, 119 Noll Laboratory, The Pennsylvania State University, University Park, PA 16802, USA. An overactive endogenous opioid peptide system (EOP) in the hypothalamus of the obese rats could contribute to a subnormal metabolic response to cold stress. Specific mu, delta, kappa opioid receptor antagonists and naloxone were infused into cannulaes aimed at the paraventricular nucleus (PVN) of awake freely moving obese (LA/N-cp corpulent) and lean littermate rats. Metabolic responses were measured by indirect calorimetry during thermoneutrality (30 degrees C) and at 10 degrees C for 60 minutes each. When expressed relative to metabolic body size (kg(-.75)) obese rats had lower values (obese = 21.1 +/- 1.9 vs. lean = 27.9 +/- 2.7 ml x kg(-.75) x min, mean +/- s.d., p < 0.05) at 10 degrees C during saline infusion. EOP antagonist infusions at 30 degrees C had no effect on metabolic rate for either lean or obese animals. Mu (23.5 +/- 3.4 ml x kg x (-75) x min) and delta (23.0 +/- 2.0) antagonism and naloxone (25.0 +/- 2.3) significantly increased the metabolic response to cold in obese but not lean rats. These data suggest that certain subtypes of EOP receptors in or near PVN are overactive in obese rats. This overactive state may inappropriately inhibit the thermogenic response to cold stress in obesity. PMID: 16353425 [PubMed - indexed for MEDLINE] 14. Physiol Res. 1994;43(6):359-63. Can haloperidol disguise fever? Vybíral S(1), Veselá R. Author information: (1)Department of Physiology and Development Biology, Faculty of Science, Charles University, Prague, Czech Republic. Haloperidol when applied intraperitoneally to cold-exposed febrile rabbits induces a strong hypothermic effect. This effect is due to the downward shift of the threshold central temperature for induction of cold thermogenesis and vasomotion. The shift occurs during the early phase of the fever and is less prominent during the late phase of the fever. The hypothermic effect of high doses of haloperidol can eliminate the increase of body temperature in febrile individuals. PMID: 7794882 [PubMed - indexed for MEDLINE] 15. Int J Obes Relat Metab Disord. 1993 Feb;17 Suppl 1:S53-6. Effects of ephedrine/xanthines on thermogenesis and cold tolerance. Vallerand AL(1). Author information: (1)Defence & Civil Institute of Environmental Medicine, Environmental Physiology Section, Toronto, Ontario, Canada. This paper reviews the use of ephedrine (E) and xanthines (X) to improve thermogenesis and cold tolerance. Recent experiments in cold-exposed subjects have shown that the beneficial effects of ingesting an E/caffeine (C) capsule on metabolic rate (M), heat debt, deep body core temperature (Tre) (P < 0.05) is entirely comparable to that observed with an E/C/theophylline (T) capsule. Although T has been reported to reduce the drop in Tre in several studies, these improvements are difficult to explain in the absence of changes in M. A theobromine-based commercial sports bar (Cold Buster) has been similarly shown to reduce the drop in Tre. However, such a claim could not be confirmed in our lab, even in two studies performed under different environmental conditions. Despite an increase in M in some studies, C had no effect on Tre in the cold. It is concluded that E/X represent, at the moment, the best pharmacological agents to enhance cold thermogenesis and to delay the onset of hypothermia in humans. PMID: 8384182 [PubMed - indexed for MEDLINE] 16. Eur J Appl Physiol Occup Physiol. 1993;67(3):239-44. Is energy substrate mobilization a limiting factor for cold thermogenesis? Vallerand AL(1), Tikuisis P, Ducharme MB, Jacobs I. Author information: (1)Defence and Civil Institute of Environmental Medicine, Environmental Physiology Section, North York, Ontario, Canada. Energy substrate mobilization has been suggested as being a limiting factor for the rate of cold-induced thermogenesis (M), and consequently in delaying hypothermia. The evidence supporting this hypothesis in humans, however, is not convincing and the hypothesis has yet to be tested in a rigorous manner using a full heat balance analysis (partitional calorimetry). The goal of this study was therefore to re-investigate whether enhancing energy substrate mobilization by feeding cold-exposed subjects would improve M and affect heat debt (S; the minute-by-minute balance of M and heat losses) as well as rectal (Tre) and mean skin temperatures (Tsk). Nine healthy semi-nude fasted subjects were exposed to 5 degrees C (3 h at rest, 1 m.s-1 wind) on three occasions following the ingestion at min 0 and 90 of either: (1) a placebo, (2) 710 kJ of pure carbohydrates (100%-CHO), or (3) 710 kJ of a high-carbohydrate bar (High-CHO). As expected in the cold, Tre and Tsk decreased whereas M, S and heat losses increased (P < 0.01). However, there were no differences between treatments, including the final Tre [mean (SEM); 36.4 (0.2); 36.5 (0.3) and 36.5 (0.2) degrees C for the placebo, 100%-CHO and High-CHO tests, respectively]. During the 100%-CHO treatment, rates of carbohydrate oxidation were the highest and fat oxidation the lowest (P < 0.05), whereas the High-CHO treatment caused smaller changes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 8223537 [PubMed - indexed for MEDLINE] 17. Int J Sports Med. 1992 Oct;13 Suppl 1:S191-3. Energy metabolism during cold exposure. Vallerand AL(1), Jacobs I. Author information: (1)Environmental Physiology Section, Defence and Civil Institute of Environmental Medicine, North York, Ontario, Canada. Recent advances on the influence of cold exposure on energy metabolism in animals and humans are summarized. Although the cold-induced enhancements in carbohydrate metabolism have been the focus of numerous studies, it was only recently that pieces of evidence from animal studies have suggested that cold exposure exerts an insulin-like effect on peripheral tissue glucose uptake, which appears to proceed primarily via insulin-independent pathways. Interestingly, this phenomenon was observed in insulin-sensitive tissues of warm- a well as cold-adapted rats. Whereas previous human studies have concentrated on the cold-induced changes in basal levels of hormones and metabolic substrates, recent work from our laboratory has demonstrated that exposure to cold at rest shifts substrate utilization from mainly lipids at thermal neutrality to carbohydrates, representing the main fuel for shivering thermogenesis. Further investigation has revealed that the marked increment in carbohydrate oxidation in cold-exposed humans is derived from a greater utilization of both circulating glucose and intramuscular glycogen. With respect to lipid metabolism, recent studies have shown that the cold-induced increase in lipid oxidation in man is fuelled primarily by the fatty acids released from white adipose tissue triglycerides (TG) and possibly intramuscular TG, not plasma TG. One practical application of this work on energy metabolism in the cold resides in the pharmacological approach to improve cold tolerance, where pharmacological agents that alter energy metabolism and substrate utilization could be used to enhance cold thermogenesis and produce warmer body temperatures. PMID: 1483772 [PubMed - indexed for MEDLINE] 18. Neuropharmacology. 1989 Jan;28(1):15-20. The role of dopaminergic pathways in thermoregulation in the rabbit. Vybíral S(1), Janský L. Author information: (1)Department of Comparative Physiology, Charles University, Prague, Czechoslovakia. Dopamine, when injected into the anterior hypothalamus of the rabbit, induced a slight hyperthermia due to an upward shift of the threshold central temperature for induction of cold thermogenesis, panting and vasodilation. A slightly reduced thermosensitivity of the controller regulating vasodilation may also contribute to the hyperthermic effect of dopamine. Intrahypothalamic injections of the dopamine agonist, apomorphine, induced a similar effect to that of dopamine, with the exception that the thermosensitivity of the controller regulating vasodilation was not changed. Intraperitoneal injections of a dopamine antagonist, haloperidol, induced a marked hypothermia, due to a downward shift of the threshold central temperature for induction of cold thermogenesis, panting and vasodilation. A slightly reduced thermosensitivity of the controller regulating vasodilation was also observed. Intrahypothalamic injections of haloperidol did not induce an antagonist effect to dopamine, but rather tended to induce hyperthermia. Thermoregulatory responses, occurring after administration of dopamine or apomorphine, partially resembled those seen after administration of neurotensin or prostaglandins. PMID: 2927577 [PubMed - indexed for MEDLINE] 19. Brain Res Bull. 1988 Oct;21(4):557-62. Mode of ACTH antipyretic action. Vybíral S(1), Cerný L, Janský L. Author information: (1)Department of Physiology and Developmental Biology, Faculty of Science, Charles University, Prague, Czechoslovakia. The method of intestinal cooling was used to analyze the effect of centrally administered ACTH in microgram quantities on hypothalamic centers regulating activity of thermoregulatory outputs (cold thermogenesis--CT, peripheral vasomotor tone--PVMT, respiratory evaporative heat loss--REHL). ACTH, when injected into the supraoptic area of the anterior hypothalamus of normal rabbits, had no significant effect on body temperature control. Intrahypothalamic administration of ACTH during the early phase of the fever, induced by intravenous injection of exogenous pyrogen, evoked dissociation of temperature thresholds for cold and warm defence, shifting the threshold for induction of cold thermogenesis to lower central temperatures. The thermosensitivity of centers controlling cold thermogenesis was lowered and the maximal values of cold thermogenesis were depressed to about 30% of those in control rabbits. Central administration of ACTH in the late phase of the fever (120 min after IV injection of endotoxin) induced a smaller effect than in the early phase of the fever--the downward shift of the temperature threshold for cold thermogenesis was less evident and the thermosensitivity of the controller remained unchanged. The changes in activity of thermoregulatory centers that occurred after ACTH in febrile rabbits correspond to those observed in the late phase of the fever in ACTH-untreated rabbits. It is suggested therefore, that the presumed increase in ACTH production during fever might represent a negative feed-back mechanism contributing to the termination of the febrile state. PMID: 2850094 [PubMed - indexed for MEDLINE] 20. Physiol Bohemoslov. 1988;37(2):173-80. The use of an intestinal thermode for studying thermoregulation of the golden hamster. Stefl B(1). Author information: (1)Department of Physiology and Developmental Biology, Faculty of Science, Charles University, Prague. Intestinal cooling induces a normal metabolic response compensating heat loss in the euthermic golden hamster. The hypothalamic and subcutaneous temperatures change unpredictably and the threshold hypothalamic temperature for the induction of cold thermogenesis, similarly as the sensitivity of the regulator related to changes in hypothalamic temperature vary considerably, however. It seems that the thermal input from the hypothalamus does not contribute significantly to the control of cold thermogenesis in euthermic golden hamsters during intestinal cooling. The use of an intestinal thermode itself is not suitable for quantitative studies of thermoregulation in the golden hamster. PMID: 2975007 [PubMed - indexed for MEDLINE] 21. Pflugers Arch. 1987 Sep;410(1-2):220-2. Thermoregulation of the rabbit during the late phase of endotoxin fever. Vybíral S(1), Székely M, Janský L, Cerný L. Author information: (1)Department of Comparative Physiology, Faculty of Science, Charles University, Prague, Czechoslovakia. In the late phase of the fever occurring 120 or more min after i.v. injection of endotoxin (1 microgram/kg) to female rabbits, marked shifts of thresholds for respiratory evaporative heat loss and for peripheral vasodilatation to higher body core temperatures were observed. In contrast, the threshold body core temperature for cold thermogenesis was shifted downwards. As a result, the interthreshold zone was widened. Within the body temperature range of 37.4 to 39.9 degrees C neither heat production or heat loss mechanisms were operant and the body temperature was determined mainly by passive heat transfer between the body and the environment. Outside this zone, the sensitivities of the heat and cold defence activities to changes in body core temperature appeared to be unchanged. PMID: 3317270 [PubMed - indexed for MEDLINE] 22. Pflugers Arch. 1986 Mar;406(3):312-4. Hyperthermic effect of neurotensin in the rabbit. Vybíral S, Nacházel J, Janský L. Neurotensin injected into the anterior hypothalamus of the rabbit induces a consistent upward shift of the threshold core temperatures for inducing cold thermogenesis, peripheral vasomotor tone and respiratory evaporative heat loss, while leaving the efficiency and the intensity of these thermoregulatory outputs unchanged. Neurotensin injections into the PH are without effect on body temperature control. The effect of neurotensin is interpreted as a selective inhibition of activity of warm sensors in the anterior hypothalamus. The possible mediating role of dopaminergic pathways in the neurotensin action is discussed. PMID: 3960708 [PubMed - indexed for MEDLINE] 23. J Appl Physiol Respir Environ Exerc Physiol. 1983 Sep;55(3):663-8. Substrates for cold thermogenesis in thyrotoxic dogs. Minaire Y, Forichon J, Fréminet A, Cagnard M, Dallevet G. The influence of thyrotoxicosis on energy supply during cold exposure was studied in normal and chronically thyroxine (T4)-treated normothermic dogs exposed to neutral (Ta,N = +25 degrees C) or cold (Ta,C = -21 degrees C) ambient temperatures. At Ta,N, T4 treatment significantly increased VO2, glucose turnover, and plasma 3-hydroxybutyrate concentration. The percentage of glucose turnover derived from alanine also increased in spite of lower alanine release. In cold, T4 treatment did not significantly modify O2 consumption, glucose turnover, or plasma alanine concentration, but plasma hydroxybutyrate, alanine clearance, and alanine conversion into glucose were significantly increased compared with control. It is suggested that in cold the main effect of thyrotoxicosis on energy supply, in addition to a trend toward lipid mobilization, is an increase in hepatic alanine extraction and conversion into glucose in the presence of lower muscular alanine delivery. PMID: 6629904 [PubMed - indexed for MEDLINE] 24. Acta Physiol Pol. 1982 Jul-Aug;33(4):327-36. Effects of exposure to cold and catecholamines on the respiratory quotient and plasma levels of free fatty acids, glucose and urea in non-acclimated rats. Uliasz-Poniewierska M. The reported experiments were carried out on 147 male Wistar rats weighing 325 to 400 g kept on normal diet or fasted for 24 hours. These rats were treated with adrenaline, noradrenaline or propranolol (400 micrograms/kg subcutaneously) or were exposed to a temperature of 15 degrees C for 2 hours before and after propranolol injection (400 micrograms/kg). The metabolic rate (MR), respiratory quotient (RQ) and the levels of free fatty acids (FFA), glucose (G) and urea (U) in the plasma were determined. The conclusion was drawn that none of the determined indices alone is a good indicator of changes in the catabolism of lipids, carbohydrates or proteins. However, in the light of the results, simultaneous determination of all parameters, MR including, can provide an indirect information on the role of different substrates in cold thermogenesis. PMID: 7184316 [PubMed - indexed for MEDLINE] 25. J Dev Physiol. 1982 Feb;4(1):53-73. The role of the adrenal gland in the metabolic response of young lambs to cold. Alexander G, Bell AW. Adrenalectomy and various replacement regimens with corticosteroids and catecholamines were used to assess the role of the adrenal secretions in cold thermogenesis in young lambs. A dose of cortisol of 0.25 mg kg-1 d-1 was sufficient to increase summit metabolism significantly in lambs that had been adrenalectomized for at least 1 week, but even the massive dose of 16 mg kg-1 d-1 restored the response to only 85--90% of that in intact lambs. However, the remaining 10-15% deficit was largely restored by additional infusion of catecholamines, principally adrenaline, and there was no significant interaction between the responses to cortisol dose and to catecholamine infusion. Heart rate, arterial blood pressure and cardiac output during summit metabolism all increased with increasing dose of cortisol. Hyperglycaemic responses to cold exposure were low in adrenalectomized lambs receiving less than 0.25 mg kg-1 d-1 of cortisol, and the normal hyperlactacidaemia in intact lambs during summit metabolism was apparent only in lambs receiving more than 1 mg kg-1 d-1, unless adrenaline was also given. The increase in summit metabolism due to adrenaline was accompanied by increased shivering. There was no effect on heart rate and blood pressure, but adrenaline increased cardiac output through an apparent increase in cardiac stroke volume and a decrease in total peripheral resistance. Strong correlations of the increase in summit metabolism with the increase in cardiac output and with adrenaline-mediated increases in plasma glucose and lactate, indicate that a role of the medullary catecholamines is to maintain maximal thermogenesis by their effects on the supplies of oxygen and energy substrates to the thermogenic tissues. PMID: 7108163 [PubMed - indexed for MEDLINE] 26. Fiziol Zh SSSR Im I M Sechenova. 1981 Feb;67(2):294-8. [Role of thyroid gland hormones in thermoregulatory reactions during adaptation to high altitude]. [Article in Russian] Bazhenov IuI, Sydykov BK. The influence of thyroid hormone in thermogenesis of animals adapting to high altitude for different periods were studied in white rats. The adaptation to high altitude hypoxia decreased reaction of the organism to cold. The antithyroid injection of mercazolil potentiated the hypoxia action in cold thermogenesis and lowered sharply the body temperature stability in cooling. The analogous injection of triiodthyronine reduced the hypoxia influence on the thermogenesis and increased the contribution of the contractile heat production in the thermoregulative metabolism. The data suggest that one of the reasons of the low heat effect of the muscle contraction in adaptation to hypoxia may be the functional weakening of the thyroid gland. PMID: 6163665 [PubMed - indexed for MEDLINE] 27. Fiziol Zh SSSR Im I M Sechenova. 1980 May;66(5):739-45. [Changes in the adrenergic regulation of thermogenesis during prolonged rat adaptation to cold]. [Article in Russian] Pastukhov IuF. Comparison of effects of catecholamines (noradrenaline, adrenaline, and isopropyl-noradrenaline) on oxygen consumption and body temperature and study of influence of beta- and alpha-adrenergic blocking agents (poropranolol and phentolamine) on their calorigenic effects in cold- and warm-adapted rats revealed that affinity of propranolol and all the catecholamines to beta-adrenoreceptors is enhanced. Influence of propranolol on the cold thermogenesis involves thermoregulatory metabolism decrease in warm-adapted rats and additional (compensatory) increase of thermoregulatory electrical muscle activity in cold-adapted rats. The sympathetic regulation of heat production and its changes at prolonged cold adaptation seem to be mainly of beta-adrenergic nature. PMID: 7398941 [PubMed - indexed for MEDLINE] 28. Int Rev Physiol. 1979;20:43-155. Cold thermogenesis. Alexander G. PMID: 387638 [PubMed - indexed for MEDLINE] 29. J Appl Physiol Respir Environ Exerc Physiol. 1977 Nov;43(5):770-7. Hypothalamic thermoregulatory pathways in the rat. Gilbert TM, Blatteis CM. The cutaneous blood flow (mbl), rate of oxygen consumption (Vo2), rectal (Tre) and cutaneous (Tsk) temperatures, and shivering activity were measured in unanthetized male rats during a 2-h exposure to 26, 33, or 5 degrees C 2 wk after selective bilateral hypothalamic microknife cuts. Animals with preoptic-anterior hypothalamic (PO/AH) junction cuts 1.5 or 3.0 mm lateral to the midline, as well as parasagittal cuts which separated connections between the PO/AH and medial forebrain bundle exhibited a higher mbl at 26 degrees C than did sham-operated rats. At 5 degrees C the extended (3.0 mm) PO/AH cuts as well as the parasagittal cuts prevented cutaneous vasoconstriction but had no effect on shivering activity; hence Tre was not maintained. None of the cuts demonstrably impaired thermoregulation in the 33 degrees C environment. These results suggest that different sites in the hypothalamus may separately control cold-induced skin vasoconstriction and shivering activity, as well as heat-induced skin vasodilation. It would seem therefore that the integrity of the PO/AH is indispensable in rats for cold-induced cutaneous vasoconstriction but not for cold thermogenesis, and also not for heat-induced cutaneous vasodilation. PMID: 591468 [PubMed - indexed for MEDLINE] 30. J Appl Physiol. 1976 Dec;41(6):848-58. Effect of altitude exposure on thermoregulatory response of man to cold. Blatteis CM, Lutherer LO. The thermoregulatory responses to 10 degrees C (for 3 h) were investigated in 1) 12 natives from sea level (lowlanders) at 150 m, and on arrival at 3,350 and 4,340 m; 2) 6 of these during a 6-wk sojourn at 4,360 m, and on return to sea level; and 3) 5 natives from each of the two altitudes (highlanders) in their respective habitat, and after descent to 150 m. The cold-induced increase in the rate of O2 consumption (Vo2) of the lowlanders was significantly smaller at both altitudes than at sea level. It did not recover substantially during the 6 wk at altitude, but was restored to its initial rate on return to sea level. By contrast, visible shivering activity was augmented on arrival at altitude. It persisted throughout the 6 wk there, but was greatly depressed on return to sea level, despite the increased Vo2. Mean skin temperatures (Tsk) stabilized in the cold at significantly higher values at altitude. Rectal temperature (Tre) decreased similarly at all altitudes. Vo2 of the highlanders in the cold was significantly greater at sea level than at their resident altitudes, although shivering activity was less intense; Tsk stabilized at significantly lower levels at 150 m than at either altitude. These results indicate that altitude exposure reduces the calorigenic response of man to cold, and that this effect is not moderated by acclimatization to altitude, yet is reversible immediately on descent to sea level. The component of cold thermogenesis which appeared to be reduced by altitude exposure was nonshivering thermogenesis rather than visible shivering. PMID: 1002639 [PubMed - indexed for MEDLINE] 31. Isr J Med Sci. 1976 Sep;12(9):1052-5. Interaction of hypothalamic and skin temperatures on cold thermogenesis in the rabbit. Hardy JD, Stitt JT. PMID: 1002432 [PubMed - indexed for MEDLINE] 32. Acta Biol Med Ger. 1975;34(7):1189-98. [Effect of brain stem lesions on hibernation of the hamster (Cricetus cricetus L.)]. [Article in German] Raths P, Bohn A. Small lesions in the brain stem (including the hypothalamus) of the European hamster were effective with respect to food intake, hibernatory disposition and thermogenic power (oxygen consumption) as well. Hyperphagia was accompanied by depression of hibernation mostly. Moreover, hibernation was hindered by impairment of the thermogenic capacity. Entrance into hibernation depended on the integrity of the middle and caudal hypothalamic areas and the rostral portions of the pons and midbrain. Hyperphagia resulted from destruction of the middle (ventromedial) hypothalamic and caudal hypothalamic areas, including transition structures to the pons. A depression of thermogenesis against cold was observed after destruction of supramammillary and neighbouring mesencephalic areas. Supplementary results: An annual metabolic rhythm characterized by a minimum in december has been established once more. Urethane anesthesia did not abolish cold thermogenesis, despite the development of a slight hypothermia. Poikilothermia resulting from brain stem damage disappeared during a three-day period. Furthermore, diencephalic lesions did not suppress arousal from hibernation significantly. PMID: 1199640 [PubMed - indexed for MEDLINE] 33. Can J Physiol Pharmacol. 1969 Aug;47(8):719-24. Catecholamines and cold thermogenesis in sheep. Webster AJ, Heitman JH, Hays FL, Olynyk GP. PMID: 5806462 [PubMed - indexed for MEDLINE]