Body temperature is highly regulated in mammals. However, thermal biology in smaller mammals (such as mice) is different from that in larger mammals (such as adult humans). For example, when mice are singly housed at room temperature, about half of caloric intake is burned to maintain body temperature (facultative thermogenesis), while humans require little facultative thermogenesis. Upon fasting, mice can reduce their body temperature by >10 C, while humans with extreme starvation lower body temperature by only 0.2 C. We are exploring the use of body temperature as an indicator of the perceived metabolic status of the mouse. For example, what is the effect on body temperature of a genetic manipulation or drug treatment? What genetic manipulations or drug treatments cause dissociation of body temperature from nutritional status? What are the neurotransmitters and neural mechanisms involved? Mice are also an ideal model system to study hypothermia, as the central regulatory mechanisms are likely conserved across mammals, but the mice show much greater changes than larger mammals. Thus mice are a more sensitive species that can suggest studies that might be productively undertaken in larger individuals such as adult humans. We are interested in the neural control of body temperature and hypothermia, and in understanding pharmacologic inducers of hypothermia. Progress in FY2016 includes the following: We quantified the effect of environmental temperature on mouse energy homeostasis and body temperature (1). Body temperature depended most on circadian phase and physical activity, but also on environmental temperature. Mice defended a higher body temperature during physical activity. The cost of the warmer body temperature during the active phase is 4 to 16% of total daily energy expenditure. The high post-mortem heat conductance demonstrates that most insulation in mice is via physiological mechanisms. At 22 C, cold-induced thermogenesis is 120% of basal metabolic rate. The higher body temperature during physical activity is due to a higher set point, not simply increased heat generation during exercise. Most insulation in mice is via physiological mechanisms, with little from fur or fat. Our analysis suggests that the definition of the upper limit of the thermoneutral zone should be re-considered. Measuring body temperature informs interpretation of energy expenditure data and improves the predictiveness and utility of the mouse to model human energy homeostasis. Prior studies from the lab showed that Brs3 contributes to the regulation of body temperature via the sympathetic system and BAT. We have now shown that Brs3 also regulates heart rate and blood pressure, via the sympathetic system (2). We studied the role of the adenosine A3 receptor (A3AR) in hypothermia, using potent, specific A3AR agonists (MRS5698, MRS5841, MRS5980) (3). The hypothermic effect of A3AR agonists is independent of A1AR activation, as the effect was fully intact in mice lacking A1AR but abolished in mice lacking A3AR. A3AR agonistinduced hypothermia was attenuated by mast cell granule depletion, demonstrating that the A3AR hypothermia is mediated via mast cells. Central agonist dosing had no clear hypothermic effect, whereas peripheral dosing of a nonbrain penetrant agonist caused hypothermia, suggesting that peripheral A3AR-expressing cells drive the hypothermia. Mast cells release histamine, and blocking central histamine H1 receptors prevented the hypothermia. The hypothermia was preceded by hypometabolism and mice with hypothermia preferred a cooler environmental temperature, demonstrating that the hypothermic state is a coordinated physiologic response with a reduced body temperature set point. Importantly, hypothermia is not required for the analgesic effects of A3AR agonists, which occur with lower agonist doses. These results support a mechanistic model for hypothermia in which A3AR agonists act on peripheral mast cells, causing histamine release, which stimulates central histamine H1 receptors to induce hypothermia. This mechanism suggests that A3AR agonists will probably not be useful for clinical induction of hypothermia.

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U.S. National Inst Diabetes/Digst/Kidney
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Reitman, Marc L (2018) Of mice and men - environmental temperature, body temperature, and treatment of obesity. FEBS Lett 592:2098-2107
Jain, Shalini; Panyutin, Anna; Liu, Naili et al. (2018) Melanotan II causes hypothermia in mice by activation of mast cells and stimulation of histamine 1 receptors. Am J Physiol Endocrinol Metab 315:E357-E366
Carlin, Jesse Lea; Jain, Shalini; Duroux, Romain et al. (2018) Activation of adenosine A2A or A2B receptors causes hypothermia in mice. Neuropharmacology 139:268-278
Xiao, Cuiying; Piñol, Ramón A; Carlin, Jesse Lea et al. (2017) Bombesin-like receptor 3 (Brs3) expression in glutamatergic, but not GABAergic, neurons is required for regulation of energy metabolism. Mol Metab 6:1540-1550
Carlin, Jesse Lea; Jain, Shalini; Gizewski, Elizabeth et al. (2017) Hypothermia in mouse is caused by adenosine A1 and A3 receptor agonists and AMP via three distinct mechanisms. Neuropharmacology 114:101-113
Carlin, Jesse Lea; Tosh, Dilip K; Xiao, Cuiying et al. (2016) Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors. J Pharmacol Exp Ther 356:474-82
Lateef, Dalya M; Xiao, Cuiying; Brychta, Robert J et al. (2016) Bombesin-like receptor 3 regulates blood pressure and heart rate via a central sympathetic mechanism. Am J Physiol Heart Circ Physiol 310:H891-8
Abreu-Vieira, Gustavo; Xiao, Cuiying; Gavrilova, Oksana et al. (2015) Integration of body temperature into the analysis of energy expenditure in the mouse. Mol Metab 4:461-70
Lateef, Dalya M; Abreu-Vieira, Gustavo; Xiao, Cuiying et al. (2014) Regulation of body temperature and brown adipose tissue thermogenesis by bombesin receptor subtype-3. Am J Physiol Endocrinol Metab 306:E681-7
Goldgof, Margalit; Xiao, Cuiying; Chanturiya, Tatyana et al. (2014) The chemical uncoupler 2,4-dinitrophenol (DNP) protects against diet-induced obesity and improves energy homeostasis in mice at thermoneutrality. J Biol Chem 289:19341-50

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