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 (referred to as cold-induced thermogenesis), while humans require little cold-induced 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 FY2018 includes the following: Extracellular adenosine is a danger/injury signal that initiates protective physiology, such as hypothermia. We previously showed that adenosine can cause hypothermia via the A3 receptor (A3AR). In 2017 we published that A1AR agonists acted centrally to cause hypothermia. In addition, the commonly used A1AR agonist drugs also agonize A3AR and cause hypothermia via that mechanism, if given peripherally. In 2018 we found that adenosine continues to elicit hypothermia in mice null for A1AR and A3AR and investigated the effect of agonism at A2AAR or A2BAR. Selective, poorly brain penetrant A2AAR agonists caused hypothermia. While vasodilation is probably a contributory mechanism, the A2AAR agonists also caused hypometabolism, suggesting that vasodilation is not the sole mechanism. An A2BAR agonist BAY60-6583 also elicited hypothermia, which was also caused by low intracerebroventricular doses, indicating a brain site of action. Thus, agonism at any one of the canonical adenosine receptors, A1AR, A2AAR, A2BAR, or A3AR, can cause hypothermia. This four-fold redundancy in adenosine-mediated initiation of hypothermia may reflect the centrality of hypothermia as a protective response.

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7
Fiscal Year
2018
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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
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
Lute, Beth; Jou, William; Lateef, Dalya M et al. (2014) Biphasic effect of melanocortin agonists on metabolic rate and body temperature. Cell Metab 20:333-45

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