What can body temperature tell us about energy homeostasis?

哺乳动物的体温是高度调节的。然而，较小哺乳动物(如老鼠)的热生物学与较大哺乳动物(如成年人类)的热生物学不同。例如，当小鼠被单独安置在室温下时，大约一半的卡路里摄入量被燃烧以维持体温(兼性生热)，而人类几乎不需要兼性生热。禁食后，老鼠的体温可以降低10摄氏度，而极度饥饿的人类只会降低0.2摄氏度。 我们正在探索使用体温作为小鼠可感知的代谢状态的指示器。例如，基因操作或药物治疗对体温有什么影响？哪些基因操作或药物治疗会导致体温与营养状态分离？涉及的神经递质和神经机制是什么？ 小鼠也是研究体温过低的理想模型系统，因为中枢调节机制在哺乳动物中很可能是保守的，但小鼠表现出比大型哺乳动物更大的变化。因此，老鼠是一种更敏感的物种，可以建议在成年人类等体型较大的个体上进行富有成效的研究。我们感兴趣的是体温和体温的神经控制，以及了解体温过低的药物诱因。 2016财年的进展包括： 我们量化了环境温度对小鼠能量平衡和体温的影响(1)。体温在很大程度上取决于昼夜节律和体力活动，也取决于环境温度。小鼠在体力活动中抵抗较高的体温。活动期体温变暖的成本是每天总能量消耗的4%至16%。死后较高的热导率表明，小鼠的大部分隔热作用是通过生理机制实现的。在22℃时，冷诱导产热是基础代谢率的120%。身体活动期间体温较高是由于较高的设定点，而不是简单地在运动过程中增加热量产生。大多数老鼠的隔热是通过生理机制进行的，很少有毛皮或脂肪。我们的分析建议重新考虑热中性区上限的定义。测量体温可以解释能量消耗数据，并提高小鼠模拟人类能量平衡的预测性和实用性。 实验室之前的研究表明，Brs3通过交感系统和蝙蝠对体温的调节起到了作用。我们现在已经证明，Brs3也通过交感系统调节心率和血压(2)。 我们使用有效的、特异的A3AR激动剂(MRS5698、MRS5841、MRS5980)研究了A3AR在低温中的作用(3)。A3AR激动剂的降温作用不依赖于A1AR的激活，因为在缺乏A1AR的小鼠中这种作用是完全完整的，而在缺乏A3AR的小鼠中这种作用就会消失。A3AR激动剂诱导的降温作用可通过耗竭肥大细胞颗粒而减弱，表明A3AR降温是通过肥大细胞介导的。中枢剂量的激动剂没有明显的降温作用，而外周剂量的非脑穿透性激动剂引起低温，这表明外周表达A3AR的细胞驱动了低温。肥大细胞释放组胺，阻断中枢组胺H1受体可以防止体温下降。低体温之前是低代谢，低体温的小鼠更喜欢较凉爽的环境温度，这表明低体温状态是一种协调的生理反应，具有降低的体温设定点。重要的是，A3AR激动剂的止痛效果不需要低温，因为A3AR激动剂的剂量较低。这些结果支持低温的机制模型，在该模型中，A3AR激动剂作用于外周肥大细胞，导致组胺释放，组胺H1受体刺激中枢组胺H1受体诱导低温。这一机制表明，A3AR激动剂可能不适用于临床诱导体温过低。

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.