Calorie restriction (CR) enhances health span (the length of time that an organism remains healthy) and increases longevity across species. In mice, these beneficial effects are partly mediated by the lowering of core body temperature that occurs during CR. Conversely, the favorable effects of CR on health span are mitigated by elevating ambient temperature to thermoneutrality (30°C), a condition in which hypothermia is blunted. In this study, we compared the global metabolic response to CR of mice housed at 22°C (the standard housing temperature) or at 30°C and found that thermoneutrality reverted 39 and 78% of total systemic or hypothalamic metabolic variations caused by CR, respectively. Systemic changes included pathways that control fuel use and energy expenditure during CR. Cognitive computing-assisted analysis of these metabolomics results helped to prioritize potential active metabolites that modulated the hypothermic response to CR. Last, we demonstrated with pharmacological approaches that nitric oxide (NO) produced through the citrulline-NO pathway promotes CR-triggered hypothermia and that leucine enkephalin directly controls core body temperature when exogenously injected into the hypothalamus. Because thermoneutrality counteracts CR-enhanced health span, the multiple metabolites and pathways altered by thermoneutrality may represent targets for mimicking CR-associated effects.

卡路里限制 (CR) 可增强健康跨度（生物体保持健康的时间长度）并延长跨物种的寿命。在小鼠中，这些有益作用部分是由 CR 期间发生的核心体温降低介导的。相反，通过将环境温度升高到热中性 (30°C)，降低了体温过低的条件，从而减轻了 CR 对健康跨度的有利影响。在这项研究中，我们比较了饲养在 22°C（标准饲养温度）或 30°C 下的小鼠对 CR 的整体代谢反应，发现热中性恢复了由 CR 引起的全身或下丘脑代谢变化的 39% 和 78%，分别。系统性变化包括控制 CR 期间燃料使用和能量消耗的途径。对这些代谢组学结果的认知计算辅助分析有助于确定调节对 CR 的低温反应的潜在活性代谢物的优先级。最后，我们用药理学方法证明，通过瓜氨酸-NO 途径产生的一氧化氮 (NO) 促进 CR 触发的体温过低，并且亮氨酸脑啡肽在外源性注射到下丘脑时直接控制核心体温。由于热中性抵消了 CR 增强的健康跨度，因此热中性改变的多种代谢物和途径可能代表模拟 CR 相关效应的目标。我们用药理学方法证明，通过瓜氨酸-NO 途径产生的一氧化氮 (NO) 促进 CR 触发的体温过低，并且亮氨酸脑啡肽在外源性注射到下丘脑时直接控制核心体温。由于热中性抵消了 CR 增强的健康跨度，因此热中性改变的多种代谢物和途径可能代表模拟 CR 相关效应的目标。我们用药理学方法证明，通过瓜氨酸-NO 途径产生的一氧化氮 (NO) 促进 CR 触发的体温过低，并且亮氨酸脑啡肽在外源性注射到下丘脑时直接控制核心体温。由于热中性抵消了 CR 增强的健康跨度，因此热中性改变的多种代谢物和途径可能代表模拟 CR 相关效应的目标。