Science Signaling：对热量限制的代谢适应研究

热量限制（Calorie restriction，CR）可以延长健康寿命（生物体保持健康的时间长度）并延长物种的寿命。在小鼠中，这些有益作用部分是通过CR期间造成的核心体温下降来介导的。相反地，通过将环境温度升高至热中性（30 ℃）将会减少CR对健康的有利影响，因为这种情况弱化了体温降低，。在本研究中，美国斯克里普斯研究所代谢组学中心的Carlos Guijas、J. Rafael Montenegro-Burke、Gary Siuzdak和斯克里普斯研究所分子医学系的Bruno Conti等人比较了在22 ℃（标准居住温度）和30 ℃ 条件下饲养的小鼠对CR的整体代谢反应，发现热中性分别恢复了由CR引起的全身或下丘脑代谢变化的39%和78%。

系统的改变了包括CR期间控制对食物利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优化调节CR低温反应的潜在活性代谢物。最后，用药理学方法证明了通过瓜氨酸-NO通路产生的一氧化氮（nitric oxide，NO）可引起CR导致的体温过低，而当亮氨酸-脑啡肽在外源注射到下丘脑时可以直接控制核心体温。因为热中性作用抵消了CR所增加的健康跨度，所以由热中性改变的多种代谢物和途径可能是模拟CR相关作用的靶标。

Abstract

Metabolic adaptation to calorie restriction

Carlos Guijas, J. Rafael Montenegro-Burke, Rigo Cintron-Colon, Xavier Domingo-Almenara, Manuel Sanchez-Alavez, Carlos A. Aguirre, Kokila Shankar, Erica L.-W. Majumder, Elizabeth Billings, Bruno Conti, Gary Siuzdak

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.

该文章《Metabolic adaptation to calorie restriction》于《Science Signaling》2020年09月出版。点击下方阅读原文即可查看摘要原文。

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翻译/编辑：袁月；责编：张睿梅

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