Research ResourceMetabolism

Metabolic adaptation to calorie restriction

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Science Signaling  08 Sep 2020:
Vol. 13, Issue 648, eabb2490
DOI: 10.1126/scisignal.abb2490

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Rewired into hypothermia by deprivation

Calorie restriction extends health span, which is thought to be mediated in part through a decrease in core body temperature. Guijas et al. compared metabolomics data from mice subjected to calorie restriction and that were housed at a temperature lower than body temperature or at thermoneutrality, reasoning that thermoneutrality would offset the metabolic changes induced by calorie restriction. The authors found that calorie restriction induced the hypothalamus to produce the gasotransmitter nitric oxide and the opioid peptide leucine enkephalin in mice housed at cooler temperature, but not in mice housed at thermoneutrality. These and other metabolites that were differentially altered by ambient temperature may form the basis for developing compounds that can deliver the beneficial effects of calorie restriction.


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.

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