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Metabolic adaptation to calorie restriction.

ABSTRACT: 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.

SUBMITTER: Guijas C

PROVIDER: S-EPMC7580877 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Metabolic adaptation to calorie restriction.

Guijas Carlos C Montenegro-Burke J Rafael JR Cintron-Colon Rigo R Domingo-Almenara Xavier X Sanchez-Alavez Manuel M Aguirre Carlos A CA Shankar Kokila K Majumder Erica L-W EL Billings Elizabeth E Conti Bruno B Siuzdak Gary G

Science signaling 20200908 648

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 m ...[more]

PMID: 32900879

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Project description:Ghrelin is a gut hormone that signals to the hypothalamus to stimulate growth hormone release, increase food intake and promote fat deposition. The ghrelin receptor, also known as growth hormone secretagogue receptor (GHS-R), is highly expressed in the brain, with the highest expression in agouti-related peptide (AgRP) neurones in the hypothalamus. Compelling evidence indicates that ghrelin serves as a survival hormone with respect to maintaining blood glucose and body weight during nutritional deficiencies. Recent studies have demonstrated that AgRP neurones are involved in metabolic and behavioural adaptation to an energy deficit to improve survival. In the present study, we used a neuronal subtype-specific GHS-R knockout mouse (AgRP-Cre;Ghsrf/f ) to investigate the role of GHS-R in hypothalamic AgRP neurones in metabolic and behavioural adaptation to hypocaloric restricted feeding. We subjected the mice to a restricted feeding regimen of 40% mild calorie restriction (CR), with one-quarter of food allotment given in the beginning of the light cycle and three-quarters given at the beginning of the dark cycle, to mimic normal mouse intake pattern. The CR-fed AgRP-Cre;Ghsrf/f mice exhibited reductions in body weight, fat mass and blood glucose. Metabolic profiling of these CR-fed AgRP-Cre;Ghsrf/f mice showed a trend toward reduced basal metabolic rate, significantly reduced core body temperature and a decreased expression of thermogenic genes in brown adipose tissue. This suggests a metabolic reset to a lower threshold. Significantly increased physical activity, a trend toward increased food anticipatory behaviour and altered fuel preferences were also observed in these mice. In addition, these CR-fed AgRP-Cre;Ghsrf/f mice exhibited a decreased counter-regulatory response, showing impaired hepatic glucose production. Lastly, hypothalamic gene expression in AgRP-Cre;Ghsrf/f mice revealed increased AgRP expression and a decreased expression of genes in ?-oxidation pathways. In summary, our data suggest that GHS-R in AgRP neurones is a key component of the neurocircuitry involved in metabolic adaptation to calorie restriction.

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Metabolic adaptation to calorie restriction.

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Metabolic adaptation to calorie restriction.

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