Calubag Mariah F, Ademi Ismail, Yeh Chung-Yang, Babygirija Reji, Pak Heidi H, Bhoopat Alyssa M, Kasza Ildiko, Green Cara L, Sonsalla Michelle M, Lamming Dudley W
Department of Medicine, University of Wisconsin-Madison, Madison, WI.
William S. Middleton Memorial Veterans Hospital, Madison, WI.
Aging Biol. 2022;1.
Calorie restriction (CR) promotes healthspan and extends the lifespan of diverse organisms, including mice, and there is intense interest in understanding the molecular mechanisms by which CR functions. Some studies have demonstrated that CR induces fibroblast growth factor 21 (FGF21), a hormone that regulates energy balance and that when overexpressed, promotes metabolic health and longevity in mice, but the role of FGF21 in the response to CR has not been fully investigated. We directly examined the role of FGF21 in the physiological and metabolic response to a CR diet by feeding and wild-type control mice either (AL) diet or a 30% CR diet for 15 weeks. Here, we find that FGF21 is largely dispensable for CR-induced improvements in body composition and energy balance, but that lack of blunts CR-induced changes aspects of glucose regulation and insulin sensitivity in females. Surprisingly, despite not affecting CR-induced changes in energy expenditure, loss of significantly blunts CR-induced beiging of white adipose tissue in male but not female mice. Our results shed new light on the molecular mechanisms involved in the beneficial effects of a CR diet, clarify that FGF21 is largely dispensable for the metabolic effects of a CR diet, and highlight a sex-dependent role for FGF21 in the molecular adaptation of white adipose tissue to CR.
热量限制（CR）可促进健康并延长包括小鼠在内的多种生物的寿命，人们对了解CR发挥作用的分子机制有着浓厚兴趣。一些研究表明，CR会诱导成纤维细胞生长因子21（FGF21），这是一种调节能量平衡的激素，在小鼠中过表达时可促进代谢健康和延长寿命，但FGF21在对CR的反应中的作用尚未得到充分研究。我们通过给野生型对照小鼠喂食正常饮食（AL）或30%热量限制饮食15周，直接研究了FGF21在对热量限制饮食的生理和代谢反应中的作用。在此，我们发现FGF21在很大程度上对于CR诱导的身体成分和能量平衡改善并非必需，但缺乏FGF21会减弱CR诱导的雌性小鼠葡萄糖调节和胰岛素敏感性方面的变化。令人惊讶的是，尽管不影响CR诱导的能量消耗变化，但FGF21的缺失显著减弱了CR诱导的雄性小鼠而非雌性小鼠白色脂肪组织的米色化。我们的结果为热量限制饮食有益作用所涉及的分子机制提供了新的见解，阐明了FGF21在很大程度上对于热量限制饮食的代谢作用并非必需，并突出了FGF21在白色脂肪组织对CR的分子适应中的性别依赖性作用。
