Diet-induced obesity is a major risk factor for metabolic syndrome, diabetes and cardiovascular disease. Here, we show that a 5-d fasting-mimicking diet (FMD), administered every 4 weeks for a period of 2 years, ameliorates the detrimental changes caused by consumption of a high-fat, high-calorie diet (HFCD) in female mice. We demonstrate that monthly FMD cycles inhibit HFCD-mediated obesity by reducing the accumulation of visceral and subcutaneous fat without causing loss of lean body mass. FMD cycles increase cardiac vascularity and function and resistance to cardiotoxins, prevent HFCD-dependent hyperglycaemia, hypercholesterolaemia and hyperleptinaemia and ameliorate impaired glucose and insulin tolerance. The effect of monthly FMD cycles on gene expression associated with mitochondrial metabolism and biogenesis in adipocytes and the sustained ketogenesis in HFCD-fed mice indicate a role for fat cell reprogramming in obesity prevention. These effects of an FMD on adiposity and cardiac ageing could explain the protection from HFCD-dependent early mortality.

饮食引起的肥胖是代谢综合征、糖尿病和心血管疾病的主要危险因素。在这里，我们展示了为期 2 年每 4 周一次的 5 天模拟禁食饮食 (FMD) 可以改善女性因食用高脂肪、高热量饮食 (HFCD) 引起的有害变化老鼠。我们证明每月 FMD 周期通过减少内脏和皮下脂肪的积累而不导致瘦体重损失来抑制 HFCD 介导的肥胖。FMD 周期增加心脏血管和功能以及对心脏毒素的抵抗力，预防 HFCD 依赖性高血糖、高胆固醇血症和高瘦素血症，并改善葡萄糖和胰岛素耐受性受损。每月一次的 FMD 周期对与线粒体代谢和脂肪细胞生物发生相关的基因表达的影响以及喂食 HFCD 的小鼠的持续生酮表明脂肪细胞重编程在肥胖预防中的作用。FMD 对肥胖和心脏老化的这些影响可以解释 HFCD 依赖性早期死亡率的保护作用。