Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vascular endothelial growth factor (VEGF) expression in white adipose tissue (WAT). Furthermore, periodic adipose-VEGF overexpression could recapitulate the metabolic improvement of IF in non-fasted animals. Importantly, fasting and adipose-VEGF induce alternative activation of adipose macrophage, which is critical for thermogenesis. Human adipose gene analysis further revealed a positive correlation of adipose VEGF-M2 macrophage-WAT browning axis. The present study uncovers the molecular mechanism of IF-mediated metabolic benefit and suggests that isocaloric IF can be a preventive and therapeutic approach against obesity and metabolic disorders.

中文翻译：

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间歇性禁食通过VEGF介导的巨噬细胞替代激活促进脂肪生热和代谢稳态

间歇性禁食（IF）是一种周期性的能量限制措施，已显示出等同于长期禁食或热量限制的健康益处。但是，我们对IF介导的代谢益处的潜在机制的理解是有限的。在这里，我们显示等热量的IF主要通过小鼠脂肪​​的生热作用来改善针对饮食引起的肥胖和代谢功能障碍的代谢稳态。IF诱导的代谢益处需要禁食介导的白色脂肪组织（WAT）中血管内皮生长因子（VEGF）表达的增加。此外，在非禁食动物中，周期性的过度表达VEGF可以概括IF的代谢改善。重要的是，禁食和脂肪VEGF诱导脂肪巨噬细胞的交替激活，这对生热至关重要。人类脂肪基因分析进一步揭示了脂肪VEGF-M2巨噬细胞-WAT褐变轴呈正相关。本研究揭示了中频介导的代谢益处的分子机制，并提出等热量中频可以作为预防和治疗肥胖和代谢异常的方法。