Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage

TLDR

Intermittent fasting (IF) provides health benefits comparable to prolonged fasting or caloric restriction, yet the mechanisms underlying these metabolic benefits remain poorly understood. This study aims to elucidate the molecular mechanism by which isocaloric intermittent fasting improves metabolic homeostasis and to evaluate its potential as a preventive and therapeutic strategy for obesity and metabolic disorders. We found that isocaloric intermittent fasting enhances metabolic homeostasis in diet‑induced obese mice by stimulating adipose thermogenesis through VEGF‑mediated alternative activation of adipose macrophages, and that adipose‑VEGF overexpression alone can mimic these benefits, with a similar VEGF‑M2 macrophage‑WAT browning axis observed in human adipose tissue.

Abstract

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.