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

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.

Lmo4‐resistin signaling contributes to adipose tissue‐liver crosstalk upon weight cycling

“…Two common dieting schemes using in rodent studies include mechanisms, such as increased browning in iWAT, increased thermogenesis, increased vascularization, and switching from M1 to M2 macrophage activation in adipose tissue. 36,37 Moreover, multiple clinical and animal studies, including the present study ( Figures 1G and 2D), indicated that healthy and unhealthy diet switch induced weight cycling ultimately increases body fat gain, specifically in the visceral adipose tissue. 4,38 Notably, the present study demonstrated increased A, qPCR results of Il-6 and Il-8 in primary hepatocytes stimulated with media from indicated 3T3-L1 cells.…”

“…Second, switching between normal chow (NC) or HF and fasting is seen in intermittent fasting study, whereas NC and HF switching is used in weight cycling study with continual access to food as is commonly seen in human society, therefore, some beneficial effects of intermittent fasting may due to a reduction in total caloric intake. However, some intermittent fasting studies with matched total caloric intake also suggest that beneficial effects may due to the physiological changes during fasting, such as fasting-induced increase of VEGF dependent activation of M2 macrophage in white adipose tissue, 37 fasting-induced modifying of gut microbiota 36 or improving of overt circadian rhythms, 39 and fasting-mimicking diet induced pancreatic β-cell regeneration. 40 Weight cycling has also been reported to be accompanied by fluctuations in biochemical parameters, such as blood glucose and blood pressure, indicators of disrupted metabolic homeostasis.…”

Differential regulation of the immune system in a brain-liver-fats organ network during short term fasting

“…The advent of high-throughput omics facilitated the elucidation of some of the cellular and molecular mechanisms underlying the beneficial effects of fasting. Nonetheless, the majority of these studies focused on single organ response (i.e., the liver) and, less often, involved two or three organs [10][11][12][13][14][15][16]. The adaptation to energy deprivation, however, requires a multi-organ integration of metabolic modulations to protect the organism from an irreversible loss of resources [17].…”

White adipose tissue coloring by intermittent fasting

“…However, it is still unclear, how activation of VEGFR2 in WAT could be achieved for the development of effective and safe treatment for humans. Kim et al [1] demonstrate that by allowing mice to fast every three days, VEGF levels were significantly increased in WAT. This was associated with angiogenesis, macrophage polarization towards antiinflammatory M2 type, and beiging of the WAT.…”

“…Rather than storing energy, these cells then start to use extra energy for heat production, which could be a promising therapeutic approach to treat obesity-related metabolic disorders. In a study recently published by Cell Research, Kim et al [1] demonstrate that IF increases vascular endothelial growth factor (VEGF) levels in WAT, which induced angiogenesis, adipose tissue macrophage polarization and WAT browning/beiging. This led to improved insulin sensitivity, which counteracted obesity, and alleviated metabolic syndrome in the mice.…”