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

The effects of intermittent fasting on obesity and metabolic disorders.

OCT 17, 2017

Written by Kyoung-Han Kim, Yun Hye Kim, Joe Eun Son, Ju Hee Lee, Sarah Kim, Min Seon Choe, Joon Ho Moon, Jian Zhong, Kiya Fu, Florine Lenglin, Jeong-Ah Yoo, Philip J Bilan, Amira Klip, Andras Nagy, Jae-Ryong Kim, Jin Gyoon Park, Samer MI Hussein, Kyung-Oh Doh, Chi-chung Hui, Hoon-Ki Sung

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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 over expression 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.



In summary, our data demonstrate that metabolic benefits of IF are largely mediated by adipose thermogenesis without overall caloric reduction. We showed that fasting-induced adipose-VEGF plays a key role in WAT browning through M2 macrophage activation. This finding is further supported by human adipose tissue gene expression analysis illustrating positive correlations between adipose-VEGF expression and both M2 macrophage and WAT browning. Together, the present study illustrates the role of IF-induced adipose-VEGF in remodeling the immunometabolic property of adipose tissue, highlighting the importance of eating pattern and physiological fasting duration to sustain metabolic homeostasis.