Volume 27, No 11, Nov 2017
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 27 Issue 11, November 2017: 1309-1326 | Open Access
ORIGINAL ARTICLES
Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage
Kyoung-Han Kim1,12,*, Yun Hye Kim2,*, Joe Eun Son1, Ju Hee Lee2,3, Sarah Kim2, Min Seon Choe1, Joon Ho Moon2, Jian Zhong2, Kiya Fu2, Florine Lenglin2, Jeong-Ah Yoo2, Philip J Bilan4, Amira Klip4, Andras Nagy5,6, Jae-Ryong Kim7, Jin Gyoon Park8, Samer MI Hussein9, Kyung-Oh Doh10, Chi-chung Hui11 and Hoon-Ki Sung2,3
1Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
2Translational Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada
3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
4Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
5Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
6Department of Obstetrics & Gynaecology and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
7Department of Biochemistry and Molecular Biology, Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea
8Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ, USA
9Centre Hospitalier Universitaire de Québec Research Center and Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
10Department of Physiology, College of Medicine, Yeungnam University, Daegu, Republic of Korea
11Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
12Current address: University of Ottawa Heart Institute and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
Correspondence: Chi-chung Hui, E-mail: cchui@sickkids.ca; Hoon-Ki Sung,(hoon-ki.sung@sickkids.ca)
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.
10.1038/cr.2017.126
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