Dietary Intake Regulates White Adipose Tissues Angiogenesis via Liver Fibroblast Growth Factor 21

Abstract

Background: Obesity and related metabolic disorders have become epidemic diseases. Intermittent fasting has been shown to promote adipose tissue angiogenesis and have an anti-obesity feature; however, the mechanisms of how intermittent fasting modulates adipose tissues angiogenesis are poorly understood. Methods: We evaluated the effect of short-time and long-term intermittent fasting on FGF21 and VEGF expression in various tissues in C57BL/6 mice. Cell fractional analysis were used to examine the target cells in WAT were involved in fasting induced VEGF expression. Tail vein injection of recombinant FGF21 to C57BL/6 mice were used to examine the direct effect of FGF21 on VEGF expression. Wild-type and liver-specific ablation of fibroblast growth factor 21 (FGF21 LKO) were fed on a high-fat diet ad libitum or intermittent fasting for 16 weeks, and metabolic phenotypes including body weight, insulin resistance, browning and white adipose tissues angiogenesis were monitored. Findings: In the current study, fasting induced a selective and drastic elevation of VEGF levels in WAT which did not occur in interscapular BAT and liver. The fasting-induced Vegfa expression occurred predominantly in mature adipocytes, but not in the stromal vascular fraction. Furthermore, a single bolus of recombinant mouse FGF21injection increased VEGF levels in WAT. Long-term intermittent fasting increased WAT angiogenesis, iWAT browning, and improved insulin resistance and inflammation, but the effect was blunted in FGF21 LKO mice. Interpretation: In summary, these data suggest that FGF21 is a potent regulator of WAT VEGF levels. The interorgan FGF21 signaling induced WAT angiogenesis by VEGF could be a potential new therapeutic target in combination with obesity-related metabolic disorders. Funding Statement: This study was supported by National Key R&D Program of China (Grant 2018YFD0501005), National Natural Science Foundation of China, PR China (Grant 31772616) and the 111 Project (D17015). Declaration of Interests: The authors have no conflict of interest to declare. Ethics Approval Statement: All animal procedures in this study were approved by the Institutional Animal Care and Research Committee of Sichuan Agricultural University (SICAU-2015-033).