Fibroblast growth factor 21 (FGF-21) has been extensively studied in recent years due to its multiple therapeutic benefits for a cluster of obesity-related cardiometabolic complications. However, an unsolved puzzle is that despite its pleiotropic metabolic benefits, FGF-21 is paradoxically elevated in obesity and diabetes in both animals and humans. Its pathophysiological relevance in response to excess energy intake remains poorly understood. Here we provide both clinical and animal evidences demonstrating that elevated endogenous FGF-21 in obesity serves as a defense mechanism against systemic insulin resistance. Serum FGF-21 levels were positively associated with subcutaneous fat area in subjects with insulin-sensitive overweight/obesity. Furthermore, FGF-21 knockout mice (FGF-21KO) showed much less subcutaneous adipose tissue (SAT) mass and were more insulin resistant when fed with high-fat diet. Replenishment of recombinant FGF-21 to a level equivalent to those occurring in diet-induced obesity restored SAT mass and reversed insulin resistance in FGF-21KO but not in adipose-specific βklotho knockout mice. Moreover, transplantation of SAT from wild type to FGF-21KO mice improved insulin sensitivity in the recipient mice. Mechanistically, circulating FGF-21 acts in an endocrine manner on subcutaneous fat to promote the healthy expansion. FGF-21 upregulates adiponectin in subcutaneous adipose tissue, accompanied with an increase of M2 macrophage polarization. This study raises the possibility that targeting subcutaneous fat through manipulation of FGF-21 may represent a promising therapeutics to combat insulin resistance.
H. Li: None. L. Qian: None. L. Wu: None.