Hepatic FGF21 protects mice against diet-induced lipid dysregulation and insulin resistance

Abstract

Fibroblast growth factor 21 (FGF21) is a potent metabolic hormone produced by a number of organs. It has been shown to confer multiple metabolic benefits on obesity. Therapeutic administration of FGF21 or its analog protects against diet-induced obesity and hyperglycemia in both rodents and humans. However, the physiological roles of FGF21 remain ambiguous. Since the liver is the major source of circulating FGF21, we propose that the endocrine actions of FGF21 derived from the liver may account for its metabolic effects on lipid metabolism. We therefore generated the liver-specific FGF21 KO (LiverKO) mice by utilizing the Cre-loxP recombination system. LiverKO mice and their age-matched wild-type (WT) littermates were fed a high fat diet (HFD) for 20 weeks and assessed for the metabolic phenotypes. Circulating FGF21 was significantly elevated in WT mice during fasting or HFD feeding. However, this elevation of circulating FGF21 was completely abolished in LiverKO mice, suggesting the liver is the major source of circulating FGF21. LiverKO mice treated with HFD showed a sign'5cant reduction in body fat mass when compared to WT mice, as revealed by NMR body composition analyzer suggesting resistance to obesity was mainly attributed to the loss at hepatic FGF21. Interestingly, although LiverKO mice were leaner, they developed more severe glucose intolerance and insulin resistance after HFD feeding as shown by GTT and ITT. In addition, LiverKO mice had higher serum triglyceride and free fatty acid levels suggesting that lipid homeostasis is lipid uptake in adipocytes. These data collectively suggest that circulating FGF21 is mainly derived from the liver. Hepatic FGF21 regulates lipid metabolism in adipocytes, and therefore protects mice against diet-induced hyperglycemia and insulin resistance possibly via reducing ectopic lipid accumulation in non-adipose tissues such as the liver and skeletal muscles. Supported By: Collaborative Research Fund Group Research Projects of Hong Kong