FGF10 and FGF21 as Regulators in Adipocyte Development and Metabolism

Hiroya      Ohta; Morichika      Konishi; Nobuyuki      Itoh

Abstract

The FGF family comprises twenty-two evolutionarily related members with diverse functions in development, metabolism, and neuronal activities. FGF10 and FGF21 play unique roles in adipocyte development and metabolism, respectively. FGF10 mediates biological responses by activating FGF receptor 2b (FGFR2b) with heparin/heparan sulfate in a paracrine manner. In contrast, FGF21 mediates biological responses by activating FGFRs with βKlotho in cultured cells. However, FGF21 acts in an autocrine manner via a β Klotho-independent signaling pathway in mice. Fgf10 knockout mice die shortly after birth. Preadipocyte proliferation and adipogenesis are greatly impaired in Fgf10 knockout mouse embryos. FGF10 stimulates preadipocyte proliferation through the Ras/MAPK pathway followed by the cyclin D2-dependent phosphorylation of p130. FGF10 also stimulates adipogenesis by inducing the expression of pRb through the Ras/MAPK pathway. pRb binds C/EBPα. The pRb-C/EBPα complex induces adipogenesis. Fgf21 is abundantly expressed in the liver. Hepatic Fgf21 expression is markedly induced in mice by fasting. FGF21 exerts pharmacological effects on glucose and lipid metabolism in hepatocytes and adipocytes. However, the phenotypes of Fgf21 knockout mice, which are apparently normal and fertile, indicate FGF21 not to be a physiological regulator for hepatic functions. Hepatic FGF21 inhibits lipolysis in adipoctyes, and so is a negative regulator of lipolysis during fasting. FGF21 may be a “thrifty factor”. Serum FGF21 levels are increased in patients with metabolic diseases related with obesity, indicating potential roles of FGF21 in adipocyte metabolism.

Keywords: Adipocyte, adipogenesis, development, disease, evolution, FGF, metabolism, proliferation, Adipose-derived stem cell, AMP-activated protein kinase, Fibroblast growth factor, Phosphoinositide 3-kinase, Sirtuin 1