Fibroblast growth factor 21 signaling: The liver in focus

Fibroblast growth factor 21 (FGF21) was first identified as a metabolic factor in a screen for proteins that induce glucose uptake in adipocytes. FGF21 is a member of the so-called hormone-like subgroup within the FGF superfamily that also contains FGF19 and FGF23. The C-terminus of FGF21 binds with high affinity to b-Klotho, which is present in a complex with FGF receptors (FGFRs) on the surface of cells (Fig. 1). FGF21 has been shown to promote antidiabetic, lipid-lowering, and weightreducing effects at pharmacological concentrations in rodents. In adipose tissue—considered a key target tissue—FGF21 stimulates production of adiponectin, which, in turn, enhances insulin sensitivity in the liver. FGF21 has also been shown to elicit many of its metabolic effects through actions on the central nervous system. Recently, a liver-to-brain hormonal axis was described in which liver-produced FGF21 functions to regulate the consumption of individual macronutrients and even substances of abuse, such as alcohol. Given the numerous metabolic actions of FGF21, FGF21-based pharmacotherapy is currently being extensively explored for prevention and therapy of a variety of metabolic disorders. Recent studies with long-acting FGF21 analogs in obese patients with type 2 diabetes indeed presented promising perspectives given that they demonstrated improvements of serum lipid profiles and weight loss, although glucose levels basically were unaffected. In this issue of HEPATOLOGY, Gong et al. significantly expand on the knowledge of molecular mechanisms underlying the effect of FGF21 in the regulation of insulin and glucose homeostasis in the liver. By combining in vitro experiments in human cultured hepatocytes and gainand loss-of-function studies in multiple mouse models, the investigators provide several layers of evidence to indicate that FGF21 acts as a novel inhibitor of the nutrient sensor, mammalian target of rapamycin complex 1 (mTORC1), in the liver (Fig. 1). First, administration of FGF21 to mice challenged with a type 2 diabetogenic diet significantly decreased hepatic mTORC1 activity and improved liver insulin sensitivity, as evidenced by reduced serine phosphorylation of insulin receptor substrate 1 (IRS-1) combined with an increased phosphorylation of Akt (protein kinase B). Consistently, adenovirus-mediated overexpression of FGF21 in liver caused a potent reduction in hepatic mTORC1 activity and IRS-1 phosphorylation together with increased phosphorylation of Akt in insulin-treated mice. In addition, increased levels of FGF21 in mice induced hepatic glycogen synthesis, as evidenced by increased phosphorylation of glycogen synthase kinase 3b and reduced phosphorylation of glycogen synthase. Reciprocal effects on mTOR activity, insulin signaling, and glycogen synthesis were observed in FGF21 knockout mice. Interestingly, the investigators found that the effects of FGF21 overexpression in mice were replicated in human HepG2 and Huh7 hepatocytes with adenovirus-delivered FGF21, suggesting a hepatocyteautonomous manner of FGF21 action. Strikingly, hepatic knockdown of the FGF21 receptor scaffold protein, b-Klotho, or hepatic hyperactivation of mTORC1/downstream effector S6 kinase 1 (S6K1) abrogated the effect of FGF21 on hepatic insulin Abbreviations: Akt, protein kinase B; FGF21, fibroblast growth factor 21; FGFRs, FGF receptors; IRS-1, insulin receptor substrate 1; mTORC1, mammalian target of rapamycin complex 1; NASH, nonalcoholic steatohepatitis; S6K1, S6 kinase 1; TSC, tuberous sclerosis complex.