Commentary: FGF21 Holds Promises for Treating Obesity-related Insulin Resistance and Hepatosteatosis

Fibroblast growth factor (FGF) 21 is the first cloned and identified member of an atypical subfamily of endocrine fibroblast growth factors lacking the conventional heparin-binding domain and secreted into the circulation as a true hormone (1). FGF21 is widely expressed in multiple peripheral tissues, including liver, skeletal muscle, pancreas, and white and brown adipose tissue (WAT and BAT, respectively). Unlike the classical fibroblast growth factors, FGF21 does not have mitogenic activities but acts as a hormone exerting several autocrine/paracrine effects, such as the control of glucose metabolism, insulin sensitivity, lipid homeostasis, and energy balance in experimental models, and results independently associated with several features of metabolic syndrome in humans (2–4). Circulating FGF21 exerts its activity through the extracellular binding to a canonical FGF receptor (FGFR) and a coreceptor called -Klotho. -Klotho coreceptor is preferentially expressed by cells that produce/release FGF21, such as hepatocytes, adipocytes, and pancreatic cells (5). In addition, mRNA expression analysis by real-time quantitative PCR demonstrated that -Klotho coreceptor was abundantly also in other organs, including gall bladder, colon, and aorta (6). The molecular mechanisms that regulate different cellspecific metabolic effects of FGF21 remain unclear even though several crucial networks have been proposed (7– 9). In fact, on binding to -Klotho coreceptor, FGFRs (particularly FGFR1c) can improve pancreatic cells by activation of downstream ERK1/2 and Akt signaling (7). Moreover, a recent study highlights that although ERK1/2 pathway in adipose tissue may be crucial for the FGF21mediated reduction of fat mass, alternative pathways (ie, peroxisome proliferator-activated receptor) and other secretory factors (ie, adiponectin) seem to be essential to lead obesity-induced impairment in insulin signaling in liver and skeletal muscle (8). Interestingly, recently, Muise et al (9) identified novel FGF21-dependent downstream molecular pathways, such as ubiquitin-protein ligase Mdm2, myosin phosphatase target subunit 1, and Signal transducer, and activator of transcription 3, in adipocytes. The first evidence of FGF21-dependent effects was reported in 2005 when Kharitonenkov et al (2) demonstrated that transgenic mice overexpressing hepatic FGF21 displayed improved insulin sensitivity, glucose clearance, and reduced triglyceride levels and were resistant to high-fat-diet–induced obesity. Moreover, FGF21 plays important roles in other physiological processes, including fasting and feeding, GH axis, and thermogenesis (10). As circulating FGF21 levels increase in human subjects affected by obesity-related diseases, including insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD), the clinical relevance of this factor has substantially increased over the years (11–13). In fact, very recently, a clinical trial demonstrated that the 28-day treatment with LY2405319, a variant of FGF21, may improve dyslipidemia, body weight, and fasting insulin, in human obese adults with type 2 diabetes (14). Furthermore, mice genetically lacking FGF21 presented an increase rather than a reduction of body weight and accumulated triglycerides in the liver in response to ketogenic diets (15). These discrepancies between the pathogenetic role of high levels of FGF21 in obesity-related diseases and