Understanding the Molecular Basis for FGF15/19 and FGF21 Actions on Energy Homeostasis

Insulin and glucagon have long been known to play essential roles in controlling energy balance during the fed and fasted states, respectively. Recently, additional metabolic hormones have been discovered within a subfamily of the fibroblast growth factor superfamily. The FGF15/19 subfamily is composed of atypical FGFs lacking the heparin-binding domain, which enables them to act in an endocrine fashion by diffusing away from their tissues of origin. They signal through cell-surface receptors complexed with β-Klotho, a membrane-spanning protein, to mediate signaling cascades that lead to physiological responses. One member, FGF19, causes reduced glucose and insulin levels with enhanced insulin sensitivity when expressed in transgenic mice. Another member, FGF21, has been shown to act as an insulin sensitizer pharmacologically by improving glucose tolerance and reducing insulin. The prevalence of metabolic disorders (e.g. type 2 diabetes) in today’s society has led to the investigation of these two endocrine FGFs for use in a clinical setting. However, the mechanisms underlying these responses have not been characterized. To elucidate the mechanisms utilized by FGF15/19, we used several animal models to show a role for FGF15/19 in regulating hepatic glucose production. Like insulin, FGF15/19 represses gluconeogenesis. Specifically, FGF15/19 inhibits expression of the transcriptional coactivator PGC1α, a key regulator of gluconeogenic gene expression. The repressive effect of FGF15/19 on gluconeogenic gene expression is lost when PGC1α is overexpressed. FGF15/19 causes the dephosphorylation and inactivation of the transcription factor CREB, thereby blunting its ability to bind and induce the PGC1α promoter. The results demonstrated that FGF15/19 works subsequent to insulin as a postprandial regulator of gluconeogenesis through inhibition of the CREB/ PGC1α pathway. To fully understand the effects of FGF21, we began studying the downstream kinase signaling cascades and the protein substrates affected by this hormone. Utilizing stable isotope labeling of amino acids in cell culture (SILAC), an unbiased phosphoproteomic profile was obtained of potential FGF21 targets in rat H4IIE hepatoma cells. One of the most highly regulated targets was FetuinA, which was dephosphorylated by FGF21 treatment. FetuinA is an inhibitor of insulin receptor signaling and the FetuinA knockout mouse exhibits aberrant glucose homeostatsis. Our in vitro data suggested a relationship between FGF21 and FetuinA in regulating insulin sensitivity but further exploration lead to the conclusion that FGF21 was not directly regulating FetuinA in vivo. Taken together, the important role of FGF15/19 and FGF21 in regulating carbohydrate metabolism as well as their pharmacological actions makes them attractive drug candidates for metabolic diseases. However, further study will be required to determine their molecular mechanisms more completely and their long-term efficacy in the clinic.