FGF21

Fibroblast growth factor 21 is a protein that in mammals is encoded by the FGF21 gene. The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family and specifically a member of the endocrine subfamily which includes FGF23 and FGF15/19. FGF21 is the primary endogenous agonist of the FGF21 receptor, which is composed of the co-receptors FGF receptor 1 and β-Klotho. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. FGFs act through a family of four FGF receptors. Binding is complicated and requires both interaction of the FGF molecule with an FGF receptor and binding to heparin through an heparin binding domain. Endocrine FGFs lack a heparin binding domain and thus can be released into the circulation. FGF21 is a hepatokine – i.e., a hormone secreted by the liver – that regulates simple sugar intake and preferences for sweet foods via signaling through FGF21 receptors in the paraventricular nucleus of the hypothalamus and correlates with reduced dopamine neurotransmission within the nucleus accumbens. A single-nucleotide polymorphism of the FGF21 gene – the FGF21 rs838133 variant – has been identified as a genetic mechanism responsible for the sweet tooth behavioral phenotype, a trait associated with cravings for sweets and high sugar consumption, in both humans and mice. FGF21 is specifically induced by mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) activity. The oxidized form of ketone bodies (acetoacetate) in a cultured medium also induced FGF21, possibly via a sirtuin 1 (SIRT1)-dependent mechanism. HMGCS2 activity has also been shown to be increased by deacetylation of lysines 310, 447, and 473 via SIRT3 in the mitochondria. While FGF21 is expressed in numerous tissues, including liver, brown adipose tissue, white adipose tissue (WAT) and pancreas, circulating levels of FGF21 are derived specifically from the liver in mice. In liver FGF21 expression is regulated by PPARα and levels rise substantially with both fasting and consumption of ketogenic diets. Liver X receptor (LXR) represses FGF21 in humans via an LXR response element located from -37 to -22 bp on the human FGF21 promoter. FGF21 stimulates glucose uptake in adipocytes but not in other cell types. This effect is additive to the activity of insulin. FGF21 treatment of adipocytes is associated with phosphorylation of FRS2, a protein linking FGF receptors to the Ras/MAP kinase pathway. FGF21 injection in ob/ob mice results in an increase in Glut1 in adipose tissue. FGF21 also protects animals from diet-induced obesity when overexpressed in transgenic mice and lowers blood glucose and triglyceride levels when administered to diabetic rodents. Treatment of animals with FGF21 results in increased energy expenditure, fat utilization and lipid excretion.