Fig. 2.

Summary of FGF21 physiology in mice and humans. In mice, consumption of a ketogenic diet leads to a PPAR-α-dependent increase of FGF21 in the liver and an increase in serum FGF21 concentrations. FGF21 expression in the liver is also induced by fatty liver disease, obesity, and PPAR-α ligands in mice. PPAR-α ligands, such as fenobibrate, also increase FGF21 messenger RNA expression in human hepatocytes. FGF21 interacts with the FGF receptor (FGFR) in the presence of β-klotho in the mouse liver and adipose tissue. This interaction leads to a PPAR-γ coactivator protein-1α (PGC-1α)-dependent upregulation of fatty acid oxidation and downregulation of lipid synthesis in the liver. In mouse adipose tissue, the presence of PPAR-γ ligands leads to the production of FGF21, and the short-term effect of FGF21 results in a decreased expression of lipolytic genes and leads to lower concentrations of circulating free fatty acids (FFA). FGF21-induced phosphorylation of extracellular signal-regulated kinase-1 (ERK) leads to the activation of glucose transporter-1 (Glut-1) and glucose uptake in mouse 3T3-L1 adipocytes and primary human adipocytes. In humans, serum concentrations of FGF21 are higher in diabetes, obesity, metabolic syndrome, and NAFLD. This effect may be mediated by increased FGF21 liver expression. [From Domouzoglou and Maratos-Flier (15).]