Fibroblast growth factor 21 (FGF-21) is a pleiotropic hormone considered as a major regulator of energy homeostasis. FGF-21 is mainly secreted by the liver, but it may also be expressed in skeletal muscle. In this sense, FGF-21 protein expression is induced by insulin in C2C12 myocytes, and FGF21 mRNA is upregulated by hyperinsulinemia in skeletal muscle in young healthy men. Moreover, it has been suggested that FGF-21 is a signal secreted by the skeletal muscle to communicate with adipose tissue under stress conditions. FGF21 has been shown to be a major regulator of hepatic lipid metabolism, with FGF-21 overexpressing mice being resistant to diet-induced obesity. Interestingly, recent studies suggest that FGF21 may exert anti-inflammatory actions in the pancreas, heart, and skeletal muscle. A reduction in the JNK and NF-κB signaling pathways has been proposed as the potential mechanism implicated in the FGF-21 anti-inflammatory effects.