Metabolic actions of fibroblast growth factor 21

FGF21 has emerged as a hormone involved in energy homeostasis. A large number of recent reports have expanded the role of FGF21 from a response factor to prolonged fasting to a key hormone that regulates free fatty acid (FFAs) levels. The therapeutic role of recombinant human FGF21 for type 2 diabetes and dyslipidemia is under study.

Recent evidence suggests that supraphysiological concentrations of FFAs induce FGF21 secretion (i.e., starvation and intense physical activity) through the peroxisome proliferator-activated receptor alpha (PPARα) pathway. The rise in FGF21 levels is aimed at improving energy production (ketogenesis) and utilization (oxidation) of FFAs. FGF21 increment may protect against chronic exposure to high concentrations of FFAs, which causes lipotoxicity in muscle, pancreas, and liver. In addition, FGF21 induces appetite and inhibits growth, probably as part of the adaptive starvation response. The autocrine function of FGF21 in adipose tissue increases PPARγ activity and glucose uptake. Increased plasma FGF21 levels have been found in insulin resistance states in humans. However, the reason for this rise in FGF21 values is still under study.

We propose that FGF21 serves as a defense mechanism against supraphysiological concentrations of FFAs. In addition, FGF21 might have a therapeutic indication in humans.