Endocrine fibroblast growth factors 15/19 and 21: from feast to famine

Abstract

We review the physiology and pharmacology of two atypical fibroblast growth factors (FGFs)-FGF15/19 and FGF21-that can function as hormones. Both FGF15/19 and FGF21 act on multiple tissues to coordinate carbohydrate and lipid metabolism in response to nutritional status. Whereas FGF15/19 is secreted from the small intestine in response to feeding and has insulin-like actions, FGF21 is secreted from the liver in response to extended fasting and has glucagon-like effects. FGF21 also acts in an autocrine fashion in several tissues, including adipose. The pharmacological actions of FGF15/19 and FGF21 make them attractive drug candidates for treating metabolic disease.

Figure 1.

Endocrine actions of FGF15. FGF15 expression is induced in the small intestine by bile acids acting on the FXR/RXR heterodimer. Secreted FGF15 acts on FGFR/β-Klotho receptor complexes in the liver to repress CYP7A1 and bile acid synthesis through a mechanism that requires SHP, to induce protein synthesis through activation of the ERK1/2–RSK pathway that activates translation factors S6 and eIF4B, to stimulate glycogen synthase (GS) activity and glycogen synthesis through inactivation of glycogen synthase kinase 3 (GSK3), and to repress gluconeogenesis by blocking the phosphorylation and activation of CREB, a transcription factor that induces peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and other gluconeogenic genes. FGF15 also acts on the gallbladder to increase cAMP levels, which promotes filling of the gallbladder with bile.

Figure 2.

Endocrine, autocrine, and pharmacological actions of FGF21. (Left panel) In response to fasting or fibrate drugs, FGF21 expression is induced in the liver by the PPARα/RXR heterodimer. Secreted FGF21 acts as an endocrine hormone to induce ketogenesis, gluconeogenesis, and torpor and to inhibit somatic growth. (Middle panel) In response to feeding or thiazolidinedione drugs (TZDs), FGF21 expression is induced by the PPARγ/RXR heterodimer in WAT, where FGF21 acts through an autocrine mechanism to stimulate PPARγ activity. (Right panel) Pharmacological administration of recombinant FGF21 (rFGF21) affects multiple tissues and has beneficial effects in metabolic disease.

Figure 3.

FGF15/19 and FGF21 function in a temporal cascade of hormones to regulate responses to nutritional stress. The temporal relationship among insulin, FGF15/19, glucagon, and FGF21 is shown along with hormone half-lives and biological actions.