Fibroblast growth factor-21 regulates PPAR? activity and the antidiabetic actions of thiazolidinediones.

ABSTRACT: Fibroblast growth factor-21 (FGF21) is a circulating hepatokine that beneficially affects carbohydrate and lipid metabolism. Here, we report that FGF21 is also an inducible, fed-state autocrine factor in adipose tissue that functions in a feed-forward loop to regulate the activity of peroxisome proliferator-activated receptor ? (PPAR?), a master transcriptional regulator of adipogenesis. FGF21 knockout (KO) mice display defects in PPAR? signaling including decreased body fat and attenuation of PPAR?-dependent gene expression. Moreover, FGF21-KO mice are refractory to both the beneficial insulin-sensitizing effects and the detrimental weight gain and edema side effects of the PPAR? agonist rosiglitazone. This loss of function in FGF21-KO mice is coincident with a marked increase in the sumoylation of PPAR?, which reduces its transcriptional activity. Adding back FGF21 prevents sumoylation and restores PPAR? activity. Collectively, these results reveal FGF21 as a key mediator of the physiologic and pharmacologic actions of PPAR?.

SUBMITTER: Dutchak PA 

PROVIDER: S-EPMC3273727 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature