Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones

Paul A. Dutchak, Takeshi Katafuchi, Angie L. Bookout, Jang Hyun Choi, Ruth T. Yu, David J. Mangelsdorf, Steven A. Kliewer

Research output: Contribution to journalArticle

343 Scopus citations

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 γ (PPARγ), a master transcriptional regulator of adipogenesis. FGF21 knockout (KO) mice display defects in PPARγ signaling including decreased body fat and attenuation of PPARγ-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 PPARγ agonist rosiglitazone. This loss of function in FGF21-KO mice is coincident with a marked increase in the sumoylation of PPARγ, which reduces its transcriptional activity. Adding back FGF21 prevents sumoylation and restores PPARγ activity. Collectively, these results reveal FGF21 as a key mediator of the physiologic and pharmacologic actions of PPARγ.

Original languageEnglish (US)
Pages (from-to)556-567
Number of pages12
JournalCell
Volume148
Issue number3
DOIs
StatePublished - Feb 3 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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