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Cell. 2012 Feb 3;148(3):556-67. doi: 10.1016/j.cell.2011.11.062.

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

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  • 1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.

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.

Copyright © 2012 Elsevier Inc. All rights reserved.

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PMID:
22304921
[PubMed - indexed for MEDLINE]
PMCID:
PMC3273727
Free PMC Article

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