Cell
Volume 148, Issue 3, 3 February 2012, Pages 556-567
Journal home page for Cell

Article
Fibroblast Growth Factor-21 Regulates PPARγ Activity and the Antidiabetic Actions of Thiazolidinediones

https://doi.org/10.1016/j.cell.2011.11.062Get rights and content
Under an Elsevier user license
open archive

Summary

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.

Highlights

► FGF21 is induced in adipose tissue by feeding and PPARγ agonists ► FGF21 increases PPARγ activity by preventing its sumoylation ► Loss of FGF21 results in impaired adipocyte function ► FGF21 mediates both beneficial and adverse effects of thiazolidinedione drugs

Cited by (0)