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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Adipose Tissue, White / metabolism
  • Animals
  • Autocrine Communication
  • Drug Resistance
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Lipid Metabolism
  • Lipodystrophy / genetics
  • Lipodystrophy / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • PPAR gamma / agonists
  • PPAR gamma / metabolism*
  • Paracrine Communication
  • Rosiglitazone
  • Sumoylation
  • Thiazolidinediones / adverse effects
  • Thiazolidinediones / therapeutic use*
  • Transcription, Genetic

Substances

  • Hypoglycemic Agents
  • PPAR gamma
  • Thiazolidinediones
  • fibroblast growth factor 21
  • Rosiglitazone
  • Fibroblast Growth Factors