Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones.
Cell, 2012/2/03;148(3):556-67.
Dutchak PA[1], Katafuchi T, Bookout AL, Choi JH, Yu RT, Mangelsdorf DJ, Kliewer SA
Affiliations
PMID: 22304921DOI: 10.1016/j.cell.2011.11.062
Impact factor: 66.85
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.
MeSH terms
Adipocytes; Adipose Tissue, White; Animals; Autocrine Communication; Drug Resistance; Fibroblast Growth Factors; Hypoglycemic Agents; Lipid Metabolism; Lipodystrophy; Liver; Mice; Mice, Knockout; PPAR gamma; Paracrine Communication; Rosiglitazone; Sumoylation; Thiazolidinediones; Transcription, Genetic
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