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

PA Dutchak, T Katafuchi, AL Bookout, JH Choi, TY Ruth… - Cell, 2012 - cell.com
PA Dutchak, T Katafuchi, AL Bookout, JH Choi, TY Ruth, DJ Mangelsdorf, SA Kliewer
Cell, 2012cell.com
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 …
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.
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