Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones.
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.
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.
Paul A
PA
Dutchak
Takeshi
T
Katafuchi
Angie L
AL
Bookout
Jang Hyun
JH
Choi
Ruth T
RT
Yu
David J
DJ
Mangelsdorf
Steven A
SA
Kliewer
D017667:Adipocytes / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication; D004351:Drug Resistance; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D050356:Lipid Metabolism; D008060:Lipodystrophy / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D019899:Paracrine Communication; D000077154:Rosiglitazone; D058207:Sumoylation; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use*; D014158:Transcription, Genetic
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; C414620:fibroblast growth factor 21; D000077154:Rosiglitazone; D005346:Fibroblast Growth Factors