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

TitleFibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones.
Publication TypeJournal Article
Year of Publication2012
AuteursDutchak, P, Katafuchi, T, Bookout, AL, Choi, JHyun, Yu, RT, Mangelsdorf, DJ, Kliewer, SA
JournalCell
Volume148
Issue3
Pagination556-67
Date Published2012 Feb 03
ISSN1097-4172
KeywordsAdipocytes, Adipose Tissue, White, Animals, Autocrine Communication, Drug Resistance, Fibroblast Growth Factors, Hypoglycemic Agents, Lipid Metabolism, Lipodystrophy, Liver, Mice, Mice, Knockout, Paracrine Communication, PPAR gamma, Rosiglitazone, Sumoylation, Thiazolidinediones, Transcription, Genetic
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.

DOI10.1016/j.cell.2011.11.062
Alternate JournalCell
PubMed ID22304921
PubMed Central IDPMC3273727
Grant ListR56DK089600 / DK / NIDDK NIH HHS / United States
T32 GM007062-38 / GM / NIGMS NIH HHS / United States
R56 DK089600 / DK / NIDDK NIH HHS / United States
U19 DK062434 / DK / NIDDK NIH HHS / United States
T32 GM007062 / GM / NIGMS NIH HHS / United States
U19DK62434 / DK / NIDDK NIH HHS / United States
R01 DK067158 / DK / NIDDK NIH HHS / United States
RL1 GM084436-05 / GM / NIGMS NIH HHS / United States
U19 DK062434-10 / DK / NIDDK NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
RL1GM084436 / GM / NIGMS NIH HHS / United States
RL1 GM084436 / GM / NIGMS NIH HHS / United States
R56 DK089600-01 / DK / NIDDK NIH HHS / United States
GM007062 / GM / NIGMS NIH HHS / United States