Title | Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Auteurs | Dutchak, P, Katafuchi, T, Bookout, AL, Choi, JHyun, Yu, RT, Mangelsdorf, DJ, Kliewer, SA |
Journal | Cell |
Volume | 148 |
Issue | 3 |
Pagination | 556-67 |
Date Published | 2012 Feb 03 |
ISSN | 1097-4172 |
Keywords | Adipocytes, 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. |
DOI | 10.1016/j.cell.2011.11.062 |
Alternate Journal | Cell |
PubMed ID | 22304921 |
PubMed Central ID | PMC3273727 |
Grant List | R56DK089600 / 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 |