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

Paul A. Dutchak; Takeshi Katafuchi; Angie L. Bookout; Jang Hyun Choi; Ruth T. Yu; David J. Mangelsdorf; Steven A. Kliewer

doi:10.1016/j.cell.2011.11.062

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

Paul A. Dutchak, Takeshi Katafuchi, Angie L. Bookout, Jang Hyun Choi, Ruth T. Yu, David J. Mangelsdorf, Steven A. Kliewer

Research output: Contribution to journal › Article › peer-review

446 Scopus citations

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.

Original language	English (US)
Pages (from-to)	556-567
Number of pages	12
Journal	Cell
Volume	148
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2011.11.062
State	Published - Feb 3 2012

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2011.11.062

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@article{3f1dc4c3fcb8458fb8dcaf29b390a0f0,

title = "Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones",

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.",

author = "Dutchak, {Paul A.} and Takeshi Katafuchi and Bookout, {Angie L.} and Choi, {Jang Hyun} and Yu, {Ruth T.} and Mangelsdorf, {David J.} and Kliewer, {Steven A.}",

note = "Funding Information: We thank Drs. Regina Goetz and Moosa Mohammadi for recombinant FGF21 protein, Dr. James Richardson for histopathology expertise, and members of the D.J.M./S.A.K. laboratory for discussion. This research was supported by the Howard Hughes Medical Institute (to D.J.M.), NIH Grants RL1GM084436 and R56DK089600 (to D.J.M. and S.A.K.), U19DK62434 (to D.J.M.), and GM007062 (to A.L.B.), the Robert A. Welch Foundation (I-1275 to D.J.M. and I-1558 to S.A.K.), and the Leona M. and Harry B. Helmsley Charitable Trust (to R.T.Y.). ",

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T1 - Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones

AU - Dutchak, Paul A.

AU - Katafuchi, Takeshi

AU - Bookout, Angie L.

AU - Choi, Jang Hyun

AU - Yu, Ruth T.

AU - Mangelsdorf, David J.

AU - Kliewer, Steven A.

N1 - Funding Information: We thank Drs. Regina Goetz and Moosa Mohammadi for recombinant FGF21 protein, Dr. James Richardson for histopathology expertise, and members of the D.J.M./S.A.K. laboratory for discussion. This research was supported by the Howard Hughes Medical Institute (to D.J.M.), NIH Grants RL1GM084436 and R56DK089600 (to D.J.M. and S.A.K.), U19DK62434 (to D.J.M.), and GM007062 (to A.L.B.), the Robert A. Welch Foundation (I-1275 to D.J.M. and I-1558 to S.A.K.), and the Leona M. and Harry B. Helmsley Charitable Trust (to R.T.Y.).

PY - 2012/2/3

Y1 - 2012/2/3

N2 - 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.

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

Abstract

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