Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ

Wei Wei; Paul A. Dutchak; Xunde Wang; Xunshan Ding; Xueqian Wang; Angie L. Bookout; Regina Goetz; Moosa Mohammadi; Robert D. Gerard; Paul C. Dechow; David J. Mangelsdorf; Steven A. Kliewer; Yihong Wan

doi:10.1073/pnas.1200797109

Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ

Wei Wei, Paul A. Dutchak, Xunde Wang, Xunshan Ding, Xueqian Wang, Angie L. Bookout, Regina Goetz, Moosa Mohammadi, Robert D. Gerard, Paul C. Dechow, David J. Mangelsdorf, Steven A. Kliewer, Yihong Wan

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323 Scopus citations

Abstract

The endocrine hormone fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism and a promising drug for type 2 diabetes. Here we identify FGF21 as a potent regulator of skeletal homeostasis. Both genetic and pharmacologic FGF21 gain of function lead to a striking decrease in bone mass. In contrast, FGF21 loss of function leads to a reciprocal high-bone-mass phenotype. Mechanistically, FGF21 inhibits osteoblastogenesis and stimulates adipogenesis from bonemarrowmesenchymal stem cells by potentiating the activity of peroxisome proliferator-activated receptor γ (PPAR-γ). Consequently, FGF21 deletion prevents the deleterious bone loss side effect of the PPAR-γ agonist rosiglitazone. Therefore, FGF21 is a critical rheostat for bone turnover and a key integrator of bone and energy metabolism. These results reveal that skeletal fragility may be an undesirable consequence of chronic FGF21 administration.

Original language	English (US)
Pages (from-to)	3143-3148
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	109
Issue number	8
DOIs	https://doi.org/10.1073/pnas.1200797109
State	Published - Feb 21 2012

Keywords

Adipocyte
Bone metabolism
Nuclear receptor
Osteoblast
Thiazolidinediones

ASJC Scopus subject areas

General

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10.1073/pnas.1200797109

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Wei, W., Dutchak, P. A., Wang, X., Ding, X., Wang, X., Bookout, A. L., Goetz, R., Mohammadi, M., Gerard, R. D., Dechow, P. C., Mangelsdorf, D. J., Kliewer, S. A., & Wan, Y. (2012). Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ. Proceedings of the National Academy of Sciences of the United States of America, 109(8), 3143-3148. https://doi.org/10.1073/pnas.1200797109

Wei, W, Dutchak, PA, Wang, X, Ding, X, Wang, X, Bookout, AL, Goetz, R, Mohammadi, M, Gerard, RD, Dechow, PC, Mangelsdorf, DJ , Kliewer, SA & Wan, Y 2012, 'Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 8, pp. 3143-3148. https://doi.org/10.1073/pnas.1200797109

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abstract = "The endocrine hormone fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism and a promising drug for type 2 diabetes. Here we identify FGF21 as a potent regulator of skeletal homeostasis. Both genetic and pharmacologic FGF21 gain of function lead to a striking decrease in bone mass. In contrast, FGF21 loss of function leads to a reciprocal high-bone-mass phenotype. Mechanistically, FGF21 inhibits osteoblastogenesis and stimulates adipogenesis from bonemarrowmesenchymal stem cells by potentiating the activity of peroxisome proliferator-activated receptor γ (PPAR-γ). Consequently, FGF21 deletion prevents the deleterious bone loss side effect of the PPAR-γ agonist rosiglitazone. Therefore, FGF21 is a critical rheostat for bone turnover and a key integrator of bone and energy metabolism. These results reveal that skeletal fragility may be an undesirable consequence of chronic FGF21 administration.",

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author = "Wei Wei and Dutchak, {Paul A.} and Xunde Wang and Xunshan Ding and Xueqian Wang and Bookout, {Angie L.} and Regina Goetz and Moosa Mohammadi and Gerard, {Robert D.} and Dechow, {Paul C.} and Mangelsdorf, {David J.} and Kliewer, {Steven A.} and Yihong Wan",

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AU - Bookout, Angie L.

AU - Goetz, Regina

AU - Mohammadi, Moosa

AU - Gerard, Robert D.

AU - Dechow, Paul C.

AU - Mangelsdorf, David J.

AU - Kliewer, Steven A.

AU - Wan, Yihong

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AB - The endocrine hormone fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism and a promising drug for type 2 diabetes. Here we identify FGF21 as a potent regulator of skeletal homeostasis. Both genetic and pharmacologic FGF21 gain of function lead to a striking decrease in bone mass. In contrast, FGF21 loss of function leads to a reciprocal high-bone-mass phenotype. Mechanistically, FGF21 inhibits osteoblastogenesis and stimulates adipogenesis from bonemarrowmesenchymal stem cells by potentiating the activity of peroxisome proliferator-activated receptor γ (PPAR-γ). Consequently, FGF21 deletion prevents the deleterious bone loss side effect of the PPAR-γ agonist rosiglitazone. Therefore, FGF21 is a critical rheostat for bone turnover and a key integrator of bone and energy metabolism. These results reveal that skeletal fragility may be an undesirable consequence of chronic FGF21 administration.

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Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ

Abstract

Keywords

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