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

Research output: Contribution to journalArticle

243 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 languageEnglish (US)
Pages (from-to)3143-3148
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number8
DOIs
StatePublished - Feb 21 2012

Keywords

  • Adipocyte
  • Bone metabolism
  • Nuclear receptor
  • Osteoblast
  • Thiazolidinediones

ASJC Scopus subject areas

  • General

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