FGF21 Is Not a Major Mediator for Bone Homeostasis or Metabolic Actions of PPARα and PPARγ Agonists

J Bone Miner Res. 2017 Apr;32(4):834-845. doi: 10.1002/jbmr.2936. Epub 2016 Sep 9.


Results of prior studies suggest that fibroblast growth factor 21 (FGF21) may be involved in bone turnover and in the actions of peroxisome proliferator-activated receptor (PPAR) α and γ in mice. We have conducted independent studies to examine the effects of FGF21 on bone homeostasis and the role of FGF21 in PPARα and γ actions. High-fat-diet-induced obesity (DIO) mice were administered vehicle or recombinant human FGF21 (rhFGF21) intraperitoneally at 0 (vehicle), 0.1, 1, and 3 mg/kg daily for 2 weeks. Additional groups of DIO mice received water or 10 mg/kg rosiglitazone daily. Mice treated with rhFGF21 or rosiglitazone showed expected metabolic improvements in glucose, insulin, and lipid levels. However, bone loss was not detected in rhFGF21-treated mice by dual-energy X-ray absorptiometry (DXA), micro-CT, and histomorphometric analyses. Mineral apposition rate, a key bone formation parameter, was unchanged by rhFGF21, while significantly decreased by rosiglitazone in DIO mice. Bone resorption markers, OPG/RANKL mRNA expression, and histological bone resorption indices were unchanged by rhFGF21 or rosiglitazone. Bone marrow fat was unchanged by rhFGF21, while increased by rosiglitazone. Furthermore, FGF21 knockout mice did not show high bone mass phenotype. Treatment with PPARα or PPARγ agonists caused similar metabolic effects in FGF21 knockout and wild-type mice. These results contrast with previous findings and suggest that FGF21 is not critical for bone homeostasis or actions of PPARα and PPARγ. © 2016 American Society for Bone and Mineral Research.

Keywords: BONE MASS; FGF21; PPARα; PPARγ.

MeSH terms

  • Animals
  • Bone Density* / drug effects
  • Bone Density* / genetics
  • Dietary Fats / adverse effects
  • Dietary Fats / pharmacology
  • Fibroblast Growth Factors* / genetics
  • Fibroblast Growth Factors* / metabolism
  • Fibroblast Growth Factors* / pharmacology
  • Gene Expression Regulation / drug effects*
  • Glucose / metabolism
  • Homeostasis* / drug effects
  • Homeostasis* / genetics
  • Humans
  • Insulin / genetics
  • Insulin / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Obesity / chemically induced
  • Obesity / metabolism
  • Osteoprotegerin / biosynthesis
  • Osteoprotegerin / genetics
  • PPAR alpha* / agonists
  • PPAR alpha* / biosynthesis
  • PPAR alpha* / genetics
  • PPAR gamma* / agonists
  • PPAR gamma* / biosynthesis
  • PPAR gamma* / genetics
  • RANK Ligand / biosynthesis
  • RANK Ligand / genetics
  • Rosiglitazone
  • Thiazolidinediones / pharmacology


  • Dietary Fats
  • Insulin
  • Osteoprotegerin
  • PPAR alpha
  • PPAR gamma
  • RANK Ligand
  • Thiazolidinediones
  • Tnfrsf11b protein, mouse
  • Tnfsf11 protein, mouse
  • fibroblast growth factor 21
  • Rosiglitazone
  • Fibroblast Growth Factors
  • Glucose