Fibroblast growth factor receptor 4 (FGFR4) deficiency improves insulin resistance and glucose metabolism under diet-induced obesity conditions

J Biol Chem. 2014 Oct 31;289(44):30470-30480. doi: 10.1074/jbc.M114.592022. Epub 2014 Sep 9.


The role of fibroblast growth factor receptor 4 (FGFR4) in regulating bile acid synthesis has been well defined; however, its reported role on glucose and energy metabolism remains unresolved. Here, we show that FGFR4 deficiency in mice leads to improvement in glucose metabolism, insulin sensitivity, and reduction in body weight under high fat conditions. Mechanism of action studies in FGFR4-deficient mice suggest that the effects are mediated in part by increased plasma levels of adiponectin and the endocrine FGF factors FGF21 and FGF15, the latter of which increase in response to an elevated bile acid pool. Direct actions of increased bile acids on bile acid receptors, and other potential indirect mechanisms, may also contribute to the observed metabolic changes. The results described herein suggest that FGFR4 antagonists alone, or in combination with other agents, could serve as a novel treatment for diabetes.

Keywords: Bile Acid; Diabetes; FGF15; FGF19; FGF21; FGFR4; Glucose Metabolism; Insulin; Obesity.

MeSH terms

  • Adiponectin / blood
  • Adipose Tissue / metabolism
  • Animals
  • Diet, High-Fat / adverse effects*
  • Female
  • Fibroblast Growth Factors / administration & dosage
  • Fibroblast Growth Factors / blood
  • Glucose / metabolism
  • HEK293 Cells
  • Humans
  • Ileum / metabolism
  • Insulin Resistance*
  • Liver / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / etiology
  • Obesity / metabolism*
  • Receptor, Fibroblast Growth Factor, Type 4 / deficiency
  • Receptor, Fibroblast Growth Factor, Type 4 / genetics*
  • Transcriptome


  • Adiponectin
  • fibroblast growth factor 15, mouse
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Fgfr4 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 4
  • Glucose