Fibroblast Growth Factor Receptor 4 (FGFR4) Deficiency Improves Insulin Resistance and Glucose Metabolism under Diet-induced Obesity Conditions

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...

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Published in:The Journal of biological chemistry 2014-10, Vol.289 (44), p.30470-30480
Main Authors: Ge, Hongfei, Zhang, Jun, Gong, Yan, Gupte, Jamila, Ye, Jay, Weiszmann, Jennifer, Samayoa, Kim, Coberly, Suzanne, Gardner, Jonitha, Wang, Huilan, Corbin, Tim, Chui, Danny, Baribault, Helene, Li, Yang
Format: Article
Language:English
Subjects:
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
Metabolism
Mice, Inbred C57BL
Mice, Knockout
Obesity - etiology
Obesity - metabolism
Receptor, Fibroblast Growth Factor, Type 4 - deficiency
Receptor, Fibroblast Growth Factor, Type 4 - genetics
Transcriptome
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M114.592022