title: Fibroblast growth factor receptor 4 (FGFR4) deficiency improves insulin resistance and glucose metabolism under diet-induced obesity conditions.
abstract: 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.
authors.affiliation: From Amgen, Inc., South San Francisco, California 94080 and.
authors.forename: Hongfei
authors.initials: H
authors.lastname: Ge
authors.affiliation: From Amgen, Inc., South San Francisco, California 94080 and.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From Amgen, Inc., South San Francisco, California 94080 and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.affiliation: From Amgen, Inc., South San Francisco, California 94080 and.
authors.forename: Jamila
authors.initials: J
authors.lastname: Gupte
authors.affiliation: From Amgen, Inc., South San Francisco, California 94080 and.
authors.forename: Jay
authors.initials: J
authors.lastname: Ye
authors.affiliation: From Amgen, Inc., South San Francisco, California 94080 and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Weiszmann
authors.affiliation: From Amgen, Inc., South San Francisco, California 94080 and.
authors.forename: Kim
authors.initials: K
authors.lastname: Samayoa
authors.affiliation: From Amgen, Inc., South San Francisco, California 94080 and.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Coberly
authors.affiliation: From Amgen, Inc., South San Francisco, California 94080 and.
authors.forename: Jonitha
authors.initials: J
authors.lastname: Gardner
authors.affiliation: Amgen, Inc., Thousand Oaks, California 91320.
authors.forename: Huilan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Amgen, Inc., Thousand Oaks, California 91320.
authors.forename: Tim
authors.initials: T
authors.lastname: Corbin
authors.affiliation: Amgen, Inc., Thousand Oaks, California 91320.
authors.forename: Danny
authors.initials: D
authors.lastname: Chui
authors.affiliation: From Amgen, Inc., South San Francisco, California 94080 and.
authors.forename: Helene
authors.initials: H
authors.lastname: Baribault
authors.affiliation: From Amgen, Inc., South San Francisco, California 94080 and. Electronic address: yangl@amgen.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000097:blood; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000172:deficiency / Q000235:genetics*; D059467:Transcriptome
chemical_list: D052242:Adiponectin; C108526:fibroblast growth factor 15, mouse; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C496372:Fgfr4 protein, mouse; D051499:Receptor, Fibroblast Growth Factor, Type 4; D005947:Glucose
keywords: Bile Acid; Diabetes; FGF15; FGF19; FGF21; FGFR4; Glucose Metabolism; Insulin; Obesity