title: Characterization of a FGF19 variant with altered receptor specificity revealed a central role for FGFR1c in the regulation of glucose metabolism.
abstract: Diabetes and associated metabolic conditions have reached pandemic proportions worldwide, and there is a clear unmet medical need for new therapies that are both effective and safe. FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Both have potent effects on normalizing glucose, lipid, and energy homeostasis, and therefore, represent attractive potential next generation therapies for combating the growing epidemics of type 2 diabetes and obesity. The mechanism responsible for these impressive metabolic effects remains unknown. While both FGF19 and FGF21 can activate FGFRs 1c, 2c, and 3c in the presence of co-receptor βKlotho in vitro, which receptor is responsible for the metabolic activities observed in vivo remains unknown. Here we have generated a variant of FGF19, FGF19-7, that has altered receptor specificity with a strong bias toward FGFR1c. We show that FGF19-7 is equally efficacious as wild type FGF19 in regulating glucose, lipid, and energy metabolism in both diet-induced obesity and leptin-deficient mouse models. These results are the first direct demonstration of the central role of the βKlotho/FGFR1c receptor complex in glucose and lipid regulation, and also strongly suggest that activation of this receptor complex alone might be sufficient to achieve all the metabolic functions of endocrine FGF molecules.
authors.affiliation: Amgen Inc., San Francisco, California, United States of America.
authors.forename: Hongfei
authors.initials: H
authors.lastname: Ge
authors.forename: Helene
authors.initials: H
authors.lastname: Baribault
authors.forename: Steven
authors.initials: S
authors.lastname: Vonderfecht
authors.forename: Bryan
authors.initials: B
authors.lastname: Lemon
authors.forename: Jennifer
authors.initials: J
authors.lastname: Weiszmann
authors.forename: Jonitha
authors.initials: J
authors.lastname: Gardner
authors.forename: Ki Jeong
authors.initials: KJ
authors.lastname: Lee
authors.forename: Jamila
authors.initials: J
authors.lastname: Gupte
authors.forename: Paramita
authors.initials: P
authors.lastname: Mookherjee
authors.forename: Minghan
authors.initials: M
authors.lastname: Wang
authors.forename: Jackie
authors.initials: J
authors.lastname: Sheng
authors.forename: Xinle
authors.initials: X
authors.lastname: Wu
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D011485:Protein Binding; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D005947:Glucose