title: Lack of overt FGF21 resistance in two mouse models of obesity and insulin resistance.
abstract: Circulating levels of fibroblast growth factor 21 (FGF21), a metabolic regulator of glucose, lipid, and energy homeostasis, are elevated in obese diabetic subjects, raising questions about potential FGF21 resistance. Here we report tissue expression changes in FGF21 and its receptor components, and we describe the target-organ and whole-body responses to FGF21 in ob/ob and diet-induced obese (DIO) mice. Plasma FGF21 concentrations were elevated 8- and 16-fold in DIO and ob/ob mice, respectively, paralleling a dramatic increase in hepatic FGF21 mRNA expression. Concurrently, expression levels of βKlotho, FGF receptor (FGFR)-1c, and FGFR2c were markedly down-regulated in the white adipose tissues (WAT) of ob/ob and DIO mice. However, dose-response curves of recombinant human FGF21 (rhFGF21) stimulation of ERK phosphorylation in the liver and WAT were not right shifted in disease models, although the magnitude of induction in ERK phosphorylation was partially attenuated in DIO mice. Whole-body metabolic responses were preserved in ob/ob and DIO mice, with disease models being more sensitive and responsive than lean mice to the glucose-lowering and weight-loss effects of rhFGF21. Endogenous FGF21 levels, although elevated in diseased mice, were below the half-maximal effective concentrations of rhFGF21, suggesting a state of relative deficiency. Hepatic and WAT FGF21 mRNA expression levels declined after rhFGF21 treatment in the absence of the increased expression levels of βKlotho and FGFR. We conclude that overt FGF21 resistance was not evident in the disease models, and increased hepatic FGF21 expression as a result of local metabolic changes is likely a major cause of elevated circulating FGF21 levels.
authors: Department of Metabolic Disorders, Amgen Inc., MS 29-1-A, One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors: Clarence
authors: C
authors: Hale
authors: Michelle M
authors: MM
authors: Chen
authors: Shanaka
authors: S
authors: Stanislaus
authors: Narumol
authors: N
authors: Chinookoswong
authors: Todd
authors: T
authors: Hager
authors: Minghan
authors: M
authors: Wang
authors: Murielle M
authors: MM
authors: Véniant
authors: Jing
authors: J
authors: Xu
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D000090265:Klotho Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: C418622:Klb protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D000090265:Klotho Proteins