Cited by 185Fibroblast Growth Factor ResearchAdipokines, Inflammation, and Metabolic DiseasesRegulation of Appetite and Obesity

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Lack of Overt FGF21 Resistance in Two Mouse Models of Obesity and Insulin Resistance

Hale, Clarence, Chen, Michelle M., Stanislaus, Shanaka, Chinookoswong, Narumol, Hager, Todd, Wang, Minghan, Véniant, Murielle M., Xu, Jing·2012·Endocrinology

DOI 10.1210/en.2010-1262

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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.

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Authors: Hale, C., Chen, M. M., Stanislaus, S., Chinookoswong, N., Hager, T., Wang, M., Véniant, M. M., & Xu, J.
Affiliations: Departments of Metabolic Disorders (C.H., M.M.C., S.S., N.C., M.W., M.M.V., J.X.), Thousand Oaks, California 91320
Amgen (United States) (US)
Corresponding author: Xu, Jing
ORCID: Hale, Clarence
Chen, Michelle M.
Véniant, Murielle M.
Xu, Jing
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2012-01-01
Volume: 153
Issue: 1
Pages: 69-80
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2010-1262
OpenAlex: W2158061384
Cited by: 185
References: 30
Citations by year: 2026: 5 · 2025: 7 · 2024: 10 · 2023: 11 · 2022: 16 · 2021: 14 · 2020: 10 · 2019: 14 · 2018: 11 · 2017: 20 · 2016: 14 · 2015: 12 · 2014: 12 · 2013: 8 · 2012: 20
FWCI: 5.19
Type: journal article
Language: en
Open access: closed
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Keywords: FGF21, FGF21 resistance, obesity, insulin resistance, ob/ob mice, diet-induced obesity, β-Klotho, FGFR1c, white adipose tissue, ERK1/2 phosphorylation, glucose-lowering effect, weight loss, metabolic regulation
MeSH terms: Klotho Proteins, Animals, Disease Models, Animal, Fibroblast Growth Factors, Humans, Insulin Resistance, Liver, Male, Membrane Proteins, Mice, Inbred C57BL, Mice, Obese, Obesity, Recombinant Proteins, RNA, Messenger, Gene Expression, MAP Kinase Signaling System, Mice, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 2, Adipose Tissue, White, Diet, High-Fat

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Lack of Overt FGF21 Resistance in Two Mouse Models of Obesity and Insulin Resistance

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