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.
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Disrupting leptin signaling using ob/ob or db/db mice abrogates the beneficial effects of FGF21 in lowering body weight in response to extended FGF21 administration.
“In addition, disrupting leptin signaling using ob/ob or db/db mice abrogates the beneficial effects of FGF21 in lowering body weight in response to extended FGF21 administration (3, 45, 51, 67, 139).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [45]
Another group failed to observe FGF21 resistance in mouse models of obesity and insulin resistance.
“However, the concept of FGF21 resistance is controversial, with another group failing to observe FGF21 resistance in mouse models of obesity and insulin resistance (45).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [45]
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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
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2012-01-01
- Volume
- 153
- Issue
- 1
- Pages
- 69-80
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- 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 › Epidemiology › 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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