Obesity Is a Fibroblast Growth Factor 21 (FGF21)-Resistant State
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OBJECTIVE: Fibroblast growth factor 21 (FGF21) is a key mediator of fatty acid oxidation and lipid metabolism. Pharmacological doses of FGF21 improve glucose tolerance, lower serum free fatty acids, and lead to weight loss in obese mice. Surprisingly, however, FGF21 levels are elevated in obese ob/ob and db/db mice and correlate positively with BMI in humans. However, the expected beneficial effects of endogenous FGF21 to increase glucose tolerance and reduce circulating triglycerides are absent in obesity. RESEARCH DESIGN AND METHODS: To test the hypothesis that obesity is a state of FGF21 resistance, we evaluated the response of obese mice to exogenous FGF21 administration. In doing this, we assessed the impact of diet-induced obesity on FGF21 signaling and resultant transcriptional events in the liver and white adipose tissue. We also analyzed the physiologic impact of FGF21 resistance by assessing serum parameters that are acutely regulated by FGF21. RESULTS: When obese mice are treated with FGF21, they display both a significantly attenuated signaling response as assessed by extracellular mitogen-activated protein kinase 1 and 2 (ERK1/2) phosphorylation as well as an impaired induction of FGF21 target genes, including cFos and EGR1. These effects were seen in both liver and fat. Similarly, changes in serum parameters such as the decline in glucose and free fatty acids are attenuated in FGF21-treated DIO mice. CONCLUSIONS: These data demonstrate that DIO mice have increased endogenous levels of FGF21 and respond poorly to exogenous FGF21. We therefore propose that obesity is an FGF21-resistant state.
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Clinical studies in humans have revealed high FGF21 circulating concentrations in obese and insulin‐resistant subjects, as well as the onset of FGF21 resistance.
“Moreover, despite evidence showing improved metabolic fitness in FGF21 treatment or overexpression studies, clinical studies in humans have revealed high FGF21 circulating concentrations in obese and insulin‐resistant subjects, as well as the onset of a so called “FGF21 resistance” 134.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [134]
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- Authors
- Fisher, F. M., Chui, P. C., Antonellis, P. J., Bina, H. A., Kharitonenkov, A., Flier, J. S., & Maratos-Flier, E.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Eli Lilly (United States) (US)
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts;
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2010-08-03
- Volume
- 59
- Issue
- 11
- Pages
- 2781-2789
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2963536
- OpenAlex
- W2134944069
- Cited by
- 830
- References
- 30
- Citations by year
- 2026: 31 · 2025: 61 · 2024: 62 · 2023: 54 · 2022: 66 · 2021: 59 · 2020: 50 · 2019: 56 · 2018: 58 · 2017: 74 · 2016: 60 · 2015: 51 · 2014: 45 · 2013: 29 · 2012: 47
- FWCI
- 13.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK028082)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- FGF21, FGF21 resistance, obesity, diet-induced obesity, ERK1/2 phosphorylation, c-fos, EGR1, liver, white adipose tissue, glucose tolerance, free fatty acids, lipid metabolism, ob/ob mice, db/db mice
- MeSH terms
- Adipose Tissue, Animals, Drug Resistance, Fibroblast Growth Factors, Humans, Injections, Intravenous, Liver, Mice, Inbred C57BL, Mice, Obese, Obesity, Recombinant Proteins, RNA, Messenger, Signal Transduction, Reverse Transcriptase Polymerase Chain Reaction, Mitogen-Activated Protein Kinase 3, Mice
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