Fibroblast growth factor 21 increases insulin sensitivity through specific expansion of subcutaneous fat
Open accessAbstract
Although the pharmacological effects of fibroblast growth factor 21 (FGF21) are well-documented, uncertainty about its role in regulating excessive energy intake remains. Here, we show that FGF21 improves systemic insulin sensitivity by promoting the healthy expansion of subcutaneous adipose tissue (SAT). Serum FGF21 levels positively correlate with the SAT area in insulin-sensitive obese individuals. FGF21 knockout mice (FGF21KO) show less SAT mass and are more insulin-resistant when fed a high-fat diet. Replenishment of recombinant FGF21 to a level equivalent to that in obesity restores SAT mass and reverses insulin resistance in FGF21KO, but not in adipose-specific βklotho knockout mice. Moreover, transplantation of SAT from wild-type to FGF21KO mice improves insulin sensitivity in the recipients. Mechanistically, circulating FGF21 upregulates adiponectin in SAT, accompanied by an increase of M2 macrophage polarization. We propose that elevated levels of endogenous FGF21 in obesity serve as a defense mechanism to protect against systemic insulin resistance.
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In obesity and type 2 diabetes, FGF21 resistance is common: circulating levels are elevated but receptor signaling is impaired.
“In obesity and type 2 diabetes, FGF21 resistance is common: circulating levels are elevated but receptor signaling is impaired, as documented in human studies [51,52,53].”
From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [53]
The Introduction (page unavailable) says circulating FGF21 is elevated in obesity and diabetes in humans. But it describes FGF21 resistance as a disputed finding from animal studies, not a common condition documented in humans. The Results section on serum FGF21 and subcutaneous fat (page unavailable) reports differences in βklotho expression among human groups, but does not establish impaired receptor signaling in obesity and type 2 diabetes. (LLM, conf=0.86)
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“In obesity and type 2 diabetes, FGF21 resistance is common: circulating levels are elevated but receptor signaling is impaired, as documented in human studies [51–53].”
- Authors
- Li, H., Wu, G., Fang, Q., Zhang, M., Hui, X., Sheng, B., Wu, L., Bao, Y., Li, P., Xu, A., & Jia, W.
- Affiliations
- Shanghai Jiao Tong University (CN)
- University of Hong Kong (HK)
- Center for Life Sciences (CN)
- Corresponding author
- Xu, Aimin
- Jia, Weiping
- ORCID
- Venue
- Nature Communications
- Published
- 2018-01-18
- Volume
- 9
- Issue
- 1
- Pages
- 272-272
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5773530
- OpenAlex
- W2783495236
- Cited by
- 178
- References
- 65
- Citations by year
- 2026: 11 · 2025: 20 · 2024: 18 · 2023: 26 · 2022: 27 · 2021: 21 · 2020: 19 · 2019: 24 · 2018: 11
- FWCI
- 6.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (61572316, 2011CB504001, 973 Project, #81220108006, 81561128016, 81200292, 17PJ1407500, 2017YQ009)
- University of Hong Kong
- Shanghai Jiao Tong University
- Xiamen University
- National Health and Medical Research Council (81561128016)
- Young Scientists Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- FGF21, insulin sensitivity, insulin resistance, subcutaneous adipose tissue, adipose tissue expansion, obesity, high-fat diet, β-Klotho, adiponectin, M2 macrophage polarization, adipose tissue transplantation, energy homeostasis
- MeSH terms
- Animals, Fibroblast Growth Factors, Insulin Resistance, Mice, Inbred C57BL, Obesity, Recombinant Proteins, Mice, Knockout, Subcutaneous Fat, Adiponectin, Diet, High-Fat
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