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Fibroblast growth factor 21: a regulator of metabolic disease and health span
Open accessAbstract
Fibroblast growth factor 21 (FGF21) is a potent endocrine regulator with physiological effects on glucose and lipid metabolism and thus garners much attention for its translational potential for the management of obesity and related metabolic syndromes. FGF21 is mainly expressed in several metabolically active tissue organs, such as the liver, adipose tissue, skeletal muscle, and pancreas, with profound effects and therapeutic relevance. Emerging experimental and clinical data point to the demonstrated metabolic benefits of FGF21, which include, but are not limited to, weight loss, glucose and lipid metabolism, and insulin sensitivity. In addition, FGF21 also acts directly through its coreceptor β-klotho in the brain to alter light-dark cycle activity. In this review, we critically appraise current advances in understanding the physiological actions of FGF21 and its role as a biomarker of various metabolic diseases, especially type 2 diabetes mellitus. We also discuss the potentially exciting role of FGF21 in improving our health and prolonging our life span. This information will provide a fuller understanding for further research into FGF21, as well as providing a scientific basis for potentially establishing health care guidelines for this promising molecule.
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“Several findings demonstrate that the overexpression of FGF21 improves healthspan”
From Human Aging and Longevity Are Characterized by High Levels of Mitokines (2019) · cites this paper as [17]
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Tolou–Ghamari, Z., & Palizban, A. (2022) · Clinical Cancer Investigation Journal · doi:10.51847/cagjahyb9e
“23-25] Fibroblast growth factor 21 (FGF21) is a potent endocrine regulator with physiological effects on glucose and lipid metabolism.”
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Endocrine fibroblast growth factors in domestic animals
Brinker, E. J., Hardcastle, M., Dittmer, K. E., & Graff, E. C. (2024) · Domestic Animal Endocrinology · doi:10.1016/j.domaniend.2024.106872
Factors of the aging process and longevity—selected data
Sosiński, D., Tokarz–Deptuła, B., & Deptuła, W. (2024) · Postępy Higieny i Medycyny Doświadczalnej · doi:10.2478/ahem-2024-0015
Fibroblast growth factor 21 responds to taurocholic acid sodium-induced acute pancreatic injury
Zhang, L., Lin, Y., Ma, X., Xu, F., & Li, P. (2025) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2025.110761
Oto, Y., Inoue, T., Otani, R., Matsushima, N., Kitajima, T., Shiihashi, A., Nitta, A., Koyama, S., Takatani, T., & Sakuta, R. (2025) · Cureus · doi:10.7759/cureus.91166
“A potential mechanism for GH resistance may involve elevated levels of fibroblast growth factor 21, which inhibits the intracellular effects of GH, including the production of IGF-1 by the liver [15].”
Wen, J., Hu, J., & Zou, G. (2025) · Annals of Medicine · doi:10.1080/07853890.2025.2575107
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Navigating molecular targets: Plant nutraceuticals in the battle against obesity
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“…primarily secreted by the liver, which can improve glucose and lipid metabolism, reduce inflammation and oxidative stress, increase insulin sensitivity, and exert autocrine, paracrine, and endocrine effects on multiple organs (Mahlapuu and Marschall 2016; Xie and Leung 2017; Hua et al. 2021).”
Mutengo, K. H., Masenga, S. K., & Kirabo, A. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48040371
“More recently, stress-responsive biomarkers such as growth differentiation factor-15 and fibroblast growth factor-21 have gained interest as indicators of mitochondrial stress and metabolic dysregulation [52,53].”
Proteomic Profile After Intervention With Eplerenone Among Persons With HIV
Murthy, A., Kolossváry, M., Walpert, A. R., Sánchez, E., Abohashem, S., Tawakol, A., Adler, G. K., Grinspoon, S. K., & Srinivasa, S. (2026) · Open Forum Infectious Diseases · doi:10.1093/ofid/ofag207
“…potentially limiting microbial translocation, immune dysregulation, and vascular inflammation in PWH. FGF-21 is an endocrine hormone produced primarily by the liver, adipose tissue, and skeletal muscle in response to metabolic stressors such as fasting, obesity, and inflammation [37, 38].”
InfluentialCéspedes, P., Buigues, C., Torregrosa, M. D., Martínez‐Arnau, F. M., Cauli, O., & Trapero, I. (2026) · Pathophysiology · doi:10.3390/pathophysiology33020031
“Fibroblast growth factor 21 (FGF21) is a polypeptide produced mainly in the liver [15] which has been identified as an endocrine and metabolic hormone due to its powerful effect on lipid and glucose metabolism, as well as on insulin sensitivity and energy balance [16].”
Hepatokines and stellakines in liver and neurological diseases: The liver-brain axis
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Liver-derived FGF21 contributes to protection against Alzheimer’s disease pathogenesis
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“FGF21 signaling, mediated by FGFR1-β -Klotho complex, engages these signaling pathways to promote mitochondrial homeostasis and neuronal survival, improve BBB integrity, and reduce inflam-mation, in addition to its effects on circadian regulation [23, 24, 42, 43].”
Metadata
- Authors
- Xie, T., & Leung, P. S.
- Affiliations
- Chinese University of Hong Kong (HK)
- Corresponding author
- Leung, Po Sing
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2017-09-01
- Volume
- 313
- Issue
- 3
- Pages
- E292-E302
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC5625087
- OpenAlex
- W2620038295
- Cited by
- 121
- References
- 110
- Citations by year
- 2026: 15 · 2025: 13 · 2024: 13 · 2023: 12 · 2022: 13 · 2021: 17 · 2020: 14 · 2019: 13 · 2018: 11
- FWCI
- 0.97
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Research Grants Council of Hong Kong (14107415)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › GDF15 and Related Biomarkers
- Keywords
- FGF21, metabolic disorders, healthspan, obesity, type 2 diabetes, glucose metabolism, lipid metabolism, insulin sensitivity, β-Klotho, circadian rhythm, biomarkers, weight loss, adipose tissue, liver
- MeSH terms
- Klotho Proteins, Adipose Tissue, Circadian Rhythm, Diabetes Mellitus, Type 2, Fibroblast Growth Factors, Humans, Insulin Resistance, Liver, Longevity, Membrane Proteins, Obesity, Pancreas, Biomarkers, Muscle, Skeletal
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