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Fibroblast growth factor 21: a regulator of metabolic disease and health span

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Xie, Ting, Leung, Po Sing·2017·American Journal of Physiology-Endocrinology and Metabolism

DOI 10.1152/ajpendo.00101.2017PMC PMC5625087

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Abstract

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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Is Trimming the Fat Enough? Fibroblast Growth Factor 21 as An Emerging Treatment for Nonalcoholic Fatty Liver Disease
Dushay, J. R., & Lai, M. (2019) · Hepatology · doi:10.1002/hep.30789 · Cited by 5
“(5,6) In rodent models of obesity and NAFLD, exogenous administration of both native and recombinant FGF21 has been shown to cause significant weight loss, improvement in several metabolic disease markers, and improvement in NAFLD disease severity, including histological improvement.(7) Some nutritional interventions,…”
Background
Effect of Aerobic Exercise Training on Circulating Fibroblast Growth Factor-21 Response to Glucose Challenge in Overweight and Obese Men: A Pilot Study
Matsui, M., Kosaki, K., Myoenzono, K., Yoshikawa, T., Park, J., Kuro‐o, M., & Maeda, S. (2022) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-1902-3872 · Cited by 5
“FGF21 was recently identified as a novel hormone that regulates postprandial blood glucose elevation [30].”
Background
Neuropathological hallmarks in autopsied cases with mitochondrial diseases caused by the mitochondrial 3243A >G mutation
Miyahara, H., Tamai, C., Inoue, M., Sekiguchi, K., Tahara, D., Tahara, N., Takeda, K., Arafuka, S., Moriyoshi, H., Koizumi, R., et al. (2023) · Brain Pathology · doi:10.1111/bpa.13199 · Cited by 5
“However, serum GDF15 levels are also known to be increased in acute respiratory distress syndrome [33], pulmonary hypertension [34], cardiac failure [35], cancer [36], and aging [37], and serum FGF21 levels are increased in obesity, type 2 DM [38, 39], and nonalcoholic fatty liver disease [17].”
BENEFICIAL EFFECTS OF ROSMARINUS OFFICINALIS AND THYMUS NUMIDICUS ON KEY ENZYMES OF CARBOHYDRATE METABOLISM IN ALLOXAN-INDUCED DIABETIC RATS
Benkhedir, A., Boussekine, S., Saker, H., Gasmi, S., & Benali, Y. (2022) · Journal of Microbiology Biotechnology and Food Sciences · doi:10.55251/jmbfs.9507 · Cited by 5
FGF21 activation-mediated Islet Autophagy in Type 2 Diabetes With Pharmacotherapeutic Potential
Leung, P. S. (2019) · Future Medicinal Chemistry · doi:10.4155/fmc-2018-0491 · Cited by 5
The Myokine FGF-21 Responds in a Time-Dependent Manner to Three Different Types of Acute Exercise
Thrones, M., Rawliuk, T., Cordingley, D. M., & Cornish, S. M. (2026) · Muscles · doi:10.3390/muscles5010003 · Cited by 4
“FGF-21 is a potent endocrine myokine and hepatokine that has effects https://doi.org/10.3390/muscles5010003 on glucose and lipid metabolism as well as influences on insulin sensitivity in skeletal muscle [17].”
Influential
Efimosfermin for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis (MASH): Mechanism of Action, Clinical Development and Emerging Therapeutic Potential
Alamgir, M., Sohal, A., & Kowdley, K. V. (2026) · Drug Design Development and Therapy · doi:10.2147/dddt.s560039 · Cited by 5
“7 While resmetirom and semaglutide exert their anti-fibrotic effects primarily through metabolic improvements, FGF-21 analogues offer a dual mechanism, combining metabolic improvements with a direct anti-fibrotic effect via hepatic stellate cells (HSC)/ macrophage pathways.”
Influence of ursodeoxycholic acid therapy on levels of fibroblast growth factor 21, adiponectin and biochemical parameters in intrahepatic cholestasis of pregnancy
Kukla, M., Kierach, R., Skonieczna, M., Hudy, D., Dąbrowski, K., Menżyk, T., Derra, A., Boroń, D., & Grabarek, B. O. (2021) · Clinical and Experimental Hepatology · doi:10.5114/ceh.2021.104419 · Cited by 5
“It is mainly produced in the liver and in smaller amounts by several metabolically active tissue organs, such as adipose tissue, skeletal muscle, and pancreas [9, 10].”
Background
Inflammatory related plasma proteins involved in acute preschool wheeze
Holmdahl, I., Chakraborty, S., Hoyer, A., Filiou, A., Asarnoj, A., Sjölander, A., Borres, M. P., van Hage, M., Hedlin, G., Konradsen, J. R., et al. (2023) · Clinical and Translational Allergy · doi:10.1002/clt2.12308 · Cited by 3
“36 FGF21 has been shown to correlate with the frequency of circulating mast cells in asthmatic patients 37,38 and is involved in energy homoeostasis.”
BackgroundResult
Non-fermented and fermented milk intake in relation to risk of ischemic heart disease and to circulating cardiometabolic proteins in swedish women and men: Two prospective longitudinal cohort studies with 100,775 participants
Michaëlsson, K., Lemming, E. W., Larsson, S. C., Höijer, J., Melhus, H., Svennblad, B., Baron, J. A., Wolk, A., & Byberg, L. (2024) · BMC Medicine · doi:10.1186/s12916-024-03651-1 · Cited by 4
“Genetically determined lower circulating concentrations of FGF21 in humans seem to lead to higher plasma cholesterol and apolipoprotein B, higher CRP, higher liver enzyme concentrations, and impaired insulin sensitivity [54, 55, 62].”
Background
Saponins from Panax japonicus Enhance Lipolysis via Acting on FGF21-β-Klotho/FGFR1 in Obese Mice
Wang, T., Huang, Y., Hu, M., Huang, X., Yu, D., Jia, L., Zhi, W., Mu, Y., Zhou, Z., & Wang, J. (2025) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5c01012 · Cited by 4
Circulating fibroblast growth factor 21 links hemodynamics with kidney function in middle-aged and older adults: A mediation analysis
Matsui, M., Kosaki, K., Kuro‐o, M., Saito, C., Yamagata, K., & Maeda, S. (2021) · Hypertension Research · doi:10.1038/s41440-021-00782-3 · Cited by 4
Dual Role of Fibroblast Growth Factor Pathways in Sleep Regulation
Forouzanfar, F., & Negah, S. S. (2022) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/1871530322666220802161031 · Cited by 4
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Long‐Acting FGF21 Analog Zalfermin
Dahl, K., Friedrichsen, M. H., Ribel‐Madsen, R., Hansen, J. S., Clausen, J. O., Axelsen, M. B., Palle, M. S., Lippert, S. L., Björkdahl, O., Toubro, S., et al. (2025) · Clinical and Translational Science · doi:10.1111/cts.70435 · Cited by 3
Circadian Regulation of Endocrine Fibroblast Growth Factors on Systemic Energy Metabolism
Yang, Z., Zarbl, H., & Guo, G. L. (2024) · Molecular Pharmacology · doi:10.1124/molpharm.123.000831 · Cited by 3
Fibroblast growth factor 21 associating with serotonin and dopamine in the cerebrospinal fluid predicts impulsivity in healthy subjects
Xu, J., Wu, F., Li, Y., Wang, F., Lin, W., Song, Q., Li, H., Fan, Y., Li, H., Chen, L., et al. (2021) · BMC Neuroscience · doi:10.1186/s12868-021-00676-7 · Cited by 4
“FGF21 is considered an important pharmacological regulator and has the potential to serve as a biomarker for many diseases [21].”
Background
Evaluation of prevention and treatment effects of fibroblast growth factor-21 in BLM-induced pulmonary fibrosis
Wang, X., Li, S., Liu, J., Sun, W., Zhao, H. Q., Han, Q., Liu, Y., Cao, X., Li, Q., Jin, Y., et al. (2023) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-023-02540-3 · Cited by 3
“Previous studies have indicated that fibroblast growth factor-21 (FGF-21) is a cytokine mainly secreted by the liver and plays a variety of biological functions such as regulating lipid and sugar metabolism, anti-oxidative, and anti-inflammatory effects (Xie and Leung 2017).”
Background
Batokine in Central Nervous System Diseases
Shen, M., Zhang, M., Mao, N., & Lin, Z. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03490-w · Cited by 3
“Compared with other FGFs, FGF21 exerts almost no mitogenic effects [19].”
Background
Changes in metabolic hormones and trace elements in CSF in active smokers indicate oxidative damage to brain cells
Zheng, P., Wang, F., Li, H., Chen, H., Li, M.-T., Ma, H., He, J., Chen, L., Liu, Y., & Xu, H. (2024) · Endocrine Connections · doi:10.1530/ec-24-0016 · Cited by 3
“It targets these tissues and improves glucose and/ or lipid homeostasis (65, 66).”
Background
Белок клото и сердечно-сосудистая система
Тюренков, И. Н., Perfilova, V. N., Нестерова, А. А., & Глинка, Е. Ю. (2021) · Biochemistry (Moscow) · doi:10.31857/s0320972521020020 · Cited by 3
Propofol Improved Glucose Tolerance Associated with Increased FGF-21 and GLP-1 Production in Male Sprague-Dawley Rats
Wu, C.-C., Hung, C.-J., Wang, Y., Lin, S., Chen, W., Kuan, Y., Liao, S., Yang, C., & Chen, C. (2020) · Molecules · doi:10.3390/molecules25143229 · Cited by 2
Next-Generation Therapies for Type 2 Diabetes Mellitus
Patra, D., Roy, S., Ramprasad, P., & Pal, D. (2024) · Smart nanomaterials technology · doi:10.1007/978-981-99-6597-7_13 · Cited by 2
Evaluating Fibroblast Growth Factor 21 (FGF21) Levels Post-Gastric Sleeve Surgery in Obese Patients
Al-Regaiey, K., Iqbal, M., Alzaid, M., Alkaoud, O. A., Alhadyani, M. A., Alagel, O. A., Alshehri, S. S., Altamimi, I., & Alsofayan, S. M. (2024) · Cureus · doi:10.7759/cureus.66122 · Cited by 3
“Administration of FGF21 has been shown to reduce body weight, lower blood glucose and TG levels, enhance insulin sensitivity, maintain β -cell function, decrease LDL, and increase HDL [21].”
Background
Does an Increase in Serum FGF21 Level Predict 28-day Mortality of Critical Patients with Sepsis and ARDS?Preprint
Li, X., Shen, H., Zhou, T., Cao, X., Chen, Y., Liang, Y., Lu, T., He, J., Dou, Z., Liu, C., et al. (2021) · Research Square · doi:10.21203/rs.3.rs-349444/v1 · Cited by 2
Sepsis and Fibroblast Growth Factor 21: A New Acute Phase Reactant?
Deveci, S., Koca, A. O., Ertuğrul, D. T., Akkan, T., & Beyan, E. (2021) · Türk yoğun bakım derneği dergisi/Türk yoğun bakım dergisi · doi:10.4274/tybd.galenos.2021.13008 · Cited by 1
“There are many findings in the literature showing that FGF 21 is increased in chronic metabolic conditions such as polycystic ovarian syndrome (PCOS), nonalcoholic steatohepatitis (NASH), diabetes mellitus (DM), and chronic kidney failure (CKD) (16-20).”
Background
Adipokines Play Important Role in Cell Proliferation and Anti-proliferation
Maurya, S. K., Bhattacharya, N., Bhattacharya, A., & Senapati, S. (2021) · Springer eBooks · doi:10.1007/978-981-16-1846-8_4 · Cited by 1
Robust human genetic evidence supporting causal effects of FGF21 on reducing alcohol consuming behaviours
Cronjé, H. T., Hu, S., Gurrell, R., Vujković, M., Larsson, S. C., Mason, R., Butt, R. P., & Gill, D. (2026) · BMC Medicine · doi:10.1186/s12916-026-04807-x · Cited by 3
“Fibroblast growth factor 21 (FGF21) is a circulating hormone that is primarily produced in the liver and has been implicated in glucose and lipid metabolism [1].”
Crosstalk in the kidney-muscle axis: myokines and muscle-relevant mediators in chronic kidney disease-associated sarcopenia
Hu, R., Zhang, X., Hu, L., Li, X., Hu, Q., & Jin, H. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1868285 · Cited by 1
Fibroblast Growth Factor 21: Possible Role in Growth and Metabolic Development during Early Life, Nutritional Interactions and Biological Actions
Wali, J. A., Ramos-Nieves, J. M., Binia, A., & van der Beek, E. M. (2026) · Advances in Nutrition · doi:10.1016/j.advnut.2026.100713 · Cited by 1
“…FGF21-FGFR1c-β -Klotho complex causes phosphorylation of FGFR substrate 2 α (FRS2 α ) and activation of downstream signaling pathways including the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase and the phosphoinositide 3-kinase/protein kinase B pathways [2,20, 73].”
Adipose FGF21 signalling mediates the anti‐senescence effects of protein restriction
Yang, X., Wu, Y., Yang, Y., Huang, L., Jin, X., Jiang, X., Jin, C., Feng, B., Che, L., Xu, S., et al. (2026) · The Journal of Physiology · doi:10.1113/jp291341 · Cited by 1
“Through binding to fibroblast growth factor receptor 1c (FGFR1c) and its obligate co-receptor β -Klotho (KLB) (Kharitonenkov et al., 2008; Ogawa et al., 2007), FGF21 exerts pleiotropic metabolic effects on peripheral tissues, including WAT (Xie & Leung, 2017).”
α‐Lipoic acid up‐regulates gene expression but reduces protein levels of fibroblast growth factor 21 in HepG2 cells
Zhang, X., Zhao, Y., Liang, X., Zhang, L., Li, K., Sun, Z., & Zhao, Y. (2022) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.13775 · Cited by 1
Exploring the role of mitochondrial dysfunction and aging in COVID-19-Related neurological complications
Hingole, P., Saha, P., Das, S., Gundu, C., & Kumar, A. (2025) · Molecular Biology Reports · doi:10.1007/s11033-025-10586-0 · Cited by 2
“FGF-21, responsive to mitochondrial stress, regulates energy homeostasis and metabolism [62], with elevated levels noted in COVID-19 patients, indicative of mitochondrial dysfunction.”
From Liver to Muscle: Crosstalk Mechanisms and Interventions in Sarcopenia
Wang, Q., Meng, Y., Wang, X., Lan, X., Fan, G., & Xiang, Y. (2025) · Health and Metabolism · doi:10.53941/hm.2025.100022 · Cited by 1
Reduced fibroblast growth factor 21 and β-Klotho secretion in untreated congenital isolated GH deficiency
Oliveira‐Santos, A. A., Salvatori, R., Bueno, A. C., Nogueira, M. C., Campos, V. C., Melo, M. A., Oliveira, C. R. P., Barros-Oliveira, C. S., Marinho, C. G., Damascena, N. P., et al. (2021) · Endocrine · doi:10.1007/s12020-021-02700-6 · Cited by 1
The use of melatonin to mitigate the adverse metabolic side effects of antipsychotics
Romo‐Nava, F., Buijs, R. M., & McElroy, S. L. (2021) · Handbook of clinical neurology · doi:10.1016/b978-0-12-819975-6.00024-8 · Cited by 1
Comment on: “Fibroblast growth factor 21 controls mitophagy and muscle mass” by Oost et al.
Wu, Y., Zhu, B., Chen, Z., Duan, J., & Yang, L. (2019) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12465 · Cited by 1
“FGF21, a member of the FGF family, consists of 209 amino acids and is physiologically decomposed into 181 amino acids for maturity, which is mainly secreted by and acts on target tissues such as liver, fat, pancreas, and muscle.(2) Importantly, there are still great divergences in the physiologic role and mechanism of…”
Background
Robust human genetic evidence supporting causal effects of FGF21 on reducing alcohol consuming behavioursPreprint
Cronjé, H. T., Hu, S., Gurrell, R., Vujković, M., Larsson, S. C., Mason, R., Butt, R., & Gill, D. (2025) · medRxiv · doi:10.1101/2025.11.15.25340305 · Cited by 1

Authors: Xie, T., & Leung, P. S.
Affiliations: Chinese University of Hong Kong (HK)
Corresponding author: Leung, Po Sing
ORCID: Xie, Ting
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
DOI: 10.1152/ajpendo.00101.2017
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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Fibroblast growth factor 21: a regulator of metabolic disease and health span

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