Understanding the Physiology of FGF21
Open accessAbstract
Fibroblast growth factor 21 (FGF21) is a peptide hormone that is synthesized by several organs and regulates energy homeostasis. Excitement surrounding this relatively recently identified hormone is based on the documented metabolic beneficial effects of FGF21, which include weight loss and improved glycemia. The biology of FGF21 is intrinsically complicated owing to its diverse metabolic functions in multiple target organs and its ability to act as an autocrine, paracrine, and endocrine factor. In the liver, FGF21 plays an important role in the regulation of fatty acid oxidation both in the fasted state and in mice consuming a high-fat, low-carbohydrate ketogenic diet. FGF21 also regulates fatty acid metabolism in mice consuming a diet that promotes hepatic lipotoxicity. In white adipose tissue (WAT), FGF21 regulates aspects of glucose metabolism, and in susceptible WAT depots, it can cause browning. This peptide is highly expressed in the pancreas, where it appears to play an anti-inflammatory role in experimental pancreatitis. It also has an anti-inflammatory role in cardiac muscle. Although typically not expressed in skeletal muscle, FGF21 is induced in situations of muscle stress, particularly mitochondrial myopathies. FGF21 has been proposed as a novel therapeutic for metabolic complications such as diabetes and fatty liver disease. This review aims to interpret and delineate the ever-expanding complexity of FGF21 physiology.
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FGF21 levels increase in patients with obesity, which might represent a state of FGF21 resistance.
“Paradoxically, FGF21 levels increase in patients with obesity [153], which might represent a state of FGF21 resistance [154].”
The metabolic adaptation mediated by FGF21 during fasting in the liver and white adipose tissue is known to increase lipolysis and hepatic ketogenesis.
“The metabolic adaptation mediated by FGF21 during fasting in the liver and WAT is known to increase lipolysis and hepatic ketogenesis.34”
From Fibroblast growth factor 21 controls mitophagy and muscle mass (2019) · cites this paper as [34]
The expression levels and metabolic functions of FGF21 are dynamically impacted by nutritional status.
“The expression levels and metabolic functions of FGF21 are dynamically impacted by nutritional status (37, 102).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [37]
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FGF21 Requires βklotho to Act In Vivo
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FGF21 mediates the lipid metabolism response to amino acid starvation
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Fibroblast growth factor 21 is a sensitive biomarker of mitochondrial disease
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FGF 21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation
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Evolution of the FGF Gene Family
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Fibroblast growth factor 21 is not required for the antidiabetic actions of the thiazoladinediones
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Methionine and choline regulate the metabolic phenotype of a ketogenic diet
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Self-citationFibroblast growth factor 21 (FGF21) and bone: is there a relationship in humans?
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Serum FGF21 levels in adult m.3243A>G carriers
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FGF21 signalling pathway and metabolic traits – genetic association analysis
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FGF-21 enhances islet engraftment in mouse syngeneic islet transplantation model
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FGF21 inhibits apolipoprotein(a) expression in HepG2 cells via the FGFR1-ERK1/2-Elk-1 pathway
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Appetite Regulation and Thermogenesis
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Human Aging and Longevity Are Characterized by High Levels of Mitokines
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FGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans
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Glucagon Regulation of Energy Expenditure
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Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates
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The FGF21 analog pegozafermin in severe hypertriglyceridemia: a randomized phase 2 trial
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Mapping the molecular signatures of diet-induced NASH and its regulation by the hepatokine Tsukushi
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Homeostatic sensing of dietary protein restriction: a case for FGF21
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Fibroblast growth factor-21 controls dietary protein intake in male mice
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Myokines: Metabolic regulation in obesity and type 2 diabetes
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“Fibroblast growth factor 21 (FGF-21) is a pleiotropic hormone secreted mostly by the liver (10) but also by muscle under stress (11).”
BackgroundEffects of Short-Term Fasting and Different Overfeeding Diets on Thyroid Hormones in Healthy Humans
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Adapting to the cold: A role for endogenous fibroblast growth factor 21 in thermoregulation?
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Plomgaard, P., & Weigert, C. (2017) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000379 · Cited by 10 · see citing works
The role of FGF21 in the metabolic adjustments required for exercise capacity
Abe, L., & Dantzer, R. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.123940 · Cited by 5 · see citing works
Advances and Emerging Therapies in the Treatment of Non-alcoholic Steatohepatitis
Brennan, P. N., The University of Edinburgh, C. F. R. M., NHS Tayside, N. H. A. M. S., The University of Dundee, D. O. M. A. C. M., Dillon, J. F., NHS Tayside, N. H. A. M. S., The University of Dundee, D. O. M. A. C. M., McCrimmon, R., NHS Tayside, N. H. A. M. S., & The University of Dundee, D. O. M. A. C. M. (2022) · European Endocrinology · doi:10.17925/ee.2022.18.2.148 · Cited by 3 · see citing works
- Authors
- Fisher, F. M., & Maratos-Flier, E.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Department of Medicine, Harvard Medical School, and Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215;
- Venue
- Annual Review of Physiology
- Publisher
- Annual Reviews
- Published
- 2016-02-10
- Volume
- 78
- Issue
- 1
- Pages
- 223-241
- ISSN
- 0066-4278 (ISSN-L)
- 1545-1585
- OpenAlex
- W2132596222
- Cited by
- 912
- References
- 115
- Citations by year
- 2026: 74 · 2025: 120 · 2024: 119 · 2023: 107 · 2022: 97 · 2021: 99 · 2020: 88 · 2019: 80 · 2018: 64 · 2017: 45 · 2016: 19
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Annual Review of Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK028082)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Oncology › Peptidase Inhibition and Analysis
- Keywords
- FGF21, peptide hormones, energy homeostasis, fatty acid oxidation, hepatic lipotoxicity, white adipose tissue browning, glucose metabolism, pancreatitis, cardiac inflammation, mitochondrial myopathy, skeletal muscle, diabetes mellitus, hepatic steatosis, therapeutic target
- MeSH terms
- Animals, Diabetes Mellitus, Fatty Acids, Fatty Liver, Fibroblast Growth Factors, Homeostasis, Humans, Metabolic Diseases, Lipid Metabolism
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