Circulating FGF21 Is Liver Derived and Enhances Glucose Uptake During Refeeding and Overfeeding
Open accessAbstract
Fibroblast growth factor (FGF)21 is an endocrine hormone that is expressed in multiple tissues and functions physiologically to maintain energy homeostasis. FGF21 is being pursued as a therapeutic target for diabetes and obesity because of its rapid and potent effects on improving insulin sensitivity. However, whether FGF21 enhances insulin sensitivity under physiologic conditions remains unclear. Here, we show that liver-derived FGF21 enters the circulation during fasting but also remains present and functional during the early stage of refeeding. After a prolonged fast, FGF21 acts as an insulin sensitizer to overcome the peripheral insulin resistance induced by fasting, thereby maximizing glucose uptake. Likewise, FGF21 is produced from the liver during overfeeding and mitigates peripheral insulin resistance. DIO FGF21 liver-specific knockout, but not FGF21 adipose-specific knockout, mice have increased insulin resistance and decreased brown adipose tissue–mediated glucose disposal. These data are compatible with the concept that FGF21 functions physiologically as an insulin sensitizer under conditions of acute refeeding and overfeeding.
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In healthy skeletal muscle, FGF21 expression is almost undetectable.
“In skeletal muscle, FGF21 expression, in healthy conditions, is almost undetectable, and therefore, the circulating FGF21 is predominantly produced and released by the liver.6, 12”
From Fibroblast growth factor 21 controls mitophagy and muscle mass (2019) · cites this paper as [12]
Circulating FGF21 is predominantly produced and released by the liver.
“In skeletal muscle, FGF21 expression, in healthy conditions, is almost undetectable, and therefore, the circulating FGF21 is predominantly produced and released by the liver.6, 12”
From Fibroblast growth factor 21 controls mitophagy and muscle mass (2019) · cites this paper as [12]
Circulating FGF21 levels are derived primarily, if not exclusively, from the liver under physiological conditions in both rodents and humans.
“circulating levels of FGF21 are now known to be derived primarily, if not exclusively, from the liver under physiological conditions in both rodents6 and humans7.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [6]
FGF21 treatment of isolated primary brown adipocytes, but not white adipocytes, enhances insulin-stimulated glucose uptake.
“FGF21 treatment of isolated primary brown adipocytes, but not white adipocytes, enhances insulin-stimulated glucose uptake6.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [6]
Lack of FGF21 exacerbates liver and metabolic dysfunction in response to high-fat diet.
“while a lack of FGF21 exacerbates liver and metabolic dysfunction in response to high-fat diet [166]”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [166]
Under most physiological conditions, circulating levels of FGF21 are derived primarily from the liver.
“Notably, despite the expression of Fgf21 mRNA in these tissues, under most physiological conditions, circulating levels of FGF21 are derived primarily from the liver (46, 86).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [86]
FGF21 functions as a metabolic switch to facilitate the transition to the refed state by enhancing insulin-stimulated glucose uptake while acutely maintaining the actions of the fasting response.
“However, when nutrients become available following a prolonged fast, FGF21 functions as a metabolic switch to facilitate the transition to the refed state by enhancing insulin-stimulated glucose uptake while acutely maintaining the actions of the fasting response (86).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [86]
Circulating FGF21 during fasting are derived from the liver, as liver-specific loss of Fgf21 ablates plasma FGF21 during fasting.
“These circulating levels of FGF21 are derived from the liver, as the genetic loss of Fgf21 specifically from the liver ablates plasma FGF21 levels during fasting (86).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [86]
During high-fat diet feeding, skeletal muscle does not contribute to circulating FGF21; circulating FGF21 is derived exclusively from the liver under these conditions.
“For example, while chronic feeding of a high-fat diet clearly represents a state of cellular and mitochondrial stress for skeletal muscle, skeletal muscle does not contribute to circulating levels of FGF21 during feeding of a high-fat diet; instead, circulating levels of FGF21 are derived exclusively from the liver under these conditions (86).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [86]
FGF21 stimulates glucose uptake in BAT in vivo.
“Multiple studies have demonstrated that FGF21 stimulates glucose uptake in BAT in vivo (11, 27, 86, 115).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [86]
FGF21 enhances insulin sensitivity in primary brown adipocytes but not in primary white adipocytes.
“In addition, FGF21 enhances insulin sensitivity in primary brown adipocytes (86) but not in primary white adipocytes (64, 86).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [86]
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“In addition, PPARa is known to mediate acute fasting-induced upregulation of both hepatic Fgf21 mRNA and circulating FGF21 protein levels (Montagner et al., 2016).”
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FGF21 and Cardiac Physiopathology
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Regulation of longevity by FGF21: interaction between energy metabolism and stress responses
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FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit
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- Authors
- Markan, K. R., Naber, M. C., Ameka, M. K., Anderegg, M. D., Mangelsdorf, D. J., Kliewer, S. A., Mohammadi, M., & Potthoff, M. J.
- Affiliations
- University of Iowa (US)
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- New York University (US)
- Corresponding author
- Potthoff, Matthew J.
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2014-11-13
- Volume
- 63
- Issue
- 12
- Pages
- 4057-4063
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC4238010
- OpenAlex
- W2133706171
- Cited by
- 590
- References
- 23
- Citations by year
- 2026: 26 · 2025: 42 · 2024: 41 · 2023: 60 · 2022: 56 · 2021: 64 · 2020: 62 · 2019: 60 · 2018: 44 · 2017: 53 · 2016: 51 · 2015: 28 · 2014: 3
- FWCI
- 18.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5p60dk020593-31)
- National Institute of Diabetes and Digestive and Kidney Diseases (P60-DK020593, DK 20593, R01DK067158, P30DK020593)
- National Institute of Dental and Craniofacial Research (R01DE013686)
- 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 › Metabolism, Diabetes, and Cancer
- Keywords
- FGF21, insulin sensitivity, insulin resistance, refeeding, overfeeding, fasting, glucose uptake, brown adipose tissue, energy homeostasis, obesity, liver-specific knockout
- MeSH terms
- Adipose Tissue, Animals, Blood Glucose, Adipose Tissue, Brown, Fasting, Fibroblast Growth Factors, Glucose, Insulin, Insulin Resistance, Liver, Mice, Knockout, Mice
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