Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans
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BACKGROUND & AIMS: Fibroblast growth factor 21 (FGF-21) is a liver-derived metabolic regulator induced by energy deprivation. However, its regulation in humans is incompletely understood. We addressed the origin and regulation of FGF-21 secretion in humans. METHODS: By determination of arterial-to-venous differences over the liver and the leg during exercise, we evaluated the organ-specific secretion of FGF-21 in humans. By four different infusion models manipulating circulating glucagon and insulin, we addressed the interaction of these hormones on FGF-21 secretion in humans. RESULTS: We demonstrate that the splanchnic circulation secretes FGF-21 at rest and that it is rapidly enhanced during exercise. In contrast, the leg does not contribute to the systemic levels of FGF-21. To unravel the mechanisms underlying the regulation of exercise-induced hepatic release of FGF-21, we manipulated circulating glucagon and insulin. These studies demonstrated that in humans glucagon stimulates splanchnic FGF-21 secretion whereas insulin has an inhibitory effect. CONCLUSIONS: Collectively, our data reveal that 1) in humans, the splanchnic bed contributes to the systemic FGF-21 levels during rest and exercise; 2) under normo-physiological conditions FGF-21 is not released from the leg; 3) a dynamic interaction of glucagon-to-insulin ratio regulates FGF-21 secretion in humans.
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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 [7]
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 [46]
In humans, in response to exercise, FGF21 is produced from the liver, not muscle.
“In addition, in humans in response to exercise, FGF21 is produced from the liver not muscle (46).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [46]
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- Authors
- Hansen, J. S., Clemmesen, J. O., Secher, N. H., Hoene, M., Drescher, A., Weigert, C., Pedersen, B. K., & Plomgaard, P.
- Affiliations
- University of Copenhagen (DK)
- Rigshospitalet (DK)
- University of Tübingen (DE)
- Helmholtz Munich (DE)
- Corresponding author
- Plomgaard, Peter
- ORCID
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 4
- Issue
- 8
- Pages
- 551-560
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC4529499
- OpenAlex
- W1906775291
- Cited by
- 123
- References
- 58
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 7 · 2023: 15 · 2022: 8 · 2021: 13 · 2020: 14 · 2019: 15 · 2018: 11 · 2017: 9 · 2016: 13 · 2015: 4
- FWCI
- 5.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Site cant be reached (submittedVersion, cc-by-nc-nd)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by-nc-nd)
- Funders
- Danmarks Grundforskningsfond (DNRF55)
- Bundesministerium für Bildung und Forschung
- Region Hovedstaden
- Strategiske Forskningsråd (09-067009, 09-075724)
- Center for Muskelforskning
- Deutsche Forschungsgemeinschaft (GRK 1302/2)
- Leibniz-Gemeinschaft (SAW-FBN-2013-3)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- FGF21, splanchnic circulation, physical activity, insulin, glucagon, legs, energy deprivation, metabolic regulation
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