FGF21, a liver hormone that inhibits alcohol intake in mice, increases in human circulation after acute alcohol ingestion and sustained binge drinking at Oktoberfest
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Abstract
OBJECTIVE: Excessive alcohol consumption is a leading cause of global morbidity and mortality. However, knowledge of the biological factors that influence ad libitum alcohol intake may be incomplete. Two large studies recently linked variants in the KLB locus with levels of alcohol intake in humans. KLB encodes β-klotho, co-receptor for the liver-derived hormone fibroblast growth factor 21 (FGF21). In mice, FGF21 reduces alcohol intake, and human Fgf21 variants are enriched among heavy drinkers. Thus, the liver may limit alcohol consumption by secreting FGF21. However, whether full-length, active plasma FGF21 (FGF21 (1-181)) levels in humans increase acutely or sub-chronically in response to alcohol ingestion is uncertain. METHODS: We recruited 10 healthy, fasted male subjects to receive an oral water or alcohol bolus with concurrent blood sampling for FGF21 (1-181) measurement in plasma. In addition, we measured circulating FGF21 (1-181) levels, liver stiffness, triglyceride, and other metabolic parameters in three healthy Danish men before and after consuming an average of 22.6 beers/person/day (4.4 g/kg/day of ethanol) for three days during Oktoberfest 2017 in Munich, Germany. We further correlated fasting FGF21 (1-181) levels in 49 healthy, non-alcoholic subjects of mixed sex with self-reports of alcohol-related behaviors, emotional responses, and problems. Finally, we characterized the effect of recombinant human FGF21 injection on ad libitum alcohol intake in mice. RESULTS: We show that alcohol ingestion (25.3 g or ∼2.5 standard drinks) acutely increases plasma levels of FGF21 (1-181) 3.4-fold in fasting humans. We also find that binge drinking for three days at Oktoberfest is associated with a 2.1-fold increase in baseline FGF21 (1-181) levels, in contrast to minor deteriorations in metabolic and hepatic biomarkers. However, basal FGF21 (1-181) levels were not correlated with differences in alcohol-related behaviors, emotional responses, or problems in our non-alcoholic subjects. Finally, we show that once-daily injection of recombinant human FGF21 reduces ad libitum alcohol intake by 21% in mice. CONCLUSIONS: FGF21 (1-181) is markedly increased in circulation by both acute and sub-chronic alcohol intake in humans, and reduces alcohol intake in mice. These observations are consistent with a role for FGF21 as an endocrine inhibitor of alcohol appetite in humans.
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FGF21 production by the liver is increased in response to alcohol intake.
“Similarly to its regulation of nutrient homeostasis, FGF21 production by the liver is also increased in response to alcohol intake132,133, and administration of FGF21 suppresses alcohol intake122,134.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [133]
Alcohol consumption robustly increases FGF21, largely by the liver.
“another nutritional intervention was shown to robustly increase FGF21: alcohol consumption. Ample evidence, in both rodents and humans, demonstrates that ethanol intake increases FGF21 production, largely by the liver”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [165]
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- Authors
- Søberg, S., Andersen, E. S., Dalsgaard, N. B., Jarlhelt, I., Hansen, N. L., Hoffmann, N., Vilsbøll, T., Chenchar, A., Jensen, M., Grevengoed, T. J., Trammell, S. A. J., Knop, F. K., & Gillum, M. P.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Knop, Filip K.
- Gillum, Matthew P.
- ORCID
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 11
- Pages
- 96-103
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC6001399
- OpenAlex
- W2950625045
- Cited by
- 94
- References
- 40
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 12 · 2023: 10 · 2022: 20 · 2021: 13 · 2020: 8 · 2019: 7 · 2018: 5
- FWCI
- 2.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Merck
- Bristol-Myers Squibb
- Novo Nordisk Foundation Center for Basic Metabolic Research
- Sanofi
- Eli Lilly and Company
- Boehringer Ingelheim
- Novo Nordisk
- Amgen
- TrygFonden
- AstraZeneca
- Novo Nordisk Fonden
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- FGF21, alcohol consumption, binge drinking, liver hormone, β-Klotho, acute alcohol ingestion, alcohol-related behavior, alcohol regulation, liver stiffness, triglycerides, Oktoberfest, heavy drinkers, alcoholism risk factors
- MeSH terms
- Adolescent, Adult, Fibroblast Growth Factors, Humans, Liver, Male, Binge Drinking
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