Elsevier

Molecular Metabolism

Volume 11, May 2018, Pages 96-103
Molecular Metabolism

Original Article
FGF21, a liver hormone that inhibits alcohol intake in mice, increases in human circulation after acute alcohol ingestion and sustained binge drinking at Oktoberfest

https://doi.org/10.1016/j.molmet.2018.03.010Get rights and content
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open access

Highlights

  • Circulating FGF21 (1–181) increases >3-fold after acute but moderate alcohol drinking in humans.

  • Also in humans, circulating FGF21 (1–181) increases >2-fold after a weekend of binge drinking.

  • FGF21 treatment reduces alcohol intake in mice.

  • FGF21 may be a conserved inhibitor of alcohol “appetite”.

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.

Keywords

Fibroblast growth factor 21
FGF21
Alcohol
Alcohol appetite

Cited by (0)

5

Susanna Søberg, Emilie S. Andersen, Filip K. Knop, Matthew P. Gillum Equally contributing authors.