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

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: Alcohol; Alcohol appetite; FGF21; Fibroblast growth factor 21.

Graphical abstract

Figure 1

A) Relative fold change in active plasma FGF21 (1–181) in humans after drinking water or ethanol in water (≈2 standard US drinks/3 UK units), normalized to FGF21 levels at t = 0 for each subject. B) Relative fold change in total plasma FGF21 in the same samples from A (n = 5/group), * denotes statistical significance (p < 0.05) where Benjamani-Hochberg Q < 0.05. C) Effect of 75 g oral sucrose on total FGF21 plasma levels in healthy volunteers, using the same reagent as in B (n = 40), ****Denotes p < 0.0001 by paired, two-tailed Student's t-test. D) Effect of intraperitoneal FGF21 administration (1 mg/kg) on average daily intake of a 4% ethanol solution in mice over four days of baseline and three days of FGF21 treatment (n = 8–9/group), * Denotes p < 0.015 by paired, two-tailed Student's t-test.

Figure 2

A) Individual-level beer consumption at Oktoberfest 2017 by festival day. B) Active plasma FGF21 (1–181) levels before and after consuming an average of 22.6 beers/day for three days. C) Change in total plasma FGF21 levels before and after 3 days at Oktoberfest and three weeks of follow-up (n = 3/group), * Denotes statistical significance, p < 0.05 by paired, two-tailed Student's t-test. D) Correlation between changes in total plasma FGF21 and the liver enzyme aspartate transaminase (ASAT) after Oktoberfest and follow-up (r² = 0.93, p < 0.002).