Hormone Treatment Suppresses Alcohol Consumption in Non-Human Primates

Vervet monkeys (Chlorocebus pygerythrus) with a strong preference for ethanol that were given an analogue of FGF21 (fibroblast growth factor 21), a powerful hormone produced by the liver, consumed 50% less alcohol.

Excessive alcohol consumption is a major health and social issue in our society.

Given that excessive alcohol consumption negatively impacts health and survival, it is not surprising that numerous physiological systems have evolved to sense and regulate it in mammals.

Unfortunately, efforts to therapeutically target pathways that regulate alcohol consumption have been limited in their ability to effectively treat alcohol use disorder.

Recently, genome-wide association studies have shown that FGF21 genetic variants are linked to increased alcohol consumption in humans.

In rodents, pharmacologic administration of this protein, which is produced in the liver, reduces alcohol consumption through actions in the brain.

But until now, the neural circuits through which FGF21 inhibits alcohol consumption were unknown, as were its effects on alcohol consumption in higher organisms.

“When considering how and why these modality specific mechanisms evolved, it is interesting to note that mammals were primarily exposed to alcohol from fermenting fruits, which possess high levels of simple sugars,” said Dr. Matthew Potthoff, a researcher at the University of Iowa Carver College of Medicine.

“Despite this, neural circuits regulating FGF21-mediated suppression of sugar and alcohol intake apparently developed independently and not in response to a shared selective pressure.”

In their study, Dr. Potthoff and colleagues showed that administration of an FGF21 analogue reduces alcohol intake by 50% in vervet monkeys with a strong innate preference for ethanol.

FGF21 and the FGF21 analogue decrease alcohol intake even when administered after prolonged ethanol exposure in mice and primates.

FGF21 alters neural transmission in the nucleus accumbens, a brain region that plays a complex role in reward and addiction, and suppresses alcohol consumption through a sub-population of neurons in the basolateral amygdala.

Specifically, FGF21 signaling in neurons that project from the basolateral amygdala to the nucleus accumbens suppresses alcohol consumption by changing the activity of a specific subpopulation of these neurons.

“Our results provide a mechanism for a liver-to-brain endocrine feedback loop that presumably functions to protect the liver from damage,” said Dr. Kyle Flippo, a researcher at the University of Iowa.

“The central molecular and cellular effects of FGF21 represent an opportunity for future research, and the present data indicates that FGF21 analogues may provide a potential treatment option against alcohol-use disorder and related diagnosis.”

The study was published in the journal Cell Metabolism.

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Kyle H. Flippo et al. 2022. FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit. Cell Metabolism 34 (2): 317-328.e6; doi: 10.1016/j.cmet.2021.12.024