Vervet monkeys (Chlorocebus pygerythrus) with a strong preference for ethanol 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 has a negative impact on health and survival, it is not surprising that many physiological systems have evolved to detect and regulate it in mammals.
Unfortunately, efforts to therapeutically target the pathways that regulate alcohol consumption have been limited in their ability to effectively treat alcohol use disorders.
Recently, genome-wide association studies have shown that genetic variants of FGF21 are linked to increased alcohol consumption in humans.
In rodents, pharmacological 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 said Dr. Matthew Potthoff, a researcher at the University of Iowa. Carver College of Medicine.
“Despite this, the neural circuits regulating FGF21-mediated suppression of sugar and alcohol consumption apparently developed independently and not in response to shared selective pressure.”
In their study, Dr. Potthoff and colleagues showed that administration of an FGF21 analog reduced alcohol consumption by 50% in vervet monkeys with a strong innate preference for ethanol.
FGF21 and FGF21 analogue decrease alcohol consumption even when given after prolonged exposure to ethanol in mice and primates.
FGF21 alters neuronal transmission in the nucleus accumbensa region of the brain that plays a complex role in reward and addiction, and suppresses alcohol consumption through a subpopulation of neurons in the basolateral tonsil.
Specifically, FGF21 signaling in neurons that project from the basolateral amygdala to the nucleus accumbens suppresses alcohol consumption by altering the activity of a specific subpopulation of these neurons.
“Our results provide a mechanism for a liver-brain endocrine feedback loop which presumably works to protect the liver from damage,” said University of Iowa researcher Dr. Kyle Flippo.
“The central molecular and cellular effects of FGF21 represent an opportunity for future research, and current data indicate that FGF21 analogs may provide a potential treatment option for alcohol use disorders and related diagnoses.”
The study was published in the journal Cell metabolism.
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