Can We Reduce Alcohol Consumption by Half?

By Brain & Behavior Staff

Mammals—including great apes and monkeys as well as early humans—began consuming alcohol from fermented fruit long before humans developed methods to distill alcohol. It is therefore not surprising that multiple bodily systems in mammals, including humans, evolved over time to sense and regulate alcohol consumption.

The prevalence of alcohol use disorder (AUD) in humans indirectly suggests that naturally evolved regulatory systems can become dysfunctional (due to genetic and/or environmental factors), removing the inherent "brake" on excessive or health-impairing alcohol intake.

Although various pathways in the body have been targeted to therapeutically address AUD, none of these approaches has proven consistently successful in addressing chronic or excessive alcohol use. A team of researchers led by 2019 BBRF Young Investigator Kyle H. Flippo, Ph.D., and Matthew J. Potthoff, Ph.D., both of the Carver College of Medicine at the University of Iowa, now reports intriguing results of experiments to substantially reduce alcohol consumption in primates by administering a molecule called FGF21. Their paper appeared in the journal Cell Metabolism.

In prior research, administration of FGF21 (fibroblast growth factor 21), which is a hormone of the body's endocrine system, had been shown to suppress alcohol consumption in rodents conditioned to prefer alcohol over water. In parallel, recent genome research has revealed that genes associated with signaling by the FGF21 hormone are associated with alcohol consumption habits in humans.

FGF21, other research has shown, is produced in the liver and has various roles in regulating energy expenditure in the body as well as the intake of carbohydrates, fats and protein. The molecule is capable of crossing the protective blood-brain barrier which keeps most toxins and viruses out of the brain, meaning that it can act upon brain cells and circuits involved in reward, including those implicated in alcohol consumption.

Drs. Flippo, Potthoff and colleagues set out to test whether administration of FGF21 as well as a synthetic analog molecule called PF-05231023 would reduce alcohol intake in alcohol-preferring non-human primates as it previously has been shown to do in rodents. They used vervet monkeys in their experiments.

The experiments yielded a wealth of results. Most important, perhaps, was that the FGF21 analog reduced alcohol consumption by about 50% in monkeys exhibiting a strong preference for alcohol.

The experiments also provided evidence of a liver-to-brain circuit that specifically regulates alcohol consumption. They also showed how the administration of the FGF21 analog apparently targeted the circuit: by enhancing signaling in a subset of neurons in the basolateral amygdala (BLA)—a neuronal subpopulation that projects directly to the brain's nucleus accumbens (NAc), which is involved in regulating feeding and reward behavior that includes drug-taking.

Interestingly the team was also able to show that FGF21's suppression of alcohol consumption operated via circuitry that is distinct from circuitry through which it regulates sugar consumption (another of its important functions). The researchers believe that the two separate pathways of action do not overlap, which could be important in applying FGF21 or an analog molecule to treating AUD.

FGF21's role in regulating both alcohol and sugar intake may reflect "an endocrine feedback loop that presumably functions to protect the liver from damage," the team wrote.

By showing that FGF21 and its analog could specifically target the postulated liver-to-brain regulatory circuit in a way that sharply reduced alcohol consumption in alcohol-preferring higher mammals, the team said that FGF21 could prove a "future treatment option" for AUD in people and related illnesses such as cirrhosis. They called for further research to investigate these possibilities.

The research team also included Brad A. Grueter, Ph.D., a 2016 and 2014 BBRF Young Investigator.