Study identifies neural pathway to target, potentially treat excessive alcohol consumption

Excessive alcohol consumption is a major health issue worldwide that leaves a lasting and negative impact on physical well-being and survival. Efforts to effectively treat such alcohol use by therapeutically targeting pathways in the body that contribute to the regulation of its consumption have historically been limited. 

A new University of Iowa-led study finds that fibroblast growth factor 21 (FGF21), an endocrine hormone, suppresses alcohol consumption through a specific population of neurons in the brain. Importantly, these results may translate to humans, as FGF21 administration greatly reduced alcohol consumption in alcohol-preferring vervet monkeys.  

“The implications are that targeting FGF21 signaling has the potential to serve as a new therapeutic strategy to prevent excessive alcohol consumption in humans,” says senior study author Matthew Potthoff, PhD, associate professor of neuroscience and pharmacology in the UI Carver College of Medicine. 

Published in Cell Metabolism on Feb. 1, the research is the first of its kind to identify the mechanism of how FGF21 behaves in a liver-to-brain circuit to naturally regulate alcohol consumption. 

According to the findings, FGF21 signals to neurons that express beta-klotho, the FGF21 co-receptor, in the basolateral amygdala of the brain. These neurons project to the nucleus accumbens to suppress alcohol consumption. 

“This is novel because beta-klotho expression and FGF21 signaling in the basolateral amygdala has not been previously described,” Potthoff says. 

The study, titled “FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit,” is a collaboration between Potthoff and co-first author Kyle Flippo, PhD, at the UI Carver College of Medicine and international colleagues, including co-first authors Matthew Gillum, PhD, and Samuel Trammell, PhD, at the University of Copenhagen in Denmark. 

Though this research demonstrates that pharmacologic compounds which mimic the activity of FGF21 suppress alcohol consumption in primates with a strong desire to consume alcohol, the same has not yet been shown for humans. Exploring the efficacy of using these pharmacologic analogues of FGF21 to decrease alcohol consumption is one of many next steps for Potthoff and his colleagues. 

“We are very interested in determining how FGF21 decreases alcohol consumption at the behavioral level,” says Flippo. “For example, does FGF21 decrease the rewarding effects associated with alcohol consumption or increase the aversive consequences of consuming alcohol in excess? Additionally, we are interested in investigating how FGF21 alters neuron activity in mice while they are seeking and consuming alcohol. These future studies will help improve the design of FGF21-based therapeutics for treating alcohol use disorders.”