Studies by researchers at the University of Iowa Carver College of Medicine have found that the hormone fibroblast growth factor 21 (FGF21), which is produced by the liver, suppresses alcohol consumption in primates. The researchers demonstrated that in vervet monkeys with a strong preference for ethanol, administering an FGF21 analogue resulted in 50% less alcohol consumption. The investigators separately analyzed brain circuits involved in mice, and found that the protein, which is also known to reduce sugar intake, acts on different circuits to reduce either alcohol or sugar consumption.

“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,” said senior study author Matthew Potthoff, PhD. “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. 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.”

Potthoff and colleagues reported on their findings in Cell Metabolism, in a paper titled “FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit,” in which they concluded, “These findings identify a homeostatic liver-to-brain circuit that regulates alcohol consumption and demonstrate the feasibility of targeting this pathway for therapeutic applications.”

Excessive alcohol consumption is a major global health and social issue. 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, the authors wrote. Unfortunately, attempts to target pathways that regulate alcohol consumption as a means to treat alcohol use disorder haven’t been wholly successful. “Efforts to therapeutically target pathways that contribute to regulation of alcohol consumption (i.e., ethanol metabolism, reward signaling, or neuropeptide signaling with the goal of cessation of alcohol consumption have been limited in their efficacy to effectively treat alcohol use disorder (AUD),” the team noted.

Produced by the liver in response to metabolic and nutritional challenges, FGF21 functions to regulate energy homeostasis and macronutrient balance, the authors continued. “…FGF21 signaling to the CNS is important for its effects to modulate energy balance and macronutrient preference.” Recently, genome-wide association studies have linked FGF21 genetic variants to increased alcohol consumption in humans. In rodents, it’s been found that pharmacologic administration of this protein reduces alcohol consumption through actions in the brain. But until now, the neural circuits through which FGF21 inhibits alcohol consumption haven’t been known unknown, and its effects on alcohol consumption in higher organisms were also uncertain.

In their newly reported study, Potthoff and University of Iowa co-authors, together with international collaborators—including University of Iowa co-first author, Kyle Flippo, PhD, and Matthew Gillum, PhD, and Samuel Trammell, PhD, of the University of Copenhagen— showed that administration of an FGF21 analogue (known as PF-05231023) reduced alcohol intake by 50% in vervet monkeys that had an otherwise strong innate preference for ethanol. And FGF21 and the FGF21 analogue decreased alcohol intake even when administered after prolonged ethanol exposure in mice and primates. Conversely, the team showed that deleting FGF21 from the liver in experimental mice resulted in significantly increased ethanol consumption.

“ … these data suggest that endogenous FGF21 signals in an endocrine fashion to regulate alcohol consumption while pharmacologic administration of FGF21 or FGF21 analogs can robustly suppress alcohol consumption in mice and alcohol-preferring primates,” the team noted. “Importantly, FGF21 and the FGF21 analog PF-05231023 effectively function to decrease alcohol intake even when administered after prolonged ethanol exposure in mice and primates … Thus, FGF21-based therapeutics may represent a promising therapeutic approach for AUD.”

Further experiments demonstrated that FGF21 alters neural transmission in the nucleus accumbens (NAc)—a brain region that plays a complex role in reward and addiction—and suppresses alcohol consumption through a subpopulation of neurons in the basolateral amygdala. Specifically, FGF21 signaling in neurons that project from the basolateral amygdala (BLA) to the nucleus accumbens suppressed alcohol consumption by changing the activity of a specific subpopulation of these neurons. Previous studies had shown that this pathway is involved in reward-seeking behavior.

“Specifically, FGF21 signaling in BLA/NAc-projecting neurons suppresses alcohol consumption by enhancing the excitability of a specific subpopulation of these neurons,” the authors pointed out. “The association of increased FGF21 levels with alcohol consumption and alcohol liver cirrhosis may suggest that a pathology in this pathway contributes to alcohol dependency.”

The researchers acknowledged that more research will be needed to investigate the specific effects of FGF21 on the activity of these neurons during alcohol consumption in animal models. Nevertheless, Flippo said, “Our results provide a mechanism for a liver-to-brain endocrine feedback loop that presumably functions to protect the liver from damage. 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.”

Interestingly, the team had previously shown that FGF21 suppresses sugar intake via a liver-to-brain signaling axis. Their newly reported research also confirmed that FGF21 suppresses alcohol consumption through a different circuit to that which mediates the effects of FGF21 on sugar intake. “Thus, FGF21 appears to be an endocrine protective factor that signals to specific, non-overlapping central neural circuits to prevent nutrient excess and associated liver damage,” they commented.

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