Regulation of alcohol intake by fibroblast growth factor 21

Alcohol Use Disorder (AUD) is a pattern of alcohol consumption accompanied by a clinically significant impairment. AUD is a major public health problem worldwide, yet effective therapies to treat individuals to reduce alcohol consumption are lacking. Further, the underlying physiology of AUD is still poorly understood. Fibroblast growth factor 21 (FGF21) is an endocrine hormone produced by the liver that regulates nutrient and energy homeostasis. Alcohol ingestion acutely increases plasma levels of FGF21 in rodents and humans. Genome-wide association studies have identified multiple single-nucleotide polymorphisms in the gene β-klotho (KLB), which is the obligate co-receptor for FGF21 signaling, as being associated with increased alcohol consumption in humans. We have shown that pharmacologic administration of FGF21 and a long-acting FGF21 analog (PF-05231023) in rodents and non-human primates reduces alcohol consumption. Our findings demonstrate the potential of a FGF21-based therapeutic in suppressing alcohol consumption. We identified that FGF21 signals to KLB BLA-to-NAc-projecting neurons to suppress alcohol consumption. We highlight that FGF21 signals to KLB+ Vglut1+ double positive neurons to reduce alcohol intake. Importantly, we reveal that this circuit is distinct from FGF21 signaling to KLB+ Vglut2+ double positive neurons to reduce sucrose intake. In addition, FGF21 uniquely impacts feeding behavior in response to sucrose versus alcohol. Together, these findings highlight a liver-to-brain feedback loop that presumably functions to protect the liver from damage. These results provide additional insight into effective pharmacological treatments and new avenues of therapy for AUD.