In the United States, alcohol use disorder (AUD) affects ~15% of adults with the prevalence of binge drinking on the rise in adolescents and young adults. AUD represents a major issue to healthcare given that chronic excessive alcohol consumption in humans is associated with cardiovascular disease, metabolic syndrome, and cancer while acute alcohol intoxication can prove lethal. Economically, AUD represents a massive burden due to loss of productivity and associated healthcare costs. Recently, the endocrine hormone fibroblast growth factor 21 (FGF21), known for its potent metabolic effects, was found to significantly reduce alcohol consumption via signaling through its obligate co-receptor, ?-klotho, in the brain. Importantly, single nucleotide polymorphisms (SNPs) in both the FGF21 and ?-klotho genomic loci are highly associated with increased alcohol consumption in humans. Our preliminary data demonstrates that FGF21 treatment markedly suppresses alcohol consumption in mice previous subjected to chronic alcohol exposure. Furthermore, excessive alcohol consumption promotes FGF21 secretion from the liver representing a homeostatic feedback loop to regulate alcohol consumption. However, the mechanism of FGF21 action in the brain and the neuronal target(s) for these effects has not been determined. The overall goal of this proposal is to identify the neural circuit(s) regulating FGF21-mediated suppression of alcohol intake.
The aims of this grant are to 1) determine the direct neuronal target(s) of FGF21 in the CNS mediating inhibition of alcohol intake, and 2) determine how FGF21 modulates reward circuits to regulate alcohol intake and preference. To accomplish these aims, we have generated novel animal models and tools to examine these experimental aims. These studies will provide new fundamental insights into the regulation of alcohol intake by peripheral endocrine signals acting on the central nervous system. In addition, these studies may identify novel therapeutic targets for the treatment of AUD.

Public Health Relevance

According to the NIAAA, in the United States roughly 6% of adults have alcohol use disorder and almost 27% of adults have engaged in binge-drinking in the last month suggesting there is a serious demand for therapies to prevent excessive alcohol consumption. Fibroblast growth factor 21 (FGF21) is a secreted endocrine factor that signals to the brain to decrease alcohol consumption and genetic variation around the loci encoding FGF21 and its receptor, ?-klotho, are associated with increased alcohol consumption in humans. Thus, by investigating the mechanism by which FGF21 inhibits alcohol consumption, we aim to discover potential mechanisms driving pathological alcohol consumption while also highlighting potential therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA027654-01A1
Application #
9887298
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Cui, Changhai
Project Start
2020-01-10
Project End
2024-12-31
Budget Start
2020-01-10
Budget End
2020-12-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Iowa
Department
Pharmacology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242