Endocrine Regulation of Alcohol Intake

项目总结/摘要 在美国，酒精使用障碍（AUD）影响约15%的成年人，并普遍存在酗酒 在青少年和年轻人中呈上升趋势。AUD是医疗保健的一个主要问题，因为慢性 人类过量饮酒与心血管疾病、代谢综合征和 而急性酒精中毒则可能致命。从经济上讲，澳元是一个巨大的负担， 生产力的损失和相关的医疗费用。最近，内分泌激素成纤维细胞生长 FGF 21因其强大的代谢作用而闻名，被发现可以显著减少酒精 通过其在大脑中的专性共受体β-klotho的信号传导来消耗。重要的是，单核苷酸 FGF 21和β-klotho基因组基因座中的多态性（SNP）与增加的 人类的酒精消费我们的初步数据表明，FGF 21治疗显著 抑制长期接触酒精的小鼠的酒精消耗。此外，委员会认为， 过量饮酒促进肝脏分泌FGF 21，代表体内平衡反馈 调节酒精消耗的回路。然而，FGF 21在脑和神经元中的作用机制是不明确的。 这些影响的目标尚未确定。这项提案的总体目标是确定神经 调节FGF 21介导的酒精摄入抑制的回路。该补助金的目的是：1）确定 CNS中FGF 21的直接神经元靶点介导酒精摄入的抑制，和2）确定如何 FGF 21调节奖赏回路以调节酒精摄入和偏好。为了实现这些目标，我们 已经产生了新的动物模型和工具来检查这些实验目的。这些研究将提供 通过外周内分泌信号调节酒精摄入量的新的基本见解， 中枢神经系统此外，这些研究可能会确定新的治疗靶点，用于治疗 澳元。

PROJECT SUMMARY / ABSTRACT 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, β-klotho, in the brain. Importantly, single nucleotide polymorphisms (SNPs) in both the FGF21 and β-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.