Project Summary Alcohol abuse and related diseases exact a staggering health and economic toll, and thus there is a dire need for novel therapeutic approaches. The hormone FGF21, which is rapidly and robustly induced in liver in response to ethanol exposure, is an exciting new pharmaceutical candidate. FGF21 acts on the brain to suppress alcohol consumption and to stimulate water drinking. In this application, we propose that FGF21 mediates these protective effects by acting directly on neurons expressing the neuropeptide, neurotensin, which is a well-established regulator of ethanol and water intake. We further propose that liver-derived FGF21 also protects against ethanol-induced hypothermia and liver injury by activating the sympathetic nervous system and stimulating thermogenesis in brown adipose tissue. We will test these hypotheses in a series of experiments that employ our unique collection of genetically-engineered mouse models, including mice selectively lacking FGF21’s obligate co-receptor -Klotho in neurotensin neurons. We anticipate that these studies will provide important insights into the tissues and underlying mechanisms whereby FGF21 protects against ethanol-induced toxicity. Moreover, since FGF21 is already in clinical trials for metabolic disease-related indications, these studies will aid in determining whether FGF21 can be repurposed pharmaceutically for treating alcohol abuse and its associated pathologies.