Obesity and diabetes are major public health issues that affect quality of life and also have high social and economic costs. According to the CDC, approximately 10% of U.S. adults have diabetes now and 33% are expected to have diabetes by 2050. At the same time, obesity has reached epidemic proportions, with over 60% of the U.S. population being overweight or obese. Therefore, there is a serious demand for the development of new therapeutics to combat obesity and diabetes. Fibroblast growth factor 21 (FGF21) is an endocrine hormone that ameliorates metabolic dysfunction in a number of obese animal models and humans. Extended administration of FGF21 causes weight loss in rodents, and administration of FGF21 analogs to obese humans increases weight loss and improves metabolic profiles. Recently, we discovered that FGF21 functions physiologically and pharmacologically to suppress carbohydrate intake and sweet taste preference. Importantly, we and others have found that many of the beneficial effects of FGF21 are mediated through its actions on the central nervous system. 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 carbohydrate intake. The aims of this grant are to 1) determine the direct neuronal target responsible for FGF21-mediated suppression of carbohydrate intake in vivo, 2) determine the role of oxytocin signaling in FGF21’s suppressive effect on simple sugar intake, and 3) determine the effect of FGF21 on the modulation of the mesolimbic dopamine system and feeding behavior. 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 whole-body glucose homeostasis and food-related reward by peripheral endocrine signals acting on the central nervous system. In addition, these studies may identify novel therapeutic targets for the treatment of diabetes and obesity.