PROJECT SUMMARY The prevalence of obesity and associated comorbidities is a major public health concern with significant personal and societal consequences. Weight loss pharmacotherapies that target known food intake-inhibitory mechanisms (e.g., hindbrain and hypothalamic circuits) have been largely unsuccessful at promoting sustained weight loss. This suggests the existence of yet-to-be-identified nodes that regulate food intake, and uncovering such mechanisms holds promise for the development of more effective obesity treatments. To this end, we recently used a “reverse translational” approach to identify and characterize a novel population of cerebellar neurons and their importance to feeding behavior. Starting with human subjects and following up with mechanistic experiments in mice, we discovered that glutamatergic neurons in the anterior, lateral deep cerebellar nuclei (aDCN-lat) are activated by food and have the ability to dramatically reduce meal size. These data demonstrate that glutamatergic aDCN-lat neurons are critical regulators of feeding behavior, and highlight this population as a potential target for obesity therapeutics. Here, we leverage these findings to understand how activity in these cerebellar neurons is regulated and how it is altered in obesity. The goals of this proposal are to (1) reveal the sensory, nutritive, and gut-brain pathways that activate cerebellar satiation neurons, (2) determine how activity in these neurons changes in obesity, and (3) test whether chronic activity in these neurons is sufficient to prevent or reverse diet-induced obesity in mice. These results will provide a comprehensive understanding of cerebellar mechanisms for feeding behavior, illuminating a novel satiation center in the brain that may be targeted for the development obesity therapeutics.