Project Summary/Abstract Common forms of human obesity have a polygenic genetic basis, highlighting the importance of understanding different genetic variants in body weight regulation. Multiple Genome-Wide Association Studies (GWAS) have linked Ankyrin Repeat and SOCS Box Containing 4 (ASB4) to human obesity, but how ASB4 regulates energy homeostasis is not well understood. Our preliminary experiments show that ASB4 is expressed in mouse brain regions that are crucial for feeding regulation. ASB4 deficiency leads to increased meal size and food intake following a fast, and ASB4 is required for the anorectic effects of CalcR agonists or long-acting amylin analogues. ASB4 deficiency also results in heightened consumption of dietary fat at the expense of dietary carbohydrates when two diets are offered. These preliminary findings strongly suggest that ASB4 is important for meal termination and food choice. In this application, we will determine the site of action and cellular mechanism by which ASB4 controls meal termination. We will investigate if ASB4 engages the brain reward system to regulate food choice. If successfully completed, this study will establish ASB4 as a pivotal regulator of homeostatic and hedonic feeding. As ASB4 is highly conserved between mice and humans and is linked to obesity by GWAS, this study will provide mechanistic insight into how ASB4 may regulate food intake in humans.