The Regeneron Genetics Center (RGC) discovered rare pLOF mutations in GPR75 that are associated with lower BMI and a lower risk of obesity in human heterozygous carriers. GPR75 is an orphan G-protein coupled receptor that is highly expressed in the brain and neuroendocrine tissues. In line with the human genetics, Gpr75 knockout mice (Gpr75-/-) exhibit lower adiposity on a standard chow diet and are protected from high-fat diet induced weight gain compared to wildtype (Gpr75+/+) mice. Here, we explore the translational mechanisms between loss of GPR75 in mice and humans that underlie the protection from obesity.