Loss of GPR75 protects against non-alcoholic fatty liver disease and body fat accumulation

Approximately 1 in 4 people worldwide have non-alcoholic fatty liver disease (NAFLD); however, there are currently no medications to treat this condition. This study investigated the role of adiposity-associated orphan G protein-coupled receptor 75 (GPR75) in liver lipid accumulation. We profiled Gpr75 expression and report that it is most abundant in the brain. Next, we generated the first single-cell-level analysis of Gpr75 and identified a subpopulation co-expressed with key appetite-regulating hypothalamic neurons. CRISPR-Cas9-deleted Gpr75 mice fed a palatable western diet high in fat adjusted caloric intake to remain in energy balance, thereby preventing NAFLD. Consistent with mouse results, analysis of whole-exome sequencing data from 428,719 individuals (UK Biobank) revealed that variants in GPR75 are associated with a reduced likelihood of hepatic steatosis. Here, we provide a significant advance in understanding of the expression and function of GPR75, demonstrating that it is a promising pharmaceutical target for NAFLD treatment. [Display omitted] •Hypothalamic RNA-seq revealed Gpr75 co-expression with hunger-promoting neurons•Gpr75 knockout mice calibrate intake of palatable, high-fat diet to remain in energy balance•A sex effect in adiposity features was detected in people and mice with GPR75 mutations•Mutations in GPR75 in people and mice protect against fatty liver disease Leeson-Payne et al. identify that mutations in orphan receptor GPR75 are protective against the development of non-alcoholic fatty liver disease. These findings provide a much-needed novel treatment target for a prevalent disease in the global population.