Global GPR75 deficiency protects against diet-induced obesity through central and peripheral mechanisms.

Loss-of-function variants of GPR75 are associated with protection against obesity in humans; however, the mechanisms through which GPR75 regulates whole-body energy homeostasis remain incompletely understood. Here, we generated Gpr75 global knockout (GKO) mice and performed comprehensive metabolic phenotyping under chow and high-fat diet (HFD) conditions. Despite high expression of GPR75 in the brain, male GKO mice exhibited unchanged food intake during the period when body weights began to diverge. Instead, GPR75 deficiency resulted in reduced whole-body energy expenditure and an elevated respiratory exchange ratio, indicating decreased fat utilization. Notably, male, but not female, GKO mice displayed markedly impaired intestinal lipid absorption, reduced chylomicron output, and increased fecal lipid excretion, consistent with limited dietary lipid assimilation under HFD feeding. To define the tissue-specific contributions of GPR75, we next examined hepatocyte-, intestinal epithelial-, endothelial/hematopoietic-, and AgRP neuron-specific Gpr75 knockout mice. Deletion of Gpr75 in hepatocytes (Alb-Cre), intestinal epithelium (Vil-Cre), or endothelial/hematopoietic lineages (Tie2-Cre) did not reproduce the pronounced protection against HFD-induced weight gain observed in GKO mice. In contrast, AgRP neuron-specific deletion reduced body weight by approximately 10%-12% in male and female mice and decreased white adipose depot mass by 27%-50%, establishing AgRP neurons as a specific neuronal population through which GPR75 contributes to body-weight regulation. However, the magnitude of this phenotype remained substantially smaller than that observed in global GPR75-deicient mice. Together, our findings demonstrate that GPR75 regulates diet-induced obesity through both central and peripheral mechanisms. AgRP-neuronal GPR75 contributes to body-weight regulation in both sexes, whereas global GPR75 deficiency additionally impairs intestinal lipid assimilation in males through a mechanism not recapitulated by deletion in the tested peripheral cell populations. These complementary effects likely contribute to the pronounced resistance to diet-induced obesity and hepatic steatosis observed in global GPR75-deficient mice and further support GPR75 as a therapeutic target for obesity and associated metabolic liver disease.