GPR75 Genetic Manipulations in Mice Reveal Central Mechanism for Weight Loss Independent of Developmental Effects

OBJECTIVE: Human genetic studies have identified GPR75 loss-of-function variants to be strongly protective against obesity, establishing GPR75 as a compelling therapeutic target. However, critical questions remain regarding the translational potential of GPR75 inhibition. These include whether adult-onset inhibition can reverse established obesity and which tissue compartments mediate weight loss. Here, we address these fundamental questions using novel genetic mouse models. METHODS: We generated whole-body inducible Gpr75 knockout mice to assess the effects of adult-onset Gpr75 deletion. Adult Gpr75flox/flox; R26-CreERT mice were treated with tamoxifen either pre-obesity and then challenged with high-fat diet (HFD) to evaluate protection from weight gain, or post-obesity establishment to evaluate weight loss. The role of brain Gpr75 was determined using neonatal intracerebroventricular injection of adeno-associated viruses carrying artificial microRNAs targeting Gpr75, and weight gain on HFD was evaluated. Both male and female mice were examined. RESULTS: Adult-onset Gpr75 knockout prevented diet-induced obesity when induced prior to HFD challenge, indicating the body weight phenotype is independent of developmental effects. Strikingly, Gpr75 deletion induced in obese mice produced robust weight loss, demonstrating the potential for therapeutic efficacy. Body composition analysis revealed specific fat mass reduction with complete lean mass preservation in Gpr75 inducible knockout mice. The body weight differences occurred with no change or only modest reductions in food intake. Postnatal brain-targeted Gpr75 knockdown was sufficient to confer significant protection from diet-induced obesity, with efficacy correlating to knockdown efficiency. CONCLUSIONS: These data provide compelling genetic evidence that Gpr75 inhibition in adulthood can achieve substantial weight loss with selective fat mass reduction and lean mass preservation, operating through a mechanism that extends beyond appetite suppression alone. In addition, Gpr75 action in the postnatal brain plays a critical role in mediating these effects. Our findings de-risk a major translational concern, i.e., the developmental impacts of GPR75 on body weight regulation, and support the exploration of brain-penetrant GPR75 inhibitors as a novel obesity therapeutic strategy.