GPR75 is an orphan G protein-coupled receptor primarily expressed in the brain that plays a crucial role in energy homeostasis and body weight regulation 123. The receptor functions through Gq protein coupling to activate downstream signaling pathways including calcium mobilization and inositol phosphate production 45. GPR75 is uniquely localized to primary cilia of hypothalamic neurons, where it regulates food intake and energy balance 3. Loss-of-function studies demonstrate that GPR75 deficiency protects against obesity, with protein-truncating variants in humans associated with 1.8 kg/m² lower BMI and 54% reduced odds of obesity 1. In mice, Gpr75 knockout results in resistance to diet-induced weight gain, improved glycemic control, and protection against non-alcoholic fatty liver disease 12. While 20-hydroxyeicosatetraenoic acid (20-HETE) has been identified as a high-affinity ligand that activates GPR75 signaling 45, and CCL5/RANTES acts as a negative regulator 4, GPR75 remains classified as an orphan receptor. The receptor's ciliary localization appears critical for its function, as variants that disrupt ciliary targeting show impaired activity 3. These findings position GPR75 as a promising therapeutic target for obesity and metabolic disorders.