The GPR75 gene encodes a transmembrane protein belonging to the G protein-coupled receptor (GPCR) family. This receptor is primarily expressed in the brain, particularly enriched in the cilia of hypothalamic neurons that regulate appetite. It couples with Gαq proteins to activate downstream signaling pathways (such as MAPK, NF-κB, etc.), participating in the regulation of energy balance, feeding behavior, and fat metabolism ^[1-2]. The encoded protein comprises 540 amino acids with a typical 7-transmembrane structure. Upon binding with ligands like 20-hydroxyeicosatetraenoic acid (20-HETE), it can trigger physiological effects such as inflammation, vasoconstriction, and lipid accumulation ^[2-3]. Research has found that loss-of-function or mutations in GPR75 (e.g., the L144P variant) can significantly reduce body weight and fat mass, resist high-fat diet-induced obesity and non-alcoholic fatty liver disease (NAFLD), and improve insulin sensitivity ^[3-4]. Furthermore, GPR75 mediates 20-HETE-induced cardiomyocyte apoptosis in the cardiovascular system, which is associated with hypertension and endothelial dysfunction ^[2-3]. In cancer, GPR75 may promote cachexia progression by regulating white adipose tissue browning ^[5]. Whole-exome sequencing has revealed that rare variants in GPR75 are closely related to low BMI and reduced obesity risk in humans, making it a promising therapeutic target for obesity, metabolic syndrome, and cardiovascular diseases ^[3].

The Gpr75 KO mouse is a knockout (KO) model in which the exon 2 of the mouse Gpr75 gene (homologous to the human GPR75 gene) has been deleted via gene-editing technology. This model can be used to study the pathogenic mechanisms of diseases such as obesity, metabolic syndrome, and cardiovascular diseases, and to provide a basis for developing related therapeutic strategies.