GPR75: A Dual-Ligand Receptor for 20-HETE and CCL5 with Emerging Roles in Central and Peripheral Regulation of...

G protein-coupled receptor 75 (GPR75) has recently attracted considerable attention as a novel regulator of metabolic, immune, and vascular processes. Current evidence suggests that two structurally distinct molecules have been proposed as candidate endogenous ligands for GPR75: 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P450-derived lipid metabolite, and C-C motif chemokine ligand 5 (CCL5; RANTES), a chemokine involved in immune regulation. Among these ligands, 20-HETE functions as a potent agonist of GPR75, leading to activation of Gαq/11-dependent signaling pathways and β-arrestin recruitment. In contrast, although CCL5 has also been reported to interact with GPR75, its role as a direct receptor agonist remains controversial and may be highly context-dependent. Notably, GPR75 is broadly expressed in tissues involved in the regulation of energy homeostasis, including the hypothalamus, adipose tissue, liver, pancreas, and vascular system. Population genetic studies have demonstrated that loss-of-function variants in GPR75 are associated with a reduced risk of obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and hypertension. Evidence from animal models further supports a role for GPR75 in the regulation of feeding behavior, insulin sensitivity, lipid metabolism, vascular tone, and inflammatory responses. This review provides a comprehensive overview of the structural characteristics, ligand recognition mechanisms, signaling properties, and tissue distribution of GPR75 and discusses its functions in both the central nervous system and peripheral metabolic tissues. Elucidating how GPR75 integrates, differentiates, and transduces signals derived from these distinct ligands may provide new opportunities for therapeutic intervention in obesity, diabetes, MASLD, and their associated complications.