Ask about this productRelated genes to: GPR75 antibody
- Gene:
- GPR75 NIH gene
- Name:
- G protein-coupled receptor 75
- Previous symbol:
- -
- Synonyms:
- WI-31133
- Chromosome:
- 2p16.2
- Locus Type:
- gene with protein product
- Date approved:
- 1999-10-22
- Date modifiied:
- 2016-10-05
Related products to: GPR75 antibody
Related articles to: GPR75 antibody
- 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. - Source: PubMed
Publication date: 2026/09/18
Cao XiaoyunChhay VannaThi Thi TunLi HuiShi YuWang YifanMin YilinSong RenhuaCheng Kai YanYang YangJong-Leong Wong JustinYu Haojie - 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. - Source: PubMed
Publication date: 2026/09/11
Hou Yu-NingLiu Shu-JingLi Liang-Ming - Diabetes mellitus (diabetes) is a major health burden with the highest mortality rate, affecting an estimated 537 million adults worldwide. The treatment of diabetes remains complex owing to insulin resistance, β-cell dysfunction, metabolic inflammation, and progressive organ damage. While G-protein-coupled receptors (GPCRs) selectively suppress many pathological diseases, the functional characteristics of orphan GPCRs (oGPCRs) remain unexplored as therapeutic targets for diabetes. This review comprehensively evaluates oGPCRs and their roles in diabetes. Orphan receptors are classified based on their functional groups: i) insulin secretagogues such as GPR119 and GPR142, ii) transcriptional and regulatory modulators such as GPR27, and iii) metabolic sensors such as GPR75 and GPR91. We further explored the biological roles of these receptors in the pancreas, adipose tissue, liver, and kidneys. In addition, we mapped the convergence of oGPCR signaling with the pharmacological properties of FDA-approved antidiabetic therapies. The major roles of incretin signaling, AMPK-mediated energy sensing, insulin secretion pathways, inflammatory signaling networks, and sodium-glucose cotransporter 2 (SGLT2) -associated organ protection are addressed. We also report the functionality of these receptors on a receptor-by-receptor basis and prioritize them based on biological relevance, druggability, and translational feasibility. Furthermore, potential repurposable drugs targeting oGPCR pathways, along with existing nondiabetic medications, are highlighted. Finally, we discuss how emerging technologies, including single-cell RNA sequencing, spatial transcriptomics, and artificial intelligence- and structure-based drug design, accelerate GPCR deorphanization and therapeutic development. Overall, this report highlights the significant role of oGPCRs as therapeutic targets and drug repurposing opportunities for developing precision medicine and emphasizes the need for further research on oGPCR signaling in the treatment of diabetes. - Source: PubMed
Publication date: 2026/08/19
Chandrabose SurekaMuniyandi VikramanGeddawy AymanThiyagarajan RameshMurugesan AkshayaKandhavelu Meenakshisundaram - Hyperuricemia-related vascular endothelial injury is closely associated with hypertension, atherosclerosis, and other cardiovascular diseases. Although GPR75 has been implicated in vascular inflammation and hypertension, whether it mediates hyperuricemia-induced endothelial dysfunction and how it is regulated upstream remain unknown. - Source: PubMed
Publication date: 2026/08/07
Fu JiawuHe JunbingLi KeshenZhang MantingLi JiekaiLiu YuchunChen YusenBi Wei - Bronchopulmonary dysplasia (BPD), a debilitating chronic respiratory condition afflicting preterm neonates, stems from oxidative injury and is characterized by arrested alveolar growth and aberrant inflammatory responses. This investigation uncovers a novel mechanistic axis in which the 20-hydroxyeicosatetraenoic acid (20-HETE)/GPR75 signaling cascade acts as a previously unrecognized driver of NLRP1 inflammasome activation in neonatal BPD, thereby linking oxidative stress to inflammatory signaling via p53. Using murine hyperoxia models, we observe that excessive oxygen exposure selectively upregulates GPR75 expression and 20-HETE biosynthesis within alveolar epithelial cells. Genetic inactivation of Gpr75 in vivo significantly attenuated hyperoxia-induced lung injury, oxidative stress, and NLRP1-dependent secretion of interleukin-1β and interleukin-18. Mechanistic dissection revealed that 20-HETE induces NLRP1 inflammasome assembly in rat alveolar epithelia via p53-mediated signaling. In vitro corroboration via lentiviral-mediated Gpr75 silencing, with scrambled shRNA serving as a negative control, further validated its role in hyperoxia-triggered NLRP1 activation and cytokine release (P < 0.01 vs. scrambled control). Collectively, these findings establish the 20-HETE/GPR75 axis as a critical regulator of inflammasome-dependent pathogenesis in BPD. Blockade of this axis inhibits inflammasome assembly and downstream inflammation by suppressing p53 signaling. These results highlight this axis as a promising therapeutic target to mitigate oxygen-induced injury and inflammatory sequelae in preterm infants. - Source: PubMed
Xu QiuXiangTian XiaoLiLi BinKang Jian