Gpr75, a G-protein-coupled receptor, has emerged as a significant player in metabolism-related biological processes. It has been identified as the high-affinity receptor of 20-hydroxyeicosatetraenoic acid (20-HETE), and is involved in pathways like PI3K/Akt and RAS/MAPK when bound to 20-HETE [3,5]. Gpr75 is most abundant in the brain and is associated with the control of metabolism, glucose homeostasis, and has implications in various metabolic disorders [1,2].

Gene knockout studies in mice have provided valuable insights into Gpr75's function. Gpr75-deficient mice are protected from high-fat diet-induced obesity, maintaining energy expenditure and not developing insulin resistance. They also have increased expression of thermogenic genes and decreased inflammatory markers in adipose tissue [2]. CRISPR-Cas9-deleted Gpr75 mice fed a high-fat diet adjusted caloric intake to maintain energy balance, preventing non-alcoholic fatty liver disease (NAFLD) [1]. Similarly, Gpr75 knockout mice exhibit lower fasting blood glucose levels, improved glucose homeostasis, and significant prevention of high-fat diet-induced metabolic dysfunction-related steatosis liver disease (MASLD) [4].

In conclusion, Gpr75 plays a crucial role in regulating metabolism, glucose homeostasis, and fat accumulation. Mouse models with Gpr75 knockout have demonstrated its significance in obesity, NAFLD, and MASLD. These findings suggest that Gpr75 could be a potential therapeutic target for treating metabolic disorders [1,2,4].

References:

1. Leeson-Payne, Alasdair, Iyinikkel, Jean, Malcolm, Cameron, Murray, Fiona, Heisler, Lora K. 2024. Loss of GPR75 protects against non-alcoholic fatty liver disease and body fat accumulation. In Cell metabolism, 36, 1076-1087.e4. doi:10.1016/j.cmet.2024.03.016. https://pubmed.ncbi.nlm.nih.gov/38653246/

2. Hossain, Sakib, Gilani, Ankit, Pascale, Jonathan, Garcia, Victor, Schwartzman, Michal Laniado. 2023. Gpr75-deficient mice are protected from high-fat diet-induced obesity. In Obesity (Silver Spring, Md.), 31, 1024-1037. doi:10.1002/oby.23692. https://pubmed.ncbi.nlm.nih.gov/36854900/

3. Dashti, Mohammad Reza, Gorbanzadeh, Fatemeh, Jafari-Gharabaghlou, Davoud, Farhoudi Sefidan Jadid, Mahdi, Zarghami, Nosratollah. 2023. G Protein-Coupled Receptor 75 (GPR75) As a Novel Molecule for Targeted Therapy of Cancer and Metabolic Syndrome. In Asian Pacific journal of cancer prevention : APJCP, 24, 1817-1825. doi:10.31557/APJCP.2023.24.5.1817. https://pubmed.ncbi.nlm.nih.gov/37247305/

4. Wang, Shuo, Gao, Shan, Wang, Fei. 2024. Effect and mechanism of GPR75 in metabolic dysfunction-related steatosis liver disease. In International journal of medical sciences, 21, 2343-2347. doi:10.7150/ijms.101094. https://pubmed.ncbi.nlm.nih.gov/39310267/

5. Garcia, Victor, Gilani, Ankit, Shkolnik, Brian, Falck, John R, Schwartzman, Michal Laniado. 2017. 20-HETE Signals Through G-Protein-Coupled Receptor GPR75 (Gq) to Affect Vascular Function and Trigger Hypertension. In Circulation research, 120, 1776-1788. doi:10.1161/CIRCRESAHA.116.310525. https://pubmed.ncbi.nlm.nih.gov/28325781/