Gpr75‐deficient mice are protected from high‐fat diet–induced obesity

Abstract Objective G‐protein coupled receptor 75 (GPR75) has been identified as the high‐affinity receptor of 20‐hydroxyeicosatetraenoic acid (20‐HETE), a vasoactive and proinflammatory lipid, and mice overproducing 20‐HETE have been shown to develop insulin resistance when fed a high‐fat diet (HFD), which was prevented by a 20‐HETE receptor blocker. Simultaneously, a large‐scale exome sequencing of 640,000 subjects identified an association between loss‐of‐function GPR75 variants and protection against obesity. Methods Wild‐type (WT) and Gpr75 ‐deficient mice were placed on HFD for 14 weeks, and their obesity phenotype was examined. Results Male and female Gpr75 null (knockout [KO]) and heterozygous mice gained less weight than WT mice when placed on HFD. KO mice maintained the same level of energy expenditure during HFD feeding, whereas WT mice showed a significant reduction in energy expenditure. Diet‐driven adiposity and adipocyte hypertrophy were greatly lessened in Gpr75 ‐deficient mice. HFD‐fed KO mice did not develop insulin resistance. Adipose tissue from Gpr75 ‐deficient mice had increased expression of thermogenic genes and decreased levels of inflammatory markers. Moreover, insulin signaling, which was impaired in HFD‐fed WT mice, was unchanged in KO mice. Conclusions These findings suggest that GPR75 is an important player in the control of metabolism and glucose homeostasis and a likely novel therapeutic target to combat obesity‐driven metabolic disorders. image