biostudies-literatureChang YCNational Taiwan University HospitalNIDDK NIH HHSNational Taiwan University Hospital (NTUH)National Science and Technology CouncilNational Science and Technology Council (NSTC)938-966https://www.ebi.ac.uk/biostudies/studies/S-EPMC12081876biostudies-literatureUnknown17(5)Peroxisome proliferator-activated receptor γ (PPARγ) is a master transcriptional regulator of systemic insulin sensitivity and energy balance. The anti-diabetic drug thiazolidinediones (TZDs) are potent synthetic PPARγ ligands with undesirable side effects, including obesity, fluid retention, and osteoporosis. 15-keto prostaglandin E2 (15-keto-PGE2) is an endogenous PPARγ ligand metabolized by prostaglandin reductase 2 (PTGR2). Here, we confirmed that 15-keto-PGE2 binds to and activates PPARγ via covalent binding. In patients with type 2 diabetes and obese mice, serum 15-keto-PGE2 levels were decreased. Administration of 15-keto-PGE2 improves glucose homeostasis and prevented diet-induced obesity in mice. Either genetic inhibition of PTGR2 or PTGR2 inhibitor BPRPT0245 protected mice from dEMBO molecular medicineIdentification of PTGR2 inhibitors as a new therapeutic strategy for diabetes and obesity.PMC12081876R01 DK132469R01 DK133528UN105-0072,UN109-008104-2314-B-002-219-MY3,106-2314-B-002-137-MY3,106-2321-B-002-040,107-2321-B-002-067Chen YALi FAChiu CHHung MSYeh TKHee SWHsu CNCheng TRChuang LMKe YYShih SFChen TYYen HYHu CMHuang JYChang CFLee HLVogel UTseng YHLin SWLiao KCLin SYTsou LKChen SYSaar DLaio DHwang JJChang YCChen YRHsieh MLKragelund BBChou YWHung AFfalseIdentification of PTGR2 inhibitors as a new therapeutic strategy for diabetes and obesity.Peroxisome proliferator-activated receptor γ (PPARγ) is a master transcriptional regulator of systemic insulin sensitivity and energy balance. The anti-diabetic drug thiazolidinediones (TZDs) are potent synthetic PPARγ ligands with undesirable side effects, including obesity, fluid retention, and osteoporosis. 15-keto prostaglandin E2 (15-keto-PGE2) is an endogenous PPARγ ligand metabolized by prostaglandin reductase 2 (PTGR2). Here, we confirmed that 15-keto-PGE2 binds to and activates PPARγ via covalent binding. In patients with type 2 diabetes and obese mice, serum 15-keto-PGE2 levels were decreased. Administration of 15-keto-PGE2 improves glucose homeostasis and prevented diet-induced obesity in mice. Either genetic inhibition of PTGR2 or PTGR2 inhibitor BPRPT0245 protected mice from d2025-01-01T00:00:00Z2025 May2026-04-08T19:51:23.506Z2026-04-08T14:31:15.146ZS-EPMC120818764011917510.1038/s44321-025-00216-4