Identification of PTGR2 inhibitors as a new therapeutic strategy for diabetes and obesity.

YI-CHENG CHANGHsieh, Meng-LunMeng-LunHsiehLee, Hsiao-LinHsiao-LinLeeHee, Siow-WeySiow-WeyHeeChang, Chi-FonChi-FonChangYen, Hsin-YungHsin-YungYenChen, Yi-AnYi-AnChenChen, Yet-RanYet-RanChenChou, Ya-WenYa-WenChouLi, Fu-AnFu-AnLiKe, Yi-YuYi-YuKeChen, Shih-YiShih-YiChenHung, Ming-ShiuMing-ShiuHungHung, Alfur Fu-HsinAlfur Fu-HsinHungHuang, Jing-YongJing-YongHuangChiu, Chu-HsuanChu-HsuanChiuLin, Shih-YaoShih-YaoLinShih, Sheue-FangSheue-FangShihHsu, Chih-NengChih-NengHsuYeh, Teng-KuangTeng-KuangYehJUEY-JEN HWANGCheng, Ting-Jen RachelTing-Jen RachelChengLiao, Karen Chia-WenKaren Chia-WenLiaoLaio, DanielDanielLaioChen, Tzu-YuTzu-YuChenSHU-WHA LINHu, Chun-MeiChun-MeiHuVogel, UllaUllaVogelSaar, DanielDanielSaarKragelund, Birthe BBirthe BKragelundTsou, Lun KelvinLun KelvinTsouTseng, Yu-HuaYu-HuaTsengLEE-MING CHUANG2025-04-082025-04-082025-03-21https://scholars.lib.ntu.edu.tw/handle/123456789/726266Peroxisome 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 diet-induced obesity, insulin resistance, and hepatic steatosis without causing fluid retention and osteoporosis. In conclusion, inhibition of PTGR2 is a new therapeutic approach to treat diabetes and obesity through increasing endogenous PPARγ ligands while avoiding side effects including increased adiposity, fluid retention, and osteoporosis.en15-keto-PGE2DiabetesObesityPPARγPTGR2Identification of PTGR2 inhibitors as a new therapeutic strategy for diabetes and obesity.journal article10.1038/s44321-025-00216-440119175