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

作者：Yi‐Cheng Chang, Meng-Lun Hsieh, Hsiao-Lin Lee, Siow‐Wey Hee, Chi‐Fon Chang, Hsin‐Yung Yen, Yi-An Chen, Yet‐Ran Chen, Ya-Wen Chou, Fu‐An Li, Yi‐Yu Ke, Shih-Yi Chen, Ming‐Shiu Hung, Alfur Fu-Hsin Hung, Jingyong Huang, Chu-Hsuan Chiu, Shih-Yao Lin, Sheue‐Fang Shih, Chih‐Neng Hsu, Juey‐Jen Hwang, Teng‐Kuang Yeh, Ting-Jen Rachel Cheng, Karen Chia-Wen Liao, Daniel Laio, Shu‐Wha Lin, Tzu‐Yu Chen, Chun‐Mei Hu, Ulla Vogel, Daniel Saar, Birthe B. Kragelund, Lun K. Tsou, Yu‐Hua Tseng, Lee‐Ming Chuang · 发表于：EMBO Molecular Medicine · 年份：2025 · DOI：10.1038/s44321-025-00216-4 · 被引用次数：3 · 研究领域：Peroxisome Proliferator-Activated Receptors、Metabolism, Diabetes, and Cancer、Inflammatory mediators and NSAID effects

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 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.