2025/03/21 by Yi‐Cheng Chang, Meng-Lun Hsieh, Hsiao-Lin Lee +30 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Peroxisome Proliferator-Activated Receptors #Metabolism, Diabetes, and Cancer #Inflammatory mediators and NSAID effects
paper · pdf · doi:10.1038/s44321-025-00216-4
openalex publication_date 2025/03/21 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/29
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.