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<p>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&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月21日

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  • 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,
  • Jing-Yong 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 Kelvin Tsou,
  • Yu-Hua Tseng,
  • Lee-Ming Chuang

摘要

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.