EMBO Molecular Medicine (Mar 2025)
Identification of PTGR2 inhibitors as a new therapeutic strategy for diabetes and obesity
- 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
Affiliations
- Yi-Cheng Chang
- Department of Internal Medicine, National Taiwan University Hospital
- Meng-Lun Hsieh
- Department of Medicinal Chemistry, University of Florida
- Hsiao-Lin Lee
- Department of Internal Medicine, National Taiwan University Hospital
- Siow-Wey Hee
- Department of Internal Medicine, National Taiwan University Hospital
- Chi-Fon Chang
- Genomics Research Center, Academia Sinica
- Hsin-Yung Yen
- Institute of Biological Chemistry, Academia Sinica
- Yi-An Chen
- Institute of Biological Chemistry, Academia Sinica
- Yet-Ran Chen
- Agricultural Biotechnology Research Center, Academia Sinica
- Ya-Wen Chou
- Agricultural Biotechnology Research Center, Academia Sinica
- Fu-An Li
- Institute of Biomedical Sciences, Academia Sinica
- Yi-Yu Ke
- Institute for Drug Evaluation Platform, Development Center for Biotechnology
- Shih-Yi Chen
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University
- Ming-Shiu Hung
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes
- Alfur Fu-Hsin Hung
- Rakuten Medical
- Jing-Yong Huang
- Department of Internal Medicine, National Taiwan University Hospital
- Chu-Hsuan Chiu
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University
- Shih-Yao Lin
- AltruBio Taiwan R&D Center
- Sheue-Fang Shih
- Taiwan Liposome Company
- Chih-Neng Hsu
- Department of Internal Medicine, National Taiwan University Hospital, Yunlin branch
- Juey-Jen Hwang
- Department of Internal Medicine, National Taiwan University Hospital
- Teng-Kuang Yeh
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes
- Ting-Jen Rachel Cheng
- Genomics Research Center, Academia Sinica
- Karen Chia-Wen Liao
- Biological Sciences Division, University of Chicago
- Daniel Laio
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University
- Shu-Wha Lin
- Centers of Genomic and Precision Medicine, National Taiwan University
- Tzu-Yu Chen
- National Laboratory Animal Center, National Applied Research Laboratories
- Chun-Mei Hu
- Genomics Research Center, Academia Sinica
- Ulla Vogel
- National Research Centre for the Working Environment
- Daniel Saar
- REPIN, University of Copenhagen
- Birthe B Kragelund
- REPIN, University of Copenhagen
- Lun Kelvin Tsou
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes
- Yu-Hua Tseng
- Joslin Diabetes Center, Harvard Medical School
- Lee-Ming Chuang
- Department of Internal Medicine, National Taiwan University Hospital
- DOI
- https://doi.org/10.1038/s44321-025-00216-4
- Journal volume & issue
-
Vol. 17,
no. 5
pp. 938 – 966
Abstract
Abstract 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.
Keywords
