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

doi:10.1038/s44321-025-00216-4

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 HwangTeng 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^*

^*Corresponding author af dette arbejde

Biomolecular Sciences

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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.

Originalsprog	Engelsk
Artikelnummer	116095
Tidsskrift	EMBO Molecular Medicine
Vol/bind	17
Udgave nummer	5
Sider (fra-til)	938-966
Antal sider	29
ISSN	1757-4676
DOI	https://doi.org/10.1038/s44321-025-00216-4
Status	Udgivet - 2025

Bibliografisk note

Publisher Copyright:
© The Author(s) 2025.

Adgang til dokumentet

10.1038/s44321-025-00216-4Licens: CC BY

FulltextForlagets udgivne version, 4,59 MBLicens: CC BY

Citationsformater

Chang, Y. C., Hsieh, M. L., Lee, H. L., Hee, S. W., Chang, C. F., Yen, H. Y., Chen, Y. A., Chen, Y. R., Chou, Y. W., Li, F. A., Ke, Y. Y., Chen, S. Y., Hung, M. S., Hung, A. F. H., Huang, J. Y., Chiu, C. H., Lin, S. Y., Shih, S. F., Hsu, C. N., ... Chuang, L. M. (2025). Identification of PTGR2 inhibitors as a new therapeutic strategy for diabetes and obesity. EMBO Molecular Medicine, 17(5), 938-966. Artikel 116095. https://doi.org/10.1038/s44321-025-00216-4

Chang, YC, Hsieh, ML, Lee, HL, Hee, SW, Chang, CF, Yen, HY, Chen, YA, Chen, YR, Chou, YW, Li, FA, Ke, YY, Chen, SY, Hung, MS, Hung, AFH, Huang, JY, Chiu, CH, Lin, SY, Shih, SF, Hsu, CN, Hwang, JJ, Yeh, TK, Cheng, TJR, Liao, KCW, Laio, D, Lin, SW, Chen, TY, Hu, CM, Vogel, U, Saar, D , Kragelund, BB, Tsou, LK, Tseng, YH & Chuang, LM 2025, 'Identification of PTGR2 inhibitors as a new therapeutic strategy for diabetes and obesity', EMBO Molecular Medicine, bind 17, nr. 5, 116095, s. 938-966. https://doi.org/10.1038/s44321-025-00216-4

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title = "Identification of PTGR2 inhibitors as a new therapeutic strategy for diabetes and obesity",

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 = "15-keto-PGE2, Diabetes, Obesity, PPARγ, PTGR2",

author = "Chang, {Yi Cheng} and Hsieh, {Meng Lun} and Lee, {Hsiao Lin} and Hee, {Siow Wey} and Chang, {Chi Fon} and Yen, {Hsin Yung} and Chen, {Yi An} and Chen, {Yet Ran} and Chou, {Ya Wen} and Li, {Fu An} and Ke, {Yi Yu} and Chen, {Shih Yi} and Hung, {Ming Shiu} and Hung, {Alfur Fu Hsin} and Huang, {Jing Yong} and Chiu, {Chu Hsuan} and Lin, {Shih Yao} and Shih, {Sheue Fang} and Hsu, {Chih Neng} and Hwang, {Juey Jen} and Yeh, {Teng Kuang} and Cheng, {Ting Jen Rachel} and Liao, {Karen Chia Wen} and Daniel Laio and Lin, {Shu Wha} and Chen, {Tzu Yu} and Hu, {Chun Mei} and Ulla Vogel and Daniel Saar and Kragelund, {Birthe B.} and Tsou, {Lun Kelvin} and Tseng, {Yu Hua} and Chuang, {Lee Ming}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

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doi = "10.1038/s44321-025-00216-4",

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pages = "938--966",

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T1 - Identification of PTGR2 inhibitors as a new therapeutic strategy for diabetes and obesity

AU - Chang, Yi Cheng

AU - Hsieh, Meng Lun

AU - Lee, Hsiao Lin

AU - Hee, Siow Wey

AU - Chang, Chi Fon

AU - Yen, Hsin Yung

AU - Chen, Yi An

AU - Chen, Yet Ran

AU - Chou, Ya Wen

AU - Li, Fu An

AU - Ke, Yi Yu

AU - Chen, Shih Yi

AU - Hung, Ming Shiu

AU - Hung, Alfur Fu Hsin

AU - Huang, Jing Yong

AU - Chiu, Chu Hsuan

AU - Lin, Shih Yao

AU - Shih, Sheue Fang

AU - Hsu, Chih Neng

AU - Hwang, Juey Jen

AU - Yeh, Teng Kuang

AU - Cheng, Ting Jen Rachel

AU - Liao, Karen Chia Wen

AU - Laio, Daniel

AU - Lin, Shu Wha

AU - Chen, Tzu Yu

AU - Hu, Chun Mei

AU - Vogel, Ulla

AU - Saar, Daniel

AU - Kragelund, Birthe B.

AU - Tsou, Lun Kelvin

AU - Tseng, Yu Hua

AU - Chuang, Lee Ming

PY - 2025

Y1 - 2025

N2 - 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.

AB - 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.

KW - 15-keto-PGE2

KW - Diabetes

KW - Obesity

KW - PPARγ

KW - PTGR2

U2 - 10.1038/s44321-025-00216-4

DO - 10.1038/s44321-025-00216-4

M3 - Journal article

C2 - 40119175

AN - SCOPUS:105000556051

SN - 1757-4676

VL - 17

SP - 938

EP - 966

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 5

M1 - 116095

ER -