Development of New Anti-Diabetic Therapies by Increasing Endogenous Ppar
<sub>γ</sub> Ligands

Peroxisome proliferator-activated receptor γ (PPARγ) is a master transcriptional regulator of systemic insulin sensitivity and energy balance. The anti-diabetic drug thiazolidinediones are potent synthetic PPARγ ligands with undesirable side effects, including increased adiposity and fluid retention, which limits their use. In this study, we discovered that 15-keto-PGE 2 is an endogenous natural PPARγ ligand catalyzed by prostaglandin reductase 2 (PTGR2) to inactive metabolites. We demonstrated that 15-keto-PGE 2 activates PPARγ through covalent binding to its cysteine 285 residue at helix 3, different from the binding mode of thiazolidinediones. Serum 15-keto-PGE 2 levels were reduced in patients with type 2 diabetes and inversely correlated with insulin resistance in non-diabetic humans. Administration of 15-keto-PGE 2 improved insulin sensitivity, glucose tolerance, and diet-induced obesity in mice. Conversely, Ptgr2 knockout mice were protected from diet-induced obesity, insulin resistance, and hepatic steatosis without fluid retention. Using a high-throughput screen, we identified a small-molecule PTGR2 inhibitor BPRPT0245, which effectively improved insulin sensitivity and outperformed pioglitazone in reducing glucose intolerance and diet-induced obesity hepatic steatosis. In conclusion, we discovered a new therapeutic approach to improve insulin sensitivity and protect diet-induced obesity through increasing endogenous natural PPARγ ligands without evident side effects of thiazolidinediones.

Keywords: 15-keto-PGE2 is an endogenous PPARg ligands through covalent binding to the cysteine 285 residue, 15-keto-PGE2 level is reduced in insulin-resistant and obese subjects, Direct administration of 15-keto-PGE2 markedly improves insulin resistance and glucose intolerance, Either genetic or chemical inhibition of PTGR2, an enzyme degrading 15-keto-PGE2, improve insulin resistance, glucose intolerance, hepatic steatosis, and prevent diet-induced obesity in mice

Suggested Citation: Suggested Citation

Chang, Yi-Cheng and Hsieh, Meng-Lun and Tsou, Lun Kelvin and Chen, Shih-Yi and Ke, Yi-Yu and Hung, Ming-Shiu and Hee, Siow-Wey and Lee, Hsiao-Lin and Nong, Jiun-Yi and Hung, Fu-Hsin and Huang, Jing-Yong and Kao, Fang-Chi and Liao, Karen Chia-Wen and Chiu, Chu-Hsuan and Lin, Shih-Yao and Liu, Bi-Yu and Tai, Chi-Ming and Li, Fu-An and Chen, Yet-Ran and Chou, Ya-Wen and Cheng, Jamie and Shih, Yvonne and Hsu, Chih-Neng and Hwang, Juey-Jen and Yeh, Teng-Kuang and Cheng, Ting-Jen Rachel and Chen, Tzu-Yu and Chen, Chung-Ming and Lin, Shu-Wha and Tseng, Yu-Hua and Chuang, Lee-Ming, Development of New Anti-Diabetic Therapies by Increasing Endogenous Ppar _γ Ligands. Available at SSRN: https://ssrn.com/abstract=4029063

This version of the paper has not been formally peer reviewed.