2. Academic Validation
  3. A novel FFA1 agonist, CPU025, improves glucose-lipid metabolism and alleviates fatty liver in obese-diabetic (ob/ob) mice

A novel FFA1 agonist, CPU025, improves glucose-lipid metabolism and alleviates fatty liver in obese-diabetic (ob/ob) mice

  • Pharmacol Res. 2020 Mar;153:104679. doi: 10.1016/j.phrs.2020.104679.
Zheng Li 1,  Chunxia Liu 2,  Zongtao Zhou 3,  Lijun Hu 3,  Liming Deng 3,  Qiang Ren 3,  Hai Qian 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China. Electronic address: li.zheng.sky@163.com.
  • 2 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 3 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
  • 4 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: qianhai24@163.com.
PMID: 32014571 DOI: 10.1016/j.phrs.2020.104679
Abstract

In the effort to identify anti-diabetic drug, we discovered a novel Free Fatty Acid Receptor 1 (FFA1) agonist CPU025, which is structurally different from previously reported FFA1 agonists. The present study revealed CPU025 is a potent FFA1 agonist (EC50 = 38.7 nM) with moderate agonistic activity on PPARδ (EC50 = 625.6 nM), and promotes Insulin secretion at a glucose-dependent manner. Modeling study also illuminated CPU025 forms interaction with key residues closely related to the agonistic effects of FFA1 and PPARδ. Long-term treatment of CPU025 exerted better glycemic control and lipid profile than TAK-875, the most advanced FFA1 partial agonist in this field. Moreover, CPU025 improved β-cell function and alleviated fatty liver in ob/ob mice. Further study suggested CPU025 could alleviate fatty liver through regulating the expression of genes involved in fatty acid β-oxidation, lipoprotein lipolysis, lipid synthesis, oxidative stress and mitochondrial function. These results indicate that long-term treatment of CPU025 improves glucose and lipid metabolism, and may be useful for the treatment of diabetes mellitus and fatty liver.

Keywords

Diabetes; FFA1; Fatty liver; Nsulin secretion; PPAR.

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