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

Publication date: Available online 31 January 2020Source: Pharmacological ResearchAuthor(s): Zheng Li, Chunxia Liu, Zongtao Zhou, Lijun Hu, Liming Deng, Qiang Ren, Hai QianAbstractIn 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.Graphical AbstractThe in vitro, in vivo and modeling studies of CPU025 were explored in this study. Chronic treatment with CPU025 revealed greater benefits on glycemic...
Source: Pharmacological Research - Category: Drugs & Pharmacology Source Type: research