PBI-4547 Improves Glucose Metabolism and Insulin Resistance, and Reduces Liver Damage in a High-Fat Diet Mouse Model of Obesity and Metabolic Syndrome

Introduction and Aims: Obesity and its resulting metabolic disturbances are major health threats and are the main cause of a host of diseases, including nonalcoholic fatty liver disease (NAFLD). PBI-4547 is a novel first-in-class orally active antidiabetic compound which displays pleiotropic activities and has been shown to reduce NASH, diabetes, and renal fibrosis in different animal models. The aim of this study was to investigate the effects of PBI-4547 in a mouse model of high-fat diet-induced obesity and metabolic syndrome. Methods: C57BL/6 mice were fed with either a standard or a high-fat diet (HFD, Harlan, TD.06414) for 14 weeks. These mice were divided in three groups [normal chow, HFD + vehicle, and HFD + PBI-4547 (10 mg/kg, oral once a day)] and treated for an additional 6 weeks. Blood glucose, serum insulin level, serum triglyceride and adiponectin, liver histology, as well as liver and white adipose tissue (WAT) pro-inflammatory/fibrotic gene expression were examined. Results: In an oral glucose tolerance test, PBI-4547 increased glucose metabolism compared to the HFD control group. Insulin resistance (measured by HOMA-IR) and β cell function (HOMA1-β) were improved by PBI-4547. Serum triglyceride level was significantly reduced by PBI-4547 while adiponectin in serum was significantly increased. Histological analysis showed a significant reduction of hepatic steatosis and ballooning by PBI-4547. To further characterize the activity of PBI-4547, quantitative RT-PCR analysis of pro-fibrotic markers was performed, demonstrating that PBI-4547 reduced CTGF and MMP2 gene expression in the liver as well as CTGF, MCP-1, MMP2 and collagen type I gene expression in the WAT. Conclusions: Taken together, these results suggest that PBI-4547 offers the potential as a novel therapy for nonalcoholic fatty liver disease, obesity and associated metabolic syndrome.