1649-P: S-309309, a Novel MGAT2 Inhibitor, Enhances Intestinal Fatty Acid Beta Oxidation and Provides Metabolic Benefits in DIO Mice

Introduction & Objective: Pharmacological inhibition of Monoacylglycerol acyltransferase 2 (MGAT2) suppresses the food intake and the gain of body weight in high fat diet (HFD)-induced obesity (DIO) mice. However, the effects on metabolic abnormalities associated with obesity and detailed mechanisms of action remain unknown. In this study, we investigated the metabolic effects of S-309309, a novel selective MGAT2 inhibitor, in DIO mice and the involvement of energy consumption in the anti-obesity effects of S-309309.

Method: Mice were fed a HFD for 4 weeks to establish a DIO model. S-309309 (3 mg/kg, b.i.d.) was orally administered to DIO mice for 13 weeks. Daily body weight and weekly food intake were recorded until Week 4, and parameters of glucose and lipid metabolism were measured on Week 12. Additionally, under pair-feeding conditions, S-309309 (3 mg/kg, b.i.d.) was orally administered to DIO mice for 6 weeks with recording daily body weight. Energy expenditure was measured during the first 7 days of S-309309 treatment, and gene expression analysis was performed 4 days after the treatment.

Results: S-309309 suppressed food intake and body weight gain in DIO mice over the course of the study. DIO mice treated with S-309309 also showed decreases in insulin resistance index, hepatic triglycerides content, plasma alanine aminotransferase and aspartate aminotransferase level, and gene expression related to fibrosis. Furthermore, S-309309 suppressed body weight gain under pair-feeding conditions with enhanced energy expenditure and upregulation of intestinal gene expression related to long-chain fatty acid beta oxidation.

Conclusion: S-309309 enhanced beta oxidation in the intestine and increased energy expenditure in DIO mice. Also, S-309309 improved insulin sensitivity and fatty liver. Taken together, these results suggest that S-309309 may be a promising anti-obesity drug that improves metabolism with multiple mechanisms of action.