The Human Monoacylglycerol Acyltransferase 2 Inhibitor VB‐85387 Is Associated With Weight Loss in Mice With Obesity

ABSTRACT Background GLP‐1 therapies for obesity are limited by side effects and weight regain is common after treatment ends. Therefore, alternative treatments with new mechanisms are needed for sustained weight loss. Human MOGAT2 regulates triglyceride metabolism and its inhibition reduces weight in people with obesity, making MOGAT2 a promising target for obesity therapy. Objective This study evaluated the therapeutic potential of the VB‐85387 MOGAT2 inhibitor for weight loss. Methods High throughput screening was used to identify human MOGAT2 inhibitors. Diet‐induced mice with obesity were treated with VB‐85387 for 7 days. Body weight, food intake, blood and liver lipid and hormone levels were assessed. Glucose tolerance and insulin sensitivity were evaluated via oral glucose tolerance and hyperinsulaemic‐euglycaemic clamp tests. Gene expression of PPARα and SREBP target genes was measured using q RT‐PCR. Results High throughput screening identified VB‐85387 as a highly potent and selective human MOGAT2 inhibitor. Mice with obesity treated with VB‐85387 experienced weight loss, reduced food intake, improved glucose tolerance, and enhanced insulin sensitivity. Treatment decreased liver triglyceride levels and increased GLP‐1 concentrations. β ‐hydroxybutyrate levels were elevated, PPARα‐dependent fatty acid β ‐oxidation gene expression was increased, and SREBP‐dependent gene expression was reduced. Conclusion VB‐85387 serves as a starting point for medicinal chemistry lead optimization. Weight loss may be attributed to PPARα activation and a sustained elevation in GLP‐1 levels.