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

Area of Science:

• Metabolic research
• Pharmacology
• Obesity therapeutics

Background:

• Current glucagon-like peptide-1 (GLP-1) therapies for obesity face limitations including side effects and common weight regain post-treatment.
• Novel therapeutic strategies targeting different mechanisms are essential for achieving sustained weight loss.
• Human MOGAT2, a regulator of triglyceride metabolism, presents a promising target for obesity treatment, as its inhibition has demonstrated weight reduction in obese individuals.

Purpose of the Study:

• To evaluate the therapeutic potential of VB-85387, a novel MOGAT2 inhibitor, for managing obesity and promoting weight loss.
• To investigate the effects of VB-85387 on metabolic parameters, including body weight, food intake, and glucose homeostasis.

Main Methods:

• High-throughput screening was employed to identify potent and selective human MOGAT2 inhibitors.
• Diet-induced obese mice were administered VB-85387 for seven days to assess its effects on body weight and food intake.
• Metabolic and hormonal profiles, including liver lipids, glucose tolerance, and insulin sensitivity, were evaluated. Gene expression analysis of key metabolic regulators (PPARα and SREBP) was performed using qRT-PCR.

Main Results:

• VB-85387 was identified as a highly potent and selective inhibitor of human MOGAT2.
• Treatment with VB-85387 resulted in significant weight loss, reduced food intake, improved glucose tolerance, and enhanced insulin sensitivity in obese mice.
• VB-85387 treatment led to decreased liver triglyceride levels, increased GLP-1 concentrations, elevated β-hydroxybutyrate, increased PPARα-dependent gene expression, and reduced SREBP-dependent gene expression.

Conclusions:

• VB-85387 demonstrates significant potential as a therapeutic agent for obesity, warranting further investigation and lead optimization.
• The observed weight loss effects are potentially mediated by the activation of PPARα and sustained increases in GLP-1 levels.