Dysregulation of fatty acid metabolism contributes to obesity and cardiometabolic diseases. Malonyl-CoA decarboxylase (MLYCD), which regulates fatty acid oxidation by controlling malonyl-CoA levels, is a promising therapeutic target. Using high-throughput virtual screening of FDA-approved drugs against MLYCD (PDB ID: 2YGW), we identified indacaterol, a β₂-adrenergic receptor agonist, as a novel MLYCD inhibitor. In 3T3-L1 adipocytes, indacaterol reduced lipid accumulation, enhanced glycolysis, and shifted metabolism from fatty acid to glucose oxidation. In obese mice, daily subcutaneous indacaterol (5 mg/kg) decreased body weight, fat mass, and food intake while preserving lean mass, outperforming Semaglutide. Indacaterol improved glucose clearance, increased metabolic rate, and activated brown adipose thermogenesis. These effects were independent of β-adrenergic signaling, confirmed in β₁β₂-AR⁻/⁻ mice and propranolol-treated models. Liver transcriptomic and metabolomic analyses showed reduced fatty acid oxidation, increased glucose metabolism, and elevated malonyl-CoA and TCA intermediates. Indacaterol thus emerges as a safe, repurposed drug for metabolic reprogramming in obesity.
Learning Objectives:
By the end of this presentation, participants will be able to:
Explain the role of malonyl-CoA decarboxylase (MLYCD) in regulating fatty acid oxidation and energy metabolism.
Describe the process of identifying Indacaterol as a potential MLYCD inhibitor through high-throughput virtual screening of FDA-approved drugs.
Evaluate the metabolic effects of Indacaterol in preclinical models, including impacts on lipid accumulation, glucose oxidation, energy expenditure, and thermogenesis.
Discuss the significance of transcriptomic and metabolomic findings that reveal Indacaterol’s mechanism of action independent of β2-adrenergic receptor signaling.
Assess the translational potential of repurposing Indacaterol as a novel anti-obesity therapeutic based on pharmacological and safety data.
