Elucidating the mechanisms by which disulfiram protects against obesity and metabolic syndrome
Michel Bernier, Dylan Harney, Yen Chin Koay, Antonio Díaz, Abhishek K. Singh, Devin Wahl, Tamara Pulpitel, Ahmed Ali, Vince Guiterrez, Sarah J. Mitchell, Eun Young Kim, John Mach, Nathan L. Price, Miguel A. Aon, David G. Le Couteur, Victoria C. Cogger, Carlos Fernández‐Hernando, John O’Sullivan, Mark Larance, Ana María Cuervo, Rafael de Cabo
Abstract
There is an unmet need and urgency to find safe and effective anti-obesity interventions. Our recent study in mice fed on obesogenic diet found that treatment with the alcohol aversive drug disulfiram reduced feeding efficiency and led to a decrease in body weight and an increase in energy expenditure. The intervention with disulfiram improved glucose tolerance and insulin sensitivity, and mitigated metabolic dysfunctions in various organs through poorly defined mechanisms. Here, integrated analysis of transcriptomic and proteomic data from mouse and rat livers unveiled comparable signatures in response to disulfiram, revealing pathways associated with lipid and energy metabolism, redox, and detoxification. In cell culture, disulfiram was found to be a potent activator of autophagy, the malfunctioning of which has negative consequences on metabolic regulation. Thus, repurposing disulfiram may represent a potent strategy to combat obesity.