Elucidating the mechanisms by which disulfiram protects against obesity and metabolic syndrome

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.

Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis

“…This has been shown in obese mice treated with similar doses of DSF [ 25 ]. Remarkably, the authors of this latter study observed that DSF increases energy expenditure and causes weight loss [ 26 ], which may explain, at least in part, poor animal growth in our study.…”

Leveraging genetic diversity to identify small molecules that reverse mouse skeletal muscle insulin resistance

“…Disulfiram, sold under the brand name Antabuse, is used as an alcohol-dependency medication. Two studies have described disulfiram’s ability to reverse diet-induced hepatic insulin resistance and reduce adiposity (71, 72). Resveratrol, a component found in red wine, is a popular antioxidant and has been demonstrated to reverse insulin resistance via reduction of reactive oxygen species (48, 73, 74).…”

ARDD 2020: from aging mechanisms to interventions

“…Moreover, disulfiram prevents pancreatic islet hyperplasia and protects against high-fat diet-induced hepatic steatosis and fibrosis. Further experiments uncovered common molecular signatures after disulfiram treatment, revealing pathways associated with lipid and energy metabolism, redox, and detoxification and identified autophagy as one of the key targets by which disulfiram mediates its beneficial effects in cell culture [84]. The link between metabolic health and age-related bone loss was highlighted by Moustapha Kassem, Molecular Endocrinology Unit, University of Southern Denmark, Denmark, who suggested targeting skeletal mesenchymal stem cells (MSC) for the treatment of age-related osteoporosis.…”