Long-term disulfiram supplementation activates an anti-inflammatory metabolic network to lower diet-induced obesity and related co-morbidities

According to the WHO, the obesity epidemic has become a global and grave public health concern. A small molecule to safely prevent and/or treat the negative pathophysiological consequences of obesity is urgently needed. We conducted long-term supplementation of the FDA-approved anti-inflammatory drug disulfiram (DSF, Antabuse®) in mice fed standard and high-fat diet (HFD), and measured various indicators of health in the animals. Our results uncover an abrogation of the adverse impact of HFD on insulin responsiveness and metabolic fitness through improvements in pancreatic islet morphology and b-cell function along with reduced occurrence of liver injury and cardiovascular remodeling, plausibly by its autophagy activating effect. Additionally, the treatment of obese mice with DSF robustly reversed diet-induced metabolic dysfunctions. These results show that the repurposing of DSF may represent a new strategy to combat obesity and associated metabolic disorders in human. The effect of disulfiram (DSF) was assessed in 14-week-old male C57BL/6J mice fed either a standard diet (SD) or high-fat diet (HFD) supplemented with a low (100 mg/kg/day) or high dose (200 mg/kg/day) of DSF for periods up to 41 weeks, and RNA isolated from livers were used for transcriptomic analyses (N=5/group in six different treatment groups for a total of 30 animals).