Chronic diazoxide treatment decreases fat mass and improves endurance capacity in an obese mouse model of Prader-Willi syndrome

Excess fat mass is a cardinal feature of Prader-Willi syndrome (PWS) that is recapitulated in the Magel2-null mouse model of this genetic disorder. There is a pressing need for drugs that can prevent or treat obesity in children with PWS. Recently, a clinical study of a controlled release form of the benzothiadiazine derivative diazoxide demonstrated improved metabolic parameters and decreased fat mass in obesechildren and adults with PWS. We tested whether chronic diazoxide administration can reduce fat mass and improve metabolism in mice lacking MAGEL2, a gene inactivated in PWS. Magel2-null and wild-type control mice were rendered obese by high fat diet feeding, then provided diazoxide while being maintained on a high fat diet. Treatment of obese mice with diazoxide reduced weight and body fat, lowered blood glucose and improved endurance capacity. Treatment with diazoxide partially normalizes obesity in children and adults with PWS and in a PWS mouse model, demonstrating that the biological pathways impacted by diazoxide may be rational pharmacological targets in PWS and other disorders diseases associated with obesity.