Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.
Mol Genet Metab. 2018 Apr;123(4):511-517. doi: 10.1016/j.ymgme.2018.02.018. Epub 2018 Feb 27.
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 obese children 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.
肥胖是 Prader-Willi 综合征（PWS）的一个主要特征，在该遗传疾病的 Magel2 基因缺失小鼠模型中得到了再现。目前迫切需要能够预防或治疗 PWS 患儿肥胖的药物。最近，一项苯并噻二嗪衍生物二氮嗪控释制剂的临床研究表明，该药物可改善肥胖的 PWS 儿童和成人的代谢参数，并减少脂肪量。我们测试了慢性二氮嗪给药是否可以减少缺乏 MAGEL2 的小鼠（PWS 中失活的基因）的脂肪量并改善其代谢。通过高脂肪饮食喂养使 Magel2 基因缺失和野生型对照小鼠肥胖，然后在高脂肪饮食的同时给予二氮嗪。用二氮嗪治疗肥胖小鼠可减轻体重和体脂肪，降低血糖并提高耐力。二氮嗪治疗可部分纠正 PWS 儿童和成人以及 PWS 小鼠模型中的肥胖症，表明二氮嗪影响的生物学途径可能是 PWS 及其他与肥胖相关的疾病的合理药物靶点。
