National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, No. 1 Beichen West Road, Chaoyang District, Beijing 100101, China.
Sci Transl Med. 2019 Apr 17;11(488). doi: 10.1126/scitranslmed.aau7116.
Recent studies have established the involvement of the fat mass and obesity-associated gene () in metabolic disorders such as obesity and diabetes. However, the precise molecular mechanism by which FTO regulates metabolism remains unknown. Here, we used a structure-based virtual screening of U.S. Food and Drug Administration-approved drugs to identify entacapone as a potential FTO inhibitor. Using structural and biochemical studies, we showed that entacapone directly bound to FTO and inhibited FTO activity in vitro. Furthermore, entacapone administration reduced body weight and lowered fasting blood glucose concentrations in diet-induced obese mice. We identified the transcription factor forkhead box protein O1 () mRNA as a direct substrate of FTO, and demonstrated that entacapone elicited its effects on gluconeogenesis in the liver and thermogenesis in adipose tissues in mice by acting on an regulatory axis.
最近的研究已经确定了脂肪量和肥胖相关基因（）在代谢紊乱中的作用，如肥胖和糖尿病。然而，FTO 调节代谢的确切分子机制尚不清楚。在这里，我们使用基于结构的美国食品和药物管理局批准药物的虚拟筛选，鉴定出恩他卡朋是 FTO 的潜在抑制剂。通过结构和生化研究，我们表明恩他卡朋直接与 FTO 结合，并在体外抑制 FTO 活性。此外，恩他卡朋给药可降低饮食诱导肥胖小鼠的体重和空腹血糖浓度。我们确定了叉头框蛋白 O1 () mRNA 作为 FTO 的直接底物，并证明恩他卡朋通过作用于调节轴，在小鼠的肝脏中影响糖异生和脂肪组织中的产热，从而发挥其作用。
