Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1

被引：259

作者：

Peng, Shiming ^{[1
]}

Xiao, Wen ^{[2
]}

Ju, Dapeng ^{[1
]}

Sun, Baofa ^{[2
,3
,4
]}

Hou, Nannan ^{[1
]}

Liu, Qianlan ^{[2
,3
]}

Wang, Yanli ^{[1
]}

Zhao, Haijiao ^{[1
]}

Gao, Chunchun ^{[2
,3
]}

Zhang, Song ^{[5
,6
]}

Cao, Ran ^{[1
]}

Li, Pengfei ^{[1
]}

Huang, Huanwei ^{[1
]}

Ma, Yongfen ^{[1
]}

Wang, Yankai ^{[1
]}

Lai, Weiyi ^{[7
]}

Ma, Zhixiong ^{[1
]}

Zhang, Wei ^{[1
]}

Huang, Song ^{[1
]}

Wang, Hailin ^{[7
]}

Zhang, Zhiyuan ^{[1
]}

Zhao, Liping ^{[1
]}

Cai, Tao ^{[1
]}

Zhao, Yong-Liang ^{[2
,3
]}

Wang, Fengchao ^{[1
]}

Nie, Yongzhan ^{[5
,6
]}

Zhi, Gang ^{[1
]}

Yang, Yun-Gui ^{[2
,3
,4
]}

Zhang, Eric Erquan ^{[1
,8
]}

Huang, Niu ^{[1
,8
]}

机构：

[1] Natl Inst Biol Sci, 7 Sci Pk Rd,Zhongguancun Life Sci Pk, Beijing 102206, Peoples R China

[2] Chinese Acad Sci, Key Lab Genom & Precis Med, Beijing Inst Genom, 1 Beichen West Rd, Beijing 100101, Peoples R China

[3] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[4] Chinese Acad Sci, Inst Stem Cell & Regenerat, Beijing 100101, Peoples R China

[5] Fourth Mil Med Univ, State Key Lab Canc Biol, 127 West Changle Rd, Xian 710032, Shaanxi, Peoples R China

[6] Fourth Mil Med Univ, Xijing Hosp Digest Dis, 127 West Changle Rd, Xian 710032, Shaanxi, Peoples R China

[7] Chinese Acad Sci, State Key Lab Environm Chem & Ecotoxicol, Res Ctr Ecoenvironm Sci, Beijing 100085, Peoples R China

[8] Tsinghua Univ, Tsinghua Inst Multidisciplinary Biomed Res, Beijing 102206, Peoples R China

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2019年 / 11卷 / 488期

基金：

中国国家自然科学基金;

关键词：

MESSENGER-RNA TRANSLATION; BINDING-SITE; FAT MASS; OBESITY; GENE; BROWN; M(6)A; BEIGE; METHYLATION; ENRICHMENT;

D O I：

10.1126/scitranslmed.aau7116

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Recent studies have established the involvement of the fat mass and obesity-associated gene (FTO) 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 (FOXO1) 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 FTO-FOXO1 regulatory axis.

引用

页数：11

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