2. Academic Validation
  3. Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1

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

  • Sci Transl Med. 2019 Apr 17;11(488):eaau7116. doi: 10.1126/scitranslmed.aau7116.
Shiming Peng 1,  Wen Xiao 2,  Dapeng Ju 1,  Baofa Sun 2 3 4,  Nannan Hou 1,  Qianlan Liu 2 3,  Yanli Wang 1,  Haijiao Zhao 1,  Chunchun Gao 2 3,  Song Zhang 5,  Ran Cao 1,  Pengfei Li 1,  Huanwei Huang 1,  Yongfen Ma 1,  Yankai Wang 1,  Weiyi Lai 6,  Zhixiong Ma 1,  Wei Zhang 1,  Song Huang 1,  Hailin Wang 6,  Zhiyuan Zhang 1,  Liping Zhao 1,  Tao Cai 1,  Yong-Liang Zhao 2 3,  Fengchao Wang 1,  Yongzhan Nie 5,  Gang Zhi 1,  Yun-Gui Yang 7 3 4,  Eric Erquan Zhang 8 9,  Niu Huang 8 9
Affiliations

Affiliations

  • 1 National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
  • 2 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.
  • 3 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
  • 5 State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, Shaanxi 710032, China.
  • 6 State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
  • 7 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. ygyang@big.ac.cn zhangerquan@nibs.ac.cn huangniu@nibs.ac.cn.
  • 8 National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China. ygyang@big.ac.cn zhangerquan@nibs.ac.cn huangniu@nibs.ac.cn.
  • 9 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China.
PMID: 30996080 DOI: 10.1126/scitranslmed.aau7116
Abstract

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.

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