Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1
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. F...
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| Published in | Science translational medicine Vol. 11; no. 488 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
17.04.2019
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| Subjects | |
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| Abstract | 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. |
|---|---|
| AbstractList | 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. |
| Author | Wang, Fengchao Wang, Yanli Zhang, Zhiyuan Huang, Song Wang, Hailin Zhao, Haijiao Zhao, Yong-Liang Nie, Yongzhan Cai, Tao Gao, Chunchun Huang, Huanwei Lai, Weiyi Sun, Baofa Ma, Yongfen Zhang, Wei Wang, Yankai Yang, Yun-Gui Cao, Ran Ma, Zhixiong Xiao, Wen Hou, Nannan Zhi, Gang Huang, Niu Zhang, Song Zhang, Eric Erquan Ju, Dapeng Liu, Qianlan Zhao, Liping Li, Pengfei Peng, Shiming |
| Author_xml | – sequence: 1 givenname: Shiming orcidid: 0000-0001-5830-243X surname: Peng fullname: Peng, Shiming organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 2 givenname: Wen orcidid: 0000-0001-6559-3036 surname: Xiao fullname: Xiao, Wen organization: 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 – sequence: 3 givenname: Dapeng orcidid: 0000-0003-1798-1362 surname: Ju fullname: Ju, Dapeng organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 4 givenname: Baofa surname: Sun fullname: Sun, Baofa organization: Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China – sequence: 5 givenname: Nannan orcidid: 0000-0002-2387-024X surname: Hou fullname: Hou, Nannan organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 6 givenname: Qianlan surname: Liu fullname: Liu, Qianlan organization: University of Chinese Academy of Sciences, Beijing 100049, China – sequence: 7 givenname: Yanli surname: Wang fullname: Wang, Yanli organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 8 givenname: Haijiao orcidid: 0000-0002-3281-7985 surname: Zhao fullname: Zhao, Haijiao organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 9 givenname: Chunchun surname: Gao fullname: Gao, Chunchun organization: University of Chinese Academy of Sciences, Beijing 100049, China – sequence: 10 givenname: Song surname: Zhang fullname: Zhang, Song organization: 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 – sequence: 11 givenname: Ran surname: Cao fullname: Cao, Ran organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 12 givenname: Pengfei surname: Li fullname: Li, Pengfei organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 13 givenname: Huanwei surname: Huang fullname: Huang, Huanwei organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 14 givenname: Yongfen orcidid: 0000-0003-1282-9142 surname: Ma fullname: Ma, Yongfen organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 15 givenname: Yankai surname: Wang fullname: Wang, Yankai organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 16 givenname: Weiyi orcidid: 0000-0002-8010-2490 surname: Lai fullname: Lai, Weiyi organization: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China – sequence: 17 givenname: Zhixiong surname: Ma fullname: Ma, Zhixiong organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 18 givenname: Wei surname: Zhang fullname: Zhang, Wei organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 19 givenname: Song surname: Huang fullname: Huang, Song organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 20 givenname: Hailin surname: Wang fullname: Wang, Hailin organization: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China – sequence: 21 givenname: Zhiyuan orcidid: 0000-0002-2910-1986 surname: Zhang fullname: Zhang, Zhiyuan organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 22 givenname: Liping surname: Zhao fullname: Zhao, Liping organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 23 givenname: Tao surname: Cai fullname: Cai, Tao organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 24 givenname: Yong-Liang surname: Zhao fullname: Zhao, Yong-Liang organization: University of Chinese Academy of Sciences, Beijing 100049, China – sequence: 25 givenname: Fengchao surname: Wang fullname: Wang, Fengchao organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 26 givenname: Yongzhan surname: Nie fullname: Nie, Yongzhan organization: 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 – sequence: 27 givenname: Gang surname: Zhi fullname: Zhi, Gang organization: National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China – sequence: 28 givenname: Yun-Gui surname: Yang fullname: Yang, Yun-Gui email: ygyang@big.ac.cn, zhangerquan@nibs.ac.cn, huangniu@nibs.ac.cn organization: Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China – sequence: 29 givenname: Eric Erquan orcidid: 0000-0002-4472-7493 surname: Zhang fullname: Zhang, Eric Erquan email: ygyang@big.ac.cn, zhangerquan@nibs.ac.cn, huangniu@nibs.ac.cn organization: Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China – sequence: 30 givenname: Niu orcidid: 0000-0002-6912-033X surname: Huang fullname: Huang, Niu email: ygyang@big.ac.cn, zhangerquan@nibs.ac.cn, huangniu@nibs.ac.cn organization: Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30996080$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Animals Blood Glucose - drug effects Body Weight - drug effects Body Weight - physiology Catechol O-Methyltransferase - genetics Catechol O-Methyltransferase - metabolism Catechols - pharmacology Enzyme Inhibitors - pharmacology Forkhead Box Protein O1 - genetics Forkhead Box Protein O1 - metabolism Humans Mice Nitriles - pharmacology RNA, Messenger - genetics RNA, Messenger - metabolism Thermogenesis - drug effects Thermogenesis - genetics Thermogenesis - physiology |
| Title | Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1 |
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