1. Biochemistry and Chemical Biology
  2. Medicine
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The hepatic AMPK-TET1-SIRT1 axis regulates glucose homeostasis

  1. Chunbo Zhang
  2. Tianyu Zhong
  3. Yuanyuan Li
  4. Xianfeng Li
  5. Xiaopeng Yuan
  6. Linlin Liu
  7. Weilin Wu
  8. Jing Wu
  9. Ye Wu
  10. Rui Liang
  11. Xinhua Xie
  12. Chuanchuan Kang
  13. Yuwen Liu
  14. Zhonghong Lai
  15. Jianbo Xiao
  16. Zhixian Tang
  17. Riqun Jin
  18. Yan Wang
  19. Yongwei Xiao
  20. Jin Zhang
  21. Jian Li  Is a corresponding author
  22. Qian Liu  Is a corresponding author
  23. Zhongsheng Sun  Is a corresponding author
  24. Jianing Zhong  Is a corresponding author
  1. Nanchang University, China
  2. Gannan Medical University, China
  3. Beijing Institutes of Life Science, Chinese Academy of Sciences, China
  4. First Affiliated Hospital of Gannan Medical University, China
  5. Xiamen University, China
  6. School of Basic Medical Sciences, Nanchang University, China
Research Article
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Cite this article as: eLife 2021;10:e70672 doi: 10.7554/eLife.70672

Abstract

Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) is involved in multiple biological functions in cell development, differentiation, and transcriptional regulation. Tet1 deficient mice display the defects of murine glucose metabolism. However, the role of TET1 in metabolic homeostasis keeps unknown. Here, our finding demonstrates that hepatic TET1 physically interacts with SIRT1 via its C-terminal and activates its deacetylase activity, further regulating the acetylation-dependent cellular trans-localization of transcriptional factors PGC-1a and FOXO1, resulting in the activation of hepatic gluconeogenic gene expression that includes PPARGC1A, G6PC, and SLC2A4. Importantly, the hepatic gluconeogenic gene activation program induced by fasting is inhibited in Tet1 heterozygous mice livers. The AMPK activators metformin or AICAR-two compounds that mimic fasting-elevate hepatic gluconeogenic gene expression dependent on in turn activation of the AMPK-TET1-SIRT1 axis. Collectively, our study identifies TET1 as a SIRT1 coactivator and demonstrates that the AMPK-TET1-SIRT1 axis represents a potential mechanism or therapeutic target for glucose metabolism or metabolic diseases.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Chunbo Zhang

    Nanchang University, Nanchang, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9618-9415
  2. Tianyu Zhong

    Gannan Medical University, Ganzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Yuanyuan Li

    Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Xianfeng Li

    Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Xiaopeng Yuan

    Nanchang University, Nanchang, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Linlin Liu

    First Affiliated Hospital of Gannan Medical University, Ganzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Weilin Wu

    Gannan Medical University, Ganzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Jing Wu

    Gannan Medical University, Ganzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Ye Wu

    Nanchang University, Nanchang, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Rui Liang

    Xiamen University, Xiamen, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Xinhua Xie

    Gannan Medical University, Ganzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Chuanchuan Kang

    First Affiliated Hospital of Gannan Medical University, Ganzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Yuwen Liu

    Gannan Medical University, Ganzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Zhonghong Lai

    Gannan Medical University, Ganzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Jianbo Xiao

    Gannan Medical University, Ganzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  16. Zhixian Tang

    First Affiliated Hospital of Gannan Medical University, Ganzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  17. Riqun Jin

    First Affiliated Hospital of Gannan Medical University, Ganzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  18. Yan Wang

    Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  19. Yongwei Xiao

    Gannan Medical University, Ganzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  20. Jin Zhang

    School of Basic Medical Sciences, Nanchang University, Nanchang, China
    Competing interests
    The authors declare that no competing interests exist.
  21. Jian Li

    Xiamen University, Xiamen, China
    For correspondence
    jianli_204@xmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  22. Qian Liu

    Gannan Medical University, Ganzhou, China
    For correspondence
    liuqiangmu2017@126.com
    Competing interests
    The authors declare that no competing interests exist.
  23. Zhongsheng Sun

    Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
    For correspondence
    sunzs@biols.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
  24. Jianing Zhong

    Gannan Medical University, Ganzhou, China
    For correspondence
    zhongning_003@163.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2781-3437

Funding

National Natural Science Foundation of China (81760160)

  • Jianing Zhong

Startup Fund for Scholars of Gannan Medical University (QD201605)

  • Jianing Zhong

Innovative Team of Gannan Medical University (TD201708)

  • Jianing Zhong

The Open Project of Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education (XN201807)

  • Jianing Zhong

JiangXi Provincial Natural Science Foundation (20202BAB206086)

  • Jianing Zhong

JiangXi Provincial Natural Science Foundation (20171ACB21001)

  • Chunbo Zhang

JiangXi Provincial Natural Science Foundation (20171BCB23029)

  • Chunbo Zhang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experiments were conducted in accordance with an approved protocol by the Institutional Animal Care and Ethics Committee of Xiamen University and Nanchang University.

Reviewing Editor

  1. Matthew A Quinn, Wake Forest School of Medicine, United States

Publication history

  1. Received: May 25, 2021
  2. Accepted: November 4, 2021
  3. Accepted Manuscript published: November 5, 2021 (version 1)
  4. Version of Record published: November 15, 2021 (version 2)
  5. Version of Record updated: November 19, 2021 (version 3)

Copyright

© 2021, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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