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A negative feedback loop between TET2 and leptin in adipocyte regulates body weight

Author

Listed:
  • Qin Zeng

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Jianfeng Song

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Xiaoxiao Sun

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Dandan Wang

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Xiyan Liao

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Yujin Ding

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Wanyu Hu

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Yayi Jiao

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Wuqian Mai

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Wufuer Aini

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Fanqi Wang

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Hui Zhou

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Limin Xie

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Ying Mei

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Yuan Tang

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Zhiguo Xie

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

  • Haijing Wu

    (The Second Xiangya Hospital of Central South University)

  • Wei Liu

    (The Second Xiangya Hospital of Central South University)

  • Tuo Deng

    (The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University
    The Second Xiangya Hospital of Central South University)

Abstract

Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2 in adipocytes during obesity are poorly understood. In this study, we demonstrate that leptin, a key adipokine in mammalian energy homeostasis regulation, suppresses adipocyte TET2 levels via JAK2-STAT3 signaling. Adipocyte Tet2 deficiency protects against high-fat diet-induced weight gain by reducing leptin levels and further improving leptin sensitivity in obese male mice. By interacting with C/EBPα, adipocyte TET2 increases the hydroxymethylcytosine levels of the leptin gene promoter, thereby promoting leptin gene expression. A decrease in adipose TET2 is associated with obesity-related hyperleptinemia in humans. Inhibition of TET2 suppresses the production of leptin in mature human adipocytes. Our findings support the existence of a negative feedback loop between TET2 and leptin in adipocytes and reveal a compensatory mechanism for the body to counteract the metabolic dysfunction caused by obesity.

Suggested Citation

  • Qin Zeng & Jianfeng Song & Xiaoxiao Sun & Dandan Wang & Xiyan Liao & Yujin Ding & Wanyu Hu & Yayi Jiao & Wuqian Mai & Wufuer Aini & Fanqi Wang & Hui Zhou & Limin Xie & Ying Mei & Yuan Tang & Zhiguo Xi, 2024. "A negative feedback loop between TET2 and leptin in adipocyte regulates body weight," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46783-x
    DOI: 10.1038/s41467-024-46783-x
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    References listed on IDEAS

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    1. Carl T. Montague & I. Sadaf Farooqi & Jonathan P. Whitehead & Maria A. Soos & Harald Rau & Nicholas J. Wareham & Ciaran P. Sewter & Janet E. Digby & Shehla N. Mohammed & Jane A. Hurst & Christopher H., 1997. "Congenital leptin deficiency is associated with severe early-onset obesity in humans," Nature, Nature, vol. 387(6636), pages 903-908, June.
    2. Simone Wahl & Alexander Drong & Benjamin Lehne & Marie Loh & William R. Scott & Sonja Kunze & Pei-Chien Tsai & Janina S. Ried & Weihua Zhang & Youwen Yang & Sili Tan & Giovanni Fiorito & Lude Franke &, 2017. "Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity," Nature, Nature, vol. 541(7635), pages 81-86, January.
    3. Jeffrey M. Friedman & Jeffrey L. Halaas, 1998. "Leptin and the regulation of body weight in mammals," Nature, Nature, vol. 395(6704), pages 763-770, October.
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