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Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance

Author

Listed:
  • A. Young Kim

    (Institute of Molecular Biology and Genetics, Seoul National University)

  • Yoon Jeong Park

    (Institute of Molecular Biology and Genetics, Seoul National University
    Seoul National University)

  • Xuebo Pan

    (State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong)

  • Kyung Cheul Shin

    (Institute of Molecular Biology and Genetics, Seoul National University
    School of Biological Sciences, Seoul National University)

  • Soo-Heon Kwak

    (Seoul National University College of Medicine)

  • Abdulelah F. Bassas

    (Obesity Research Center, College of Medicine, King Saud University)

  • Reem M. Sallam

    (Obesity Research Center, College of Medicine, King Saud University)

  • Kyong Soo Park

    (Seoul National University College of Medicine
    Graduate School of Convergence Science and Technology, Seoul National University)

  • Assim A. Alfadda

    (Obesity Research Center, College of Medicine, King Saud University
    King Saud University)

  • Aimin Xu

    (State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong
    The University of Hong Kong
    The University of Hong Kong)

  • Jae Bum Kim

    (Institute of Molecular Biology and Genetics, Seoul National University
    School of Biological Sciences, Seoul National University)

Abstract

Adiponectin plays a key role in the regulation of the whole-body energy homeostasis by modulating glucose and lipid metabolism. Although obesity-induced reduction of adiponectin expression is primarily ascribed to a transcriptional regulation failure, the underlying mechanisms are largely undefined. Here we show that DNA hypermethylation of a particular region of the adiponectin promoter suppresses adiponectin expression through epigenetic control and, in turn, exacerbates metabolic diseases in obesity. Obesity-induced, pro-inflammatory cytokines promote DNMT1 expression and its enzymatic activity. Activated DNMT1 selectively methylates and stimulates compact chromatin structure in the adiponectin promoter, impeding adiponectin expression. Suppressing DNMT1 activity with a DNMT inhibitor resulted in the amelioration of obesity-induced glucose intolerance and insulin resistance in an adiponectin-dependent manner. These findings suggest a critical role of adiponectin gene epigenetic control by DNMT1 in governing energy homeostasis, implying that modulating DNMT1 activity represents a new strategy for the treatment of obesity-related diseases.

Suggested Citation

  • A. Young Kim & Yoon Jeong Park & Xuebo Pan & Kyung Cheul Shin & Soo-Heon Kwak & Abdulelah F. Bassas & Reem M. Sallam & Kyong Soo Park & Assim A. Alfadda & Aimin Xu & Jae Bum Kim, 2015. "Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8585
    DOI: 10.1038/ncomms8585
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    Cited by:

    1. Jisu Oh & Amy E. Riek & Kevin T. Bauerle & Adriana Dusso & Kyle P. McNerney & Ruteja A. Barve & Isra Darwech & Jennifer E. Sprague & Clare Moynihan & Rong M. Zhang & Greta Kutz & Ting Wang & Xiaoyun X, 2023. "Embryonic vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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