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TonEBP/NFAT5 promotes obesity and insulin resistance by epigenetic suppression of white adipose tissue beiging

Author

Listed:
  • Hwan Hee Lee

    (Ulsan National Institute of Science and Technology)

  • Seung Min An

    (Ulsan National Institute of Science and Technology)

  • Byeong Jin Ye

    (Ulsan National Institute of Science and Technology)

  • Jun Ho Lee

    (Ulsan National Institute of Science and Technology)

  • Eun Jin Yoo

    (Ulsan National Institute of Science and Technology)

  • Gyu Won Jeong

    (Ulsan National Institute of Science and Technology)

  • Hyun Je Kang

    (Ulsan National Institute of Science and Technology)

  • Assim A. Alfadda

    (King Saud University)

  • Sun Woo Lim

    (Catholic University of Korea)

  • Jiyoung Park

    (Ulsan National Institute of Science and Technology)

  • Whaseon Lee-Kwon

    (Ulsan National Institute of Science and Technology)

  • Jae Bum Kim

    (Seoul National University)

  • Soo Youn Choi

    (Ulsan National Institute of Science and Technology)

  • Hyug Moo Kwon

    (Ulsan National Institute of Science and Technology)

Abstract

Tonicity-responsive enhancer binding protein (TonEBP or NFAT5) is a regulator of cellular adaptation to hypertonicity, macrophage activation and T-cell development. Here we report that TonEBP is an epigenetic regulator of thermogenesis and obesity. In mouse subcutaneous adipocytes, TonEBP expression increases > 50-fold in response to high-fat diet (HFD) feeding. Mice with TonEBP haplo-deficiency or adipocyte-specific TonEBP deficiency are resistant to HFD-induced obesity and metabolic defects (hyperglycemia, hyperlipidemia, and hyperinsulinemia). They also display increased oxygen consumption, resistance to hypothermia, and beiging of subcutaneous fat tissues. TonEBP suppresses the promoter of β3-adrenoreceptor gene, a critical regulator of lipolysis and thermogenesis, in ex vivo and cultured adipocytes. This involves recruitment of DNMT1 DNA methylase and methylation of the promoter. In human subcutaneous adipocytes TonEBP expression displays a correlation with body mass index but an inverse correlation with β3-adrenoreceptor expression. Thus, TonEBP is an attractive therapeutic target for obesity, insulin resistance, and hyperlipidemia.

Suggested Citation

  • Hwan Hee Lee & Seung Min An & Byeong Jin Ye & Jun Ho Lee & Eun Jin Yoo & Gyu Won Jeong & Hyun Je Kang & Assim A. Alfadda & Sun Woo Lim & Jiyoung Park & Whaseon Lee-Kwon & Jae Bum Kim & Soo Youn Choi &, 2019. "TonEBP/NFAT5 promotes obesity and insulin resistance by epigenetic suppression of white adipose tissue beiging," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11302-w
    DOI: 10.1038/s41467-019-11302-w
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