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

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 () and Hyug Moo Kwon ()
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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

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11302-w

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