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

• DOI: 10.1038/s41467-019-11302-w
• Publication Date: 2019-08-06T10:22:49Z
• Authors: 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; Hyug Moo Kwon
• Keywords: DNA (Cytosine-5-)-Methyltransferase 1; Male; 0301 basic medicine; Science; Primary Cell Culture; Mice, Transgenic; Diet, High-Fat; Article; Body Mass Index; Epigenesis, Genetic; Mice; 03 medical and health sciences; Adipocytes; Animals; Humans; Obesity; 2. Zero hunger; Q; 3T3 Cells; Adipose Tissue, Beige; DNA Methylation; Disease Models, Animal; MicroRNAs; HEK293 Cells; Insulin Resistance; Energy Metabolism

AbstractTonicity-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.