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

Nat Commun. 2019 Aug 6;10(1):3536. doi: 10.1038/s41467-019-11302-w.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adipocytes / metabolism
  • Adipose Tissue, Beige / cytology
  • Adipose Tissue, Beige / metabolism
  • Animals
  • Body Mass Index
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
  • DNA Methylation / genetics
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Energy Metabolism / genetics
  • Epigenesis, Genetic*
  • HEK293 Cells
  • Humans
  • Insulin Resistance / genetics*
  • Male
  • Mice
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Obesity / etiology
  • Obesity / metabolism*
  • Primary Cell Culture
  • Receptors, Adrenergic, beta-3 / metabolism
  • Subcutaneous Fat / cytology
  • Subcutaneous Fat / metabolism
  • Thermogenesis / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Adrb3 protein, mouse
  • MicroRNAs
  • Mirn30d microRNA, mouse
  • NFAT5 protein, human
  • Nfat5 protein, mouse
  • Receptors, Adrenergic, beta-3
  • Transcription Factors
  • DNA (Cytosine-5-)-Methyltransferase 1
  • Dnmt1 protein, mouse