TET1 is a beige adipocyte-selective epigenetic suppressor of thermogenesis

Nat Commun. 2020 Aug 27;11(1):4313. doi: 10.1038/s41467-020-18054-y.


It has been suggested that beige fat thermogenesis is tightly controlled by epigenetic regulators that sense environmental cues such as temperature. Here, we report that subcutaneous adipose expression of the DNA demethylase TET1 is suppressed by cold and other stimulators of beige adipocyte thermogenesis. TET1 acts as an autonomous repressor of key thermogenic genes, including Ucp1 and Ppargc1a, in beige adipocytes. Adipose-selective Tet1 knockout mice generated by using Fabp4-Cre improves cold tolerance and increases energy expenditure and protects against diet-induced obesity and insulin resistance. Moreover, the suppressive role of TET1 in the thermogenic gene regulation of beige adipocytes is largely DNA demethylase-independent. Rather, TET1 coordinates with HDAC1 to mediate the epigenetic changes to suppress thermogenic gene transcription. Taken together, TET1 is a potent beige-selective epigenetic breaker of the thermogenic gene program. Our findings may lead to a therapeutic strategy to increase energy expenditure in obesity and related metabolic disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, Beige / metabolism*
  • Animals
  • Calorimetry, Indirect
  • Cell Line
  • Cold Temperature / adverse effects
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Energy Metabolism / genetics
  • Epigenesis, Genetic*
  • Gene Expression Regulation / physiology
  • HEK293 Cells
  • Humans
  • Insulin Resistance / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Obesity / etiology
  • Obesity / metabolism*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA-Seq
  • Subcutaneous Fat / cytology
  • Subcutaneous Fat / metabolism
  • Thermogenesis / genetics*
  • Uncoupling Protein 1 / metabolism


  • DNA-Binding Proteins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Proto-Oncogene Proteins
  • TET1 protein, mouse
  • Ucp1 protein, mouse
  • Uncoupling Protein 1