LAUSR

Significance The β3-adrenergic receptor (β3-AR) is a major regulator of energy expenditure that triggers lipolysis and thermogenesis in adipose tissue, thereby significantly attenuating the risk of obesity. Obesity is associated with diminished β3-AR expression and decreased β-adrenergic responses, but the underlying molecular mechanisms remain elusive. Here, we show that ten-eleven translocation (TET) proteins, the crucial modifiers of DNA methylation, act as epigenetic suppressors of β3-AR in adipocytes by recruiting histone deacetylases to its promoter, thereby reducing the sensitivity to β-adrenergic stimulation. Adipose-specific ablation of all TET proteins in mice prevents body weight gain and metabolic disorders under high-fat diet challenge via enhanced fat browning, lipolysis, and thermogenesis. Modulation of adipocyte TET proteins may provide a new therapeutic avenue to treat obesity.