Loss of adipose TET proteins enhances ??-adrenergic responses and protects against obesity by epigenetic regulation of ??3-AR expression

??-adrenergic receptor (??-AR) signaling plays predominant roles in modulating energy expenditure by triggering lipolysis and thermogenesis in adipose tissue, thereby conferring obesity resistance. Obesity is associated with diminished ??3-adrenergic receptor (??3-AR) expression and decreased ??-adrenergic responses, but the molecular mechanism coupling nutrient overload to catecholamine resistance remains poorly defined. Ten-eleven translocation (TET) proteins are dioxygenases that alter the methylation status of DNA by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine and further oxidized derivatives. Here, we show that TET proteins are pivotal epigenetic suppressors of ??3-AR expression in adipocytes, thereby attenuating the responsiveness to ??-adrenergic stimulation. Deletion of all three Tet genes in adipocytes led to increased ??3-AR expression and thereby enhanced the downstream ??-adrenergic responses, including lipolysis, thermogenic gene induction, oxidative metabolism, and fat browning in vitro and in vivo. In mouse adipose tissues, Tet expression was elevated after mice ate a high-fat diet. Mice with adipose-specific ablation of all TET proteins maintained higher levels of ??3-AR in both white and brown adipose tissues and remained sensitive to ??-AR stimuli under high-fat diet challenge, leading to augmented energy expenditure and decreased fat accumulation. Consequently, they exhibited improved cold tolerance and were substantially protected from diet-induced obesity, inflammation, and metabolic complications, including insulin resistance and hyperlipidemia. Mechanistically, TET proteins directly repressed ??3-AR transcription, mainly in an enzymatic activity-independent manner, and involved the recruitment of histone deacetylases to increase deacetylation of its promoter. Thus, the TET-histone deacetylase-??3-AR axis could be targeted to treat obesity and related metabolic diseases