| First Author | Byun S | Year | 2022 |
| Journal | Proc Natl Acad Sci U S A | Volume | 119 |
| Issue | 26 | Pages | e2205626119 |
| PubMed ID | 35737830 | Mgi Jnum | J:351317 |
| Mgi Id | MGI:7412740 | Doi | 10.1073/pnas.2205626119 |
| Citation | Byun S, et al. (2022) Loss of adipose TET proteins enhances beta-adrenergic responses and protects against obesity by epigenetic regulation of beta3-AR expression. Proc Natl Acad Sci U S A 119(26):e2205626119 |
| abstractText | beta-adrenergic receptor (beta-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 beta3-adrenergic receptor (beta3-AR) expression and decreased beta-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 beta3-AR expression in adipocytes, thereby attenuating the responsiveness to beta-adrenergic stimulation. Deletion of all three Tet genes in adipocytes led to increased beta3-AR expression and thereby enhanced the downstream beta-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 beta3-AR in both white and brown adipose tissues and remained sensitive to beta-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 beta3-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-beta3-AR axis could be targeted to treat obesity and related metabolic diseases. |
