β-adrenergic receptor (β-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 β3-adrenergic receptor (β3-AR) expression and decreased β-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 β3-AR expression in adipocytes, thereby attenuating the responsiveness to β-adrenergic stimulation. Deletion of all three Tet genes in adipocytes led to increased β3-AR expression and thereby enhanced the downstream β-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 β3-AR in both white and brown adipose tissues and remained sensitive to β-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 β3-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–β3-AR axis could be targeted to treat obesity and related metabolic diseases.
A team of researchers, affiliated with UNIST has identified TET proteins as pivotal epigenetic suppressors of β3-AR in adipocytes that reduced the sensitivity to β-adrenergic stimulation in vitro and in vivo.
Published in the June 2022 issue of PNAS, this breakthrough has been jointly led by Professor Myung Gon Ko in the Department of Biological Sciences at UNIST, in collaboration with researchers from Jeonbuk National University.
Figure 1. Adipocyte Tet expression is elevated in obesity, and Tet TKO mice resist diet-induced obesity. (A) Changes in body weight of WT and Tet TKO mice fed either CD or HFD, (B) Consistent with reduced fat cell size, Tet TKO mice were markedly protected from inflammation and metabolic defects when fed an HFD, and (C) TET-deficient mice exhibited improved cold tolerance and were substantially protected from diet-induced obesity, inflammation, and metabolic complications, including insulin resistance.
“Our findings shed light on the epigenetic control of β-adrenergic responses via TET–HDAC cooperation,” noted the research team. “Because loss of TET proteins in adipocytes robustly defended against the suppressive effects of chronic overnutrition on β-adrenergic sensitivity, thermogenesis, and energy expenditure, targeting the TET–HDAC-β3–AR axis may increase therapeutic options for treating obesity and related metabolic diseases.”
This study has been supported by the National Research Foundation of Korea, the Institute for Basic Science (IBS), and UNIST.
Seongjun Byun, Chan Hyeong Lee, Hyeongmin Jeong, et al., ‘Loss of adipose TET proteins enhances β-adrenergic responses and protects against obesity by epigenetic regulation of β3-AR expression,’ PNAS, (2022).