한빛사 논문
Seongjun Byuna,1, Chan Hyeong Leeb,1, Hyeongmin Jeonga,1, Hyejin Kima, Hyug Moo Kwona, Sungho Parka, Kyungjae Myungc,d, Jungeun Anb,2, and Myunggon Koa,d,2
aDepartment of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea; bDepartment of Life Sciences, Jeonbuk National University, Jeonju 54896, Republic of Korea; cDepartment of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea; and dCenter for Genomic Integrity, Institute for Basic Science, Ulsan 44919, Republic of Korea
1S.B., C.H.L., and H.J. contributed equally to this work.
2To whom correspondence may be addressed.
Abstract
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.
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