TonEBP/NFAT5 promotes obesity and insulin resistance by epigenetic suppression of white adipose tissue beiging
TonEBP/NFAT5 promotes obesity and insulin resistance by epigenetic suppression of white adipose tissue beiging
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DOI：
10.1038/s41467-019-11302-w
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发表时间：
2019-08-06
影响因子：
16.6
通讯作者：
Kwon, Hyug Moo
中科院分区：
文献类型：
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作者：
Lee, Hwan Hee;An, Seung Min;Kwon, Hyug Moo
张力反应增强子结合蛋白(TONEBP或NFAT5)是细胞适应高张力、巨噬细胞活化和T细胞发育的调节因子。在此，我们报道了TONEBP是产热和肥胖的表观遗传调节因子。在小鼠皮下脂肪细胞中，TONEBP的表达在高脂饮食(HFD)喂养下增加50倍。具有TONEBP单倍体缺陷或脂肪细胞特异性TONEBP缺陷的小鼠对HFD引起的肥胖和代谢缺陷(高血糖、高脂血症和高胰岛素血症)具有抵抗力。它们还表现出氧气消耗增加，对低温的抵抗力，以及皮下脂肪组织的褐变。在体外和培养的脂肪细胞中，TONEBP抑制β3肾上腺素受体基因的启动子，β3肾上腺素受体基因是脂肪分解和产热的关键调节因子。这包括DNMT1 DNA甲基酶的招募和启动子的甲基化。在人类皮下脂肪细胞中，TONEBP的表达与体重指数呈正相关，而与β3-肾上腺素受体的表达呈负相关。因此，TONEBP是治疗肥胖、胰岛素抵抗和高脂血症的有吸引力的靶点。
Tonicity-responsive enhancer binding protein (TonEBP or NFAT5) is a regulator of cellular adaptation to hypertonicity, macrophage activation and T-cell development. Here we report that TonEBP is an epigenetic regulator of thermogenesis and obesity. In mouse subcutaneous adipocytes, TonEBP expression increases > 50-fold in response to high-fat diet (HFD) feeding. Mice with TonEBP haplo-deficiency or adipocyte-specific TonEBP deficiency are resistant to HFD-induced obesity and metabolic defects (hyperglycemia, hyperlipidemia, and hyperinsulinemia). They also display increased oxygen consumption, resistance to hypothermia, and beiging of subcutaneous fat tissues. TonEBP suppresses the promoter of beta 3-adrenoreceptor gene, a critical regulator of lipolysis and thermogenesis, in ex vivo and cultured adipocytes. This involves recruitment of DNMT1 DNA methylase and methylation of the promoter. In human subcutaneous adipocytes TonEBP expression displays a correlation with body mass index but an inverse correlation with beta 3-adrenoreceptor expression. Thus, TonEBP is an attractive therapeutic target for obesity, insulin resistance, and hyperlipidemia.