HDAC11 suppresses the thermogenic program of adipose tissue via BRD2
HDAC11 suppresses the thermogenic program of adipose tissue via BRD2
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DOI：
10.1172/jci.insight.120159
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发表时间：
2018-08-09
期刊：
影响因子：
8
通讯作者：
McKinsey, Timothy A.
中科院分区：
文献类型：
--
作者：
Bagchi, Rushita A.;Ferguson, Bradley S.;McKinsey, Timothy A.
组蛋白脱乙酰酶11(HDAC11)是唯一的IV类HDAC，其生物学功能目前知之甚少。在这里，我们证明了在小鼠中HDAC11的缺失刺激棕色脂肪组织(BAT)的形成和白色脂肪组织(WAT)的褐变。因此，HDAC11缺陷小鼠表现出增强的生热潜力，并在高脂肪喂养的反应下，减轻肥胖，改善胰岛素敏感性，并减少肝脏脂肪变性。体外和基于细胞的分析表明，HDAC11的催化活性在基础状态和对β-肾上腺素能受体信号的反应中都抑制了BAT的转录程序，其机制依赖于与BRD2的物理结合。BRD2是一种溴域和端外(BET)乙酰组蛋白结合蛋白。这些发现定义了能量平衡调节的表观遗传途径，并暗示了HDAC11选择性抑制剂治疗肥胖症和糖尿病的潜力。
Little is known about the biological function of histone deacetylase 11 (HDAC11), which is the lone class IV HDAC. Here, we demonstrate that deletion of HDAC11 in mice stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT). Consequently, HDAC11-deficient mice exhibit enhanced thermogenic potential and, in response to high-fat feeding, attenuated obesity, improved insulin sensitivity, and reduced hepatic steatosis. Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to beta-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone-binding protein. These findings define an epigenetic pathway for the regulation of energy homeostasis and suggest the potential for HDAC11-selective inhibitors for the treatment of obesity and diabetes.