Department of Medicine, Division of Cardiology, and.
Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
JCI Insight. 2018 Aug 9;3(15). doi: 10.1172/jci.insight.120159.
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 β-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.
关于组蛋白去乙酰化酶 11（HDAC11）的生物学功能知之甚少，它是唯一的 IV 类 HDAC。在这里，我们证明了在小鼠中删除 HDAC11 会刺激棕色脂肪组织（BAT）的形成和白色脂肪组织（WAT）的褐变。因此，HDAC11 缺陷型小鼠表现出增强的产热潜力，并且对高脂肪喂养的反应是肥胖减轻、胰岛素敏感性提高和肝脂肪变性减少。离体和基于细胞的测定显示，HDAC11 的催化活性通过一种依赖于与 BRD2（一种溴结构域和末端（BET）乙酰化组蛋白结合蛋白）的物理结合的机制，在基础状态和对β-肾上腺素能受体信号的反应中，抑制 BAT 转录程序。这些发现定义了能量平衡调节的表观遗传途径，并表明 HDAC11 选择性抑制剂在治疗肥胖症和糖尿病方面具有潜力。
