Epigenetic regulation of HDAC9 in obesity and atherosclerosis

 描述(申请人提供)：肥胖症的发病率在全球范围内以惊人的速度增长，是糖尿病和心血管疾病的主要危险因素。在饮食诱导肥胖(DIO)中，脂肪组织主要通过先前存在的脂肪细胞肥大来膨胀，这是人类最常见的肥胖形式。虽然前脂肪细胞向脂肪细胞的转化在DIO中发生，但这不足以匹配热量消耗。随着时间的推移，脂肪细胞会扩大到超过其生理极限，并变得机械应激、炎症和胰岛素抵抗，从而导致心脏代谢性疾病。在DIO过程中，这种有效的成脂分化受阻的原因和后果尚不清楚。我们提出了新的证据，组蛋白脱乙酰酶9(HDAC9)是一种内源性成脂分化抑制因子，在DIO过程中脂肪组织中的表达显著上调，与成脂分化受损有关。基因去除HDAC9可以减轻成脂分化的障碍，改善糖耐量和胰岛素敏感性。此外，HDAC9的消融刺激了生热的“米色”脂肪细胞，从而改善了能量平衡，防止了异位脂肪沉积。HDAC9基因缺失也有利于影响LDLR基因敲除小鼠的血管周围脂肪组织(PVAT)和减轻动脉粥样硬化。我们假设HDAC9在DIO过程中作为成脂分化的“分子刹车”，从而导致胰岛素抵抗和加速的动脉粥样硬化。为了验证这一假说，我们提出了三个具体目标：目标1将确定导致DIO过程中HDAC9异常表达的表观遗传学机制，重点是组蛋白甲基转移酶EZH2。我们的初步数据表明，在DIO过程中，EZH2未能“沉默”HDAC9启动子，从而导致成脂分化受损。在目标2中，我们将使用一种新的为此应用而创建的小鼠来确定脂肪细胞特异性HDAC9基因缺失是否改善了DIO过程中的成脂分化、葡萄糖耐量和胰岛素敏感性。在目标3中，我们将确定脂肪细胞特异性HDAC9基因缺失是否足以在DIO环境下减轻LDLR基因敲除小鼠的动脉粥样硬化。利用我们实验室开发的一种新的PVAT移植模型，我们还将确定PVAT中HDAC9的缺失是否局部调控动脉粥样硬化的发展。建议的研究将为HDAC9在脂肪组织生物学和动脉粥样硬化中的作用提供新的见解，并可能为开发选择性HDAC9阻滞剂来对抗DIO奠定基础。

 DESCRIPTION (provided by applicant): The incidence of obesity is increasing at an alarming rate world-wide and represents a major risk factor for both diabetes and cardiovascular disease. In diet-induced obesity (DIO), the most common form of human obesity, adipose tissue expands predominately by hypertrophy of pre-existing adipocytes. Although conversion of preadipocytes to adipocytes occurs in DIO, it is insufficient to match caloric consumption. Over time, adipocytes enlarge beyond their physiological limit and become mechanically stressed, inflamed, and insulin resistant, thus contributing to cardiometabolic disease. The causes and consequences of this "block" in efficient adipogenic differentiation during DIO are unclear. We present novel evidence that expression of histone deacetylase 9 (HDAC9), an endogenous repressor of adipogenic differentiation, is markedly upregulated in adipose tissues during DIO, in conjunction with impaired adipogenic differentiation. Genetic ablation of HDAC9 alleviates the block in adipogenic differentiation and improves glucose tolerance and insulin sensitivity. Moreover, ablation of HDAC9 stimulates thermogenic "beige" adipocytes, thus improving energy balance and preventing ectopic lipid deposition. HDAC9 gene deletion also favorably impacts perivascular adipose tissue (PVAT) and diminishes atherosclerosis in LDLr knockout mice. We hypothesize that HDAC9 acts as a "molecular brake" on adipogenic differentiation during DIO, thus contributing to insulin resistance and accelerated atherosclerosis. To test this hypothesis, we propose three specific aims: Aim 1 will identify the epigenetic mechanisms leading to aberrant HDAC9 expression during DIO, focusing on the histone methyltransferase EZH2. Our preliminary data suggest that EZH2 fails to "silence" the HDAC9 promoter during DIO, thus contributing to impaired adipogenic differentiation. In Aim 2, we will determine whether adipocyte-specific HDAC9 gene deletion improves adipogenic differentiation, glucose tolerance and insulin sensitivity during DIO using a novel floxed mouse created for this application. In Aim 3, we will determine whether adipocyte-specific HDAC9 gene deletion is sufficient to attenuate atherosclerosis in LDLr knockout mice in the setting of DIO. Using a novel PVAT transplantation model developed in our lab, we will also determine whether deletion of HDAC9 in PVAT locally modulates the development of atherosclerosis. The proposed studies will provide novel insight into the role of HDAC9 in adipose tissue biology and atherosclerosis and may also form the basis for development of selective HDAC9 blocking agents to counter DIO.