Epigenetic regulation of HDAC9 in obesity and atherosclerosis

 描述（由申请人提供）：肥胖症的发病率在世界范围内以惊人的速度增加，并且是糖尿病和心血管疾病的主要危险因素。在饮食诱导的肥胖症（DIO）（人类肥胖症的最常见形式）中，脂肪组织主要通过预先存在的脂肪细胞的肥大而膨胀。尽管DIO中发生前脂肪细胞向脂肪细胞的转化，但其不足以匹配热量消耗。随着时间的推移，脂肪细胞扩大超过其生理极限，并成为机械应力，发炎，胰岛素抵抗，从而有助于心脏代谢疾病。在DIO过程中有效的脂肪形成分化中的这种“阻滞”的原因和后果尚不清楚。我们提出了新的证据表明，表达组蛋白脱乙酰酶9（HDAC9），脂肪形成分化的内源性阻遏物，是显着上调脂肪组织在DIO期间，与受损的脂肪形成分化。HDAC9的基因切除消除了脂肪形成分化中的阻滞，并改善了葡萄糖耐量和胰岛素敏感性。此外，HDAC9的消融刺激产热“米色”脂肪细胞，从而改善能量平衡并防止异位脂质沉积。HDAC9基因缺失也有利地影响血管周围脂肪组织（PVAT）并减少LDLr敲除小鼠中的动脉粥样硬化。我们假设HDAC9在DIO过程中作为脂肪形成分化的“分子制动器”，从而导致胰岛素抵抗和加速动脉粥样硬化。为了验证这一假设，我们提出了三个具体的目标：目标1将确定在DIO过程中导致异常HDAC9表达的表观遗传机制，重点是组蛋白甲基转移酶EZH2。我们的初步数据表明，EZH2未能在DIO过程中“沉默”HDAC 9启动子，从而导致脂肪形成分化受损。在目标2中，我们将使用为此应用创建的新型floxed小鼠来确定脂肪细胞特异性HDAC9基因缺失是否改善DIO期间的脂肪形成分化、葡萄糖耐受性和胰岛素敏感性。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背景下减弱LDLr敲除小鼠中的动脉粥样硬化。使用我们实验室开发的新型PVAT移植模型，我们还将确定PVAT中HDAC9的缺失是否局部调节动脉粥样硬化的发展。拟议的研究将为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，也可能成为开发选择性HDAC9阻断剂以对抗DIO的基础。

 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.