Epigenetic regulation of HDAC9 in obesity and atherosclerosis

HDAC9 在肥胖和动脉粥样硬化中的表观遗传调控

基本信息

批准号：
9030314
负责人：
Neal L Weintraub
金额：
$ 44.84万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9030314
关键词：
Ablation Adipocytes Adipose tissue Atherogenic Diet Atherosclerosis Attenuated Biology Blood Vessels Breeding Cardiovascular Diseases Cells Consumption Data Deposition Development Diabetes Mellitus Diet Disease Energy Metabolism Enhancers Enzymes Epigenetic Process Equilibrium Failure Fatty acid glycerol esters Gene Deletion Gene Expression Genes Genetic HDAC9 gene Hepatocyte High Fat Diet Histology Homeostasis Homologous Gene Human Hypertrophy Immune Incidence Inflammation Inflammatory Insulin Resistance Knockout Mice Lead Lipids LoxP-flanked allele Malignant Neoplasms Metabolic Modeling Modification Molecular Monitor Mus Myocardial Infarction Names Neurodegenerative Disorders Obesity Obesity associated disease Pathogenesis Phenotype Physiological Play Predisposition Proteins Publications Research Risk Factors Role Skeletal Muscle Stress Testing Therapeutic Thermogenesis Time Tissue Transplantation Tissues Vascular Diseases Work adiponectin base energy balance epigenetic regulation feeding glucose tolerance histone methyltransferase improved insight insulin sensitivity lipid biosynthesis novel obesogenic pandemic disease prevent promoter protein expression public health relevance therapeutic target

项目摘要

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.

描述（由适用提供）：肥胖的发生率在全球范围内以惊人的速度增加，代表了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）中，是人类肥胖的最常见形式，脂肪组织主要通过现有脂肪细胞的肥大而主要扩展。尽管在DIO中发生了前脂肪细胞向脂肪细胞的转化，但不足以匹配热量消耗。随着时间的流逝，脂肪细胞扩大了其物理极限，并在机械压力，发炎和抗胰岛素上变得耐药，从而导致心脏代谢疾病。在DIO期间有效的掺杂分化中，这种“障碍”的原因和后果尚不清楚。我们提供了新的证据，表明组蛋白脱乙酰基酶9（HDAC9）是脂肪生成分化的内源性复制品，在DIO期间的脂肪组织中明显更新，并结合脂肪性分化受损。 HDAC9的遗传消融减轻了成脂分化的块，并提高了葡萄糖耐受性和胰岛素敏感性。此外，HDAC9的消融刺激了热的“米色”脂肪细胞，从而改善了能量平衡并防止生态脂质沉积。 HDAC9基因缺失还有利地影响周围的脂肪组织（PVAT），并减少LDLR敲除小鼠的动脉粥样硬化。我们假设HDAC9充当DIO期间成脂分化的“分子制动”，从而有助于胰岛素抵抗并加速动脉粥样硬化。为了检验这一假设，我们提出了三个具体目标：AIM 1将识别导致DIO期间异常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在DIO期间未能“沉默” HDAC9启动子，从而导致脂肪生成分化受损。在AIM 2中，我们将使用为该应用创建的新型Floxed小鼠在DIO期间脂肪细胞特异性的HDAC9基因缺失改善脂肪生成分化，葡萄糖耐受性和胰岛素敏感性。在AIM 3中，我们将确定脂肪细胞特异性的HDAC9基因缺失是否足以在DIO的情况下减轻LDLR敲除小鼠的动脉粥样硬化。使用在实验室中开发的新型PVAT移植模型，我们还将确定pVAT中HDAC9的删除是否在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，也可能构成开发选择性HDAC9阻断剂以对抗DIO的基础。