DNA Methylation Profiles in a Polygenic Mouse Model of Diet-Induced Obesity

饮食引起肥胖的多基因小鼠模型中的 DNA 甲基化谱

• 批准号: 7392255
• 负责人: Jan Bressler
• 金额: $ 14.85万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392255
• 关键词: Address; Adoption; Adult; Aging; Animal Model; Apolipoprotein E; Appearance; Arterial Fatty Streak; Atherogenic Diet; Atherosclerosis; Body Weight; C57BL/6 Mouse; Candidate Disease Gene; Cardiovascular Diseases; Cholesterol; Complex; Control Animal; Coronary heart disease; CpG dinucleotide; DNA Methylation; Development; Diabetes Mellitus; Diet; Disease; Drug Formulations; Environmental Exposure; Exposure to; Fatty acid glycerol esters; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genetic; Genome; Goals; Human; Hyperinsulinism; In Vitro; Individual; Insulin; Insulin Resistance; Lesion; Libraries; Methylation; Microarray Analysis; Modification; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Normal Range; Nutrient; Nutrition, Other; Obesity; Organ; Pathogenesis; Pattern; Plasma; Population; Predisposition; Process; Reporting; Risk; Risk Factors; Role; Suggestion; Testing; Tissue-Specific Gene Expression; Tissues; Twin Multiple Birth; Twin Studies; Variant; Weight; Weight Gain; Wild Type Mouse; base; cohort; comparison group; concept; feeding; in vivo; mouse model; normal aging; novel; promoter; research study; response

DESCRIPTION (provided by applicant): Obesity is a major risk factor for the development of coronary heart disease (CHD) and non-insulin dependent diabetes mellitus (NIDDM). Although the results of twin studies and adoption studies provide strong support for a genetic influence on body weight, mutations causing obesity are rare in the population and major genes contributing to common obesity have not been identified. This has led to the suggestion that the variation in adiposity between individuals may be determined by multiple genetic loci with variations in any single gene producing only a moderate effect. In accordance with this formulation, obesity has been reported to be associated with differential gene expression, and the composite effect of these alterations may be at least partly responsible for the susceptibility to NIDDM and CHD. It is the long-term goal of this proposal to evaluate whether modifications in DNA methylation patterns that may result in either activation or silencing of genes can be detected when comparing obese and lean individuals. The first step in approaching this long-term goal is a proof-of-concept study using an animal model in an experimental setting. Provision of a high-fat diet to C57BL/6 mice results in increased body weight, hyperinsulinemia and insulin-resistance, and the accelerated appearance of aortic fatty streak lesions when compared to littermates fed normal mouse chow. The use of these mice will allow nutrient exposure to be varied while keeping genetic background constant. Based on previous reports that changes in DNA methylation may precede the development of atherosclerotic lesions in mice with a mutation in the apolipoprotein E gene causing elevated plasma cholesterol, the goal of this proposal is to test the hypotheses that (a) the pathogenesis of adult-onset obesity and atherosclerosis in wild- type mice fed an atherogenic diet may be correlated with functional differences in DNA methylation between treated and control animals and (b) that acquired variability in DNA methylation may be involved in normal aging and could contribute to the development of complex disease by pursuing the following specific aims: 1) to evaluate whether diet-induced obesity and atherosclerosis in C57BL/6 mice entails alterations in DNA methylation patterns in atherosclerotic lesions and other target organs by genome-wide microarray analysis. 2) to identify and clone methylated sequences, and validate that genes with altered methylation patterns detected by microarray analysis are regulated by methylation in vitro and in vivo. 3) to assess global and gene-specific DNA methylation in multiple tissues during aging in C57BL/6 mice. These experiments may reveal the role and sequence of DNA methylation changes in simultaneous disease processes in response to nutrition and other environmental influences, and may also yield a set of novel candidate genes that can later be tested in association studies in human cohorts. Consuming a high-fat diet is an environmental exposure that may alter DNA methylation and change gene expression. This will be studied first in mice to see whether this type of change could help to explain the increased risk for non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD) with obesity.

描述（由申请人提供）：肥胖是冠心病（CHD）和非胰岛素依赖型糖尿病（NIDDM）发展的主要危险因素。虽然双胞胎研究和收养研究的结果为基因对体重的影响提供了强有力的支持，但导致肥胖的突变在人群中很少见，导致常见肥胖的主要基因尚未确定。这导致了一种观点，即个体之间的肥胖差异可能是由多个基因位点决定的，任何一个基因的变异只会产生适度的影响。根据这一说法，肥胖已被报道与差异基因表达有关，这些改变的综合作用可能至少部分地导致NIDDM和冠心病的易感性。本研究的长期目标是评估在比较肥胖和瘦弱个体时，是否可以检测到可能导致基因激活或沉默的DNA甲基化模式的修饰。实现这一长期目标的第一步是在实验环境中使用动物模型进行概念验证研究。给C57BL/6小鼠提供高脂肪饮食会导致体重增加、高胰岛素血症和胰岛素抵抗，并且与喂食正常小鼠食物的窝鼠相比，主动脉脂肪条纹病变的出现速度加快。使用这些老鼠可以在保持遗传背景不变的情况下，改变营养物质的暴露。根据先前的报道，在载脂蛋白E基因突变导致血浆胆固醇升高的小鼠中，DNA甲基化的变化可能先于动脉粥样硬化病变的发展，本研究的目的是验证以下假设：(a)在喂食致动脉粥样硬化饮食的野生型小鼠中，成年发病的肥胖和动脉粥样硬化的发病机制可能与治疗动物和对照动物之间DNA甲基化的功能差异有关；(b) DNA甲基化的获得性变异可能与正常衰老有关，并可能通过追求以下具体目标来促进复杂疾病的发展：1)通过全基因组微阵列分析，评估C57BL/6小鼠饮食诱导的肥胖和动脉粥样硬化是否与动脉粥样硬化病变和其他靶器官的DNA甲基化模式改变有关。2)鉴定和克隆甲基化序列，验证微阵列分析检测到的甲基化模式改变的基因在体内和体外受到甲基化的调控。3)评估C57BL/6小鼠衰老过程中多个组织的整体和基因特异性DNA甲基化。这些实验可能揭示了DNA甲基化变化在应对营养和其他环境影响的同时疾病过程中的作用和顺序，也可能产生一组新的候选基因，这些基因可以在随后的人类群体关联研究中进行测试。食用高脂肪饮食是一种环境暴露，可能会改变DNA甲基化和基因表达。这将首先在老鼠身上进行研究，看看这种类型的变化是否有助于解释肥胖导致非胰岛素依赖型糖尿病（NIDDM）和冠心病（CHD）风险增加的原因。