Epigenetic mechanisms and genes that regulate adipose tissue expansion

调节脂肪组织扩张的表观遗传机制和基因

基本信息

批准号：
8184856
负责人：
Robert A Koza
金额：
$ 33.3万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8184856
关键词：
Accounting Acyltransferase Adipocytes Adipose tissue Adolescent Adult Age Animals Binding Biological Biopsy Body Composition Body Weight Cell Differentiation process Cell Line Cell physiology Chromatin Structure Comorbidity Coupled Databases Development Developmental Gene Diabetes Mellitus Diet Disease Drug Delivery Systems EP300 gene Embryo Endoplasmic Reticulum Enhancers Environment Epidemic Epidemiology Epigenetic Process Epoxide hydrolase Epoxy Compounds Etiology Fatty Acids Fatty acid glycerol esters Fibroblasts Gene Deletion Gene Expression Gene Expression Profile Gene Targeting Genes Genetic Genetic Variation Genomics Golgi Apparatus Growth Health Heterogeneity Human Hydrolase Inbred Mouse Inbreeding Individual Inherited Life Link Lipase Lipids Measurement Mediator of activation protein Mesenchymal Stem Cells Mesoderm Metabolic Modeling Molecular Mus Neonatal Non-Insulin-Dependent Diabetes Mellitus Nutritional status Obesity Pathway interactions Persons Phenotype Population Predisposition Regulation Role Scientist Signal Transduction Testing Tissue Expansion Transcript Variant Vascularization Weight Gain angiogenesis base bisulfite cell growth energy balance feeding glucose uptake imprint in utero knockout gene lipid biosynthesis mRNA Expression male member metabolomics mouse model new therapeutic target non-genetic obesity treatment programs promoter protein expression research study therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): The global obesity epidemic is caused by multifactorial interactions between inherited allelic variation and the environment. Other components of obesity, based on variations in epigenetic programming, have been established by human epidemiological and animal studies that link nutritional status in utero and during early post-natal growth to the development of obesity and diabetes in adults. However, the mechanisms associated with these epigenetic contributions to obesity are not well understood. To identify epigenetic determinants of obesity, global analyses of gene expression was used to identify gene targets that are associated with phenotypic variations in the development of diet-induced obesity in a genetically identical population of mice. These analyses identified a set of genes that included imprinted developmental genes, antagonists of Wnt signaling and genes of angiogenesis and vascularization. One of these genes, mesoderm specific transcript (Mest); a maternally imprinted gene localized in the endoplasmic reticulum/Golgi apparatus where it may function as an epoxide hydrolase, lipase or acyltransferase based on homology with members of the 1/2 hydrolase superfamily, is highly expressed when fat mass is rapidly expanding. Mest was shown to be elevated in adipose tissue biopsies of juvenile mice destined to develop diet-induced obesity as adults suggesting that molecular changes regulating it have been established prior to feeding a high fat diet. The positive association of Mest with variations of fat mass expansion in genetically identical mice suggests that epigenetic mechanisms are involved in its regulation. The studies in this proposal will determine the functional role for Mest in fat mass expansion by using mouse models and primary cell lines with targeted deletions for Mest (Aim 1), will identify the molecular/catalytic function of MEST in facilitating fat mass expansion (Aim 2) and will uncover epigenetic mechanisms that regulate Mest by identifying changes in chromatin structure that is associated with variable expression of Mest in adipose tissue of inbred mice fed an obesogenic diet (Aim 3).Understanding the mechanisms that regulate Mest and the catalytic function by which it controls fat mass expansion could identify novel therapeutic targets for the treatment of obesity. PUBLIC HEALTH RELEVANCE: Scientists have shown that factors such as genetics and the environment interact to determine a person's susceptibility to developing diseases such as obesity and diabetes; however, very little is known about the molecular pathways that are involved in these interactions. Therefore, we are studying a mouse model in where all of the individuals are genetically identical to understand the basis for these alterations. We have identified several genes that are associated with variations in obesity and propose to study how one these genes, mesoderm specific transcript, functions in order to determine whether it could be used as drug target for the treatment of obesity.

描述（由申请人提供）：全球肥胖流行是由遗传等位基因变异与环境之间的多因素相互作用引起的。人类流行病学和动物研究已经根据表观遗传编程的变化确定了肥胖的其他组成部分，这些研究将子宫内和产后早期生长期间的营养状况与成人肥胖和糖尿病的发展联系起来。然而，与这些表观遗传对肥胖的影响相关的机制尚不清楚。为了确定肥胖的表观遗传决定因素，使用基因表达的全局分析来确定与遗传相同的小鼠群体中饮食诱发的肥胖发展的表型变异相关的基因靶标。这些分析确定了一组基因，包括印记发育基因、Wnt 信号传导拮抗剂以及血管生成和血管化基因。这些基因之一，中胚层特异性转录本（Mest）；一种位于内质网/高尔基体中的母系印记基因，基于与 1/2 水解酶超家族成员的同源性，它可以充当环氧化物水解酶、脂肪酶或酰基转移酶，当脂肪量快速膨胀时，该基因会高度表达。在成年后注定会患上饮食引起的肥胖的幼年小鼠的脂肪组织活检中，Mest 被证明是升高的，这表明在喂养高脂肪饮食之前就已经建立了调节它的分子变化。在基因相同的小鼠中，Mest 与脂肪量扩张的变化呈正相关，这表明表观遗传机制参与了其调节。本提案中的研究将通过使用小鼠模型和具有 Mest 定向删除的原代细胞系来确定 Mest 在脂肪量扩张中的功能作用（目标 1），将确定 MEST 在促进脂肪量扩张中的分子/催化功能（目标2) 并将通过识别染色质结构的变化来揭示调节 Mest 的表观遗传机制，该变化与喂食致胖饮食的近交小鼠脂肪组织中 Mest 的可变表达相关（目标 3）。了解调节机制Mest 及其控制脂肪量扩张的催化功能可以确定治疗肥胖的新治疗靶点。公共健康相关性：科学家已经表明，遗传和环境等因素相互作用，决定了一个人患肥胖症和糖尿病等疾病的易感性；然而，人们对参与这些相互作用的分子途径知之甚少。因此，我们正在研究一种小鼠模型，其中所有个体的基因都相同，以了解这些改变的基础。我们已经鉴定了几个与肥胖变异相关的基因，并建议研究这些基因（中胚层特异性转录本）如何发挥作用，以确定它是否可以用作治疗肥胖的药物靶点。