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

• 批准号: 8616203
• 负责人: Robert A Koza
• 金额: $ 24.53万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 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/8616203
• 关键词: Epigenetic; mechanisms; genes; regulate; adipose

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. Two of these genes, mesoderm specific transcript (Mest); a maternally imprinted gene localized in the endoplasmic reticulum/Golgi apparatus where it may function as a lipase or acyltransferase based on homology with members of the 1/2 hydrolase superfamily; and, bone morphogenetic protein 3 (Bmp3), an antagonist of bone formation that may act as an agonist of adiposity, are highly and coordinately expressed when fat mass is rapidly expanding. Mest and Bmp3 expression 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 these genes have been established prior to feeding a high fat diet. The coordinated expression and positive association of Mest and Bmp3 with variations of fat mass expansion in genetically identical mice suggests that epigenetic mechanisms are involved in their regulation. The studies in this proposal will determine the functional role for Mest and Bmp3 in fat mass expansion by using mouse models (Aim 1) and primary cell lines (Aim 2) with adipose tissue specific deletions for both genes; and, to uncover epigenetic mechanisms that regulate Mest and Bmp3 (Aim 3) by identifying changes in chromatin structure that are associated with their variable expression in adipose tissue of inbred mice. Understanding the mechanisms that regulate Mest and Bmp3 and how these genes control fat mass expansion could identify novel therapeutic targets 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。其中两个基因，中胚层特异性转录本（Mest）；母系印记基因位于内质网/高尔基体中，基于与 1/2 水解酶超家族成员的同源性，它可以充当脂肪酶或酰基转移酶；骨形态发生蛋白 3 (Bmp3) 是一种骨形成拮抗剂，可作为肥胖的激动剂，在脂肪量快速膨胀时高度协调表达。在成年后注定会发生饮食诱导肥胖的幼年小鼠的脂肪组织活检中，Mest 和 Bmp3 表达升高，表明在喂养高脂肪饮食之前调节这些基因的分子变化已经确定。在基因相同的小鼠中，Mest 和 Bmp3 的协调表达以及与脂肪量扩张变化的正相关表明，表观遗传机制参与了它们的调节。本提案中的研究将通过使用小鼠模型（目标 1）和原代细胞系（目标 2）确定 Mest 和 Bmp3 在脂肪量扩张中的功能作用，这两个基因均具有脂肪组织特异性缺失；通过识别与近交小鼠脂肪组织中的可变表达相关的染色质结构变化，揭示调节 Mest 和 Bmp3 的表观遗传机制（目标 3）。了解调节 Mest 和 Bmp3 的机制以及这些基因如何控制脂肪量扩张可以确定治疗肥胖的新治疗靶点。