CHROMATIN REMODELING AND ADIPONECTIN GENE EXPRESSION: REGULATION BY OBESITY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目前，超过4400万美国人根据身体质量指数(BMI)被认为肥胖，这一数字自1991年以来增长了74%。在同一时间框架内，糖尿病增加了61%，反映了肥胖和糖尿病发展之间的强烈相关性。根据疾病控制和预防中心的这项研究，目前美国估计有1700万人患有糖尿病。肥胖与糖尿病、心血管疾病和许多其他健康问题有关。最近的研究表明，脂肪组织不仅是一种简单的能量储存组织，还具有重要的内分泌功能。有几种激素由脂肪组织合成和分泌，调节其他器官或系统的能量代谢，如食物摄入量和胰岛素敏感性。脂联素是一种脂肪来源的激素，在维持能量和葡萄糖代谢方面起着关键作用。脂联素基因表达减弱和低血浓度在肥胖症和2型糖尿病中都有很好的记录。然而，调控脂联素表达的分子机制以及在肥胖和2型糖尿病中损害脂联素基因表达的致病机制仍然知之甚少。我们的初步数据表明，在人类脂联素基因的第一内含子中存在新的脂肪细胞特异性调节元件(增强子)，并且转录因子C/EBP是调节脂联素表达所必需的。此外，已证明C/EBP将SWI/SNF染色质重塑复合体招募到靶基因中，并参与成脂过程。我们建议研究染色质重塑在脂肪细胞分化过程中对脂联素基因表达的调控作用，并探讨肥胖症中脂联素表达下调的分子机制。这项研究将为脂联素合成的调节提供新的见解，并最终可能导致肥胖相关糖尿病和心血管疾病的新疗法。重要的是，这些研究将提供令人信服的初步数据，支持NIH R01的应用。这个Cobre项目还将为我提供一个独特的机会，让我与其他PI合作，将我的研究转化为与肥胖相关的心血管疾病。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Currently, more than 44 million Americans are considered obese by body mass index (BMI), reflecting an increase of 74 percent since 1991. During the same time frame, diabetes increased by 61 percent, reflecting the strong correlation between obesity and the development of diabetes. Today an estimated 17 million people have diabetes in the United States, according to the study by the Centers for Disease Control and Prevention. Obesity is associated with diabetes, cardiovascular diseases, and many other health problems. Recent studies indicate that adipose tissue is not simply a tissue for energy storage, but also serves an important endocrine function. There are several hormones that are synthesized and secreted from adipose tissue and regulate energy metabolism of other organs or system, such as food intake and insulin sensitivity. Adiponectin is an adipose-derived hormone that plays a critical role in maintaining energy and glucose metabolism. Diminished adiponectin gene expression and low blood concentrations have been well documented in both obesity and type 2 diabetes. However, the molecular mechanisms that regulate adiponectin expression and the causative mechanisms that impair adiponectin gene expression in obesity and type 2 diabetes remain poorly understood. Our preliminary data demonstrate novel adipocyte-specific regulatory elements (enhancer) in the first intron of the human adiponectin gene, and that the transcription factor C/EBP¿ is required for regulating adiponectin expression. Furthermore, it has been demonstrated that C/EBP¿ recruits SWI/SNF chromatin-remodeling complexes into target genes and is involved in the adipogenic process. We propose to investigate the role of chromatin remodeling in controlling adiponectin gene expression during adipocyte differentiation, and also to explore the molecular mechanisms that cause down-regulation of adiponectin expression in obesity. This study will provide novel insight into the regulation of adiponectin synthesis and ultimately may lead to a new therapy for obesity related diabetes and cardiovascular disease. Importantly, these studies will provide compelling preliminary data supporting an NIH R01 application. This COBRE project will also provide a unique opportunity for me to collaborate with other PIs to translate my research into obesity-associated cardiovascular disease.