权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

CONTROL OF ADIPOGENESIS AND ENERGY METABOLISM

脂肪生成和能量代谢的控制

基本信息

批准号：
8053723
负责人：
STEPHEN ROBERT FARMER
金额：
$ 33.84万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-06-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8053723
关键词：
2,4-thiazolidinedione Acute-Phase Proteins Adipocytes Adult Attention Award CCAAT-Enhancer-Binding Proteins CCL2 gene Code Complex Data Deacetylase Development Disease Energy Metabolism Enhancers Epidemic FGF21 gene Family Funding Future GLUT4 gene Gene Expression Genes Goals Grant HDAC3 gene Haptoglobins Health Homeostasis Individual Inflammatory Insulin Insulin Resistance Ligand Binding Domain Ligands Metabolic Metabolic Control Molecular Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity Organism Overweight Oxidoreductase Peroxisome Proliferator-Activated Receptors Phase Phosphorylation Post-Translational Protein Processing Process Proteins Research Design Role Series Signal Pathway Signal Transduction Small Interfering RNA Technology Thiazolidinediones adiponectin energy balance glucose uptake insulin sensitivity insulin sensitizing drugs lipid biosynthesis multicatalytic endopeptidase complex novel programs promoter protein expression response transcription factor

项目摘要

DESCRIPTION (provided by applicant): The modern world is in the midst of an obesity epidemic that is growing to the extent that, in 2003-2004, 32% of US adults were obese and >50% were overweight. This increase in adiposity has led to a significant increase in the number of individuals with obesity-related disorders including type 2-diabetes. It is well accepted that the adipocyte is a central player in the development of insulin resistance that leads to type 2 diabetes. It is important, therefore, to define the mechanisms by which adipocytes regulate insulin responsive processes in the body. To this end, we have focused our attention on understanding the role of adipogenic transcription factors, most notably C/EBPs and PPAR?, in regulating the formation and function of adipocytes. During these studies, we identified a domain in PPAR? that facilitates inhibition of the Wnt signaling pathway in order to promote adipogenesis. These studies have led to a series of novel and exciting data that represent the core of our future aims. Specifically, we have demonstrated that helix 7 within the ligand-binding domain of PPAR? is required for its response to endogenous ligands. We also demonstrate that helix 7 regulates expression of a novel subset (Group 2) of adipogenic genes, including FGF21 and Ero1-La, that respond to the activity of the NAD-dependent deacetylase, SIRT1. We show that adiponectin secretion is regulated by Ero1-La and changes in PPAR? and SIRT1 activity. We have also identified two other subsets of adipogenic genes: Group 3 genes encode inflammatory proteins such as Ccl2/MCP-1 and are down-regulated during adipogenesis in a PPAR?-associated manner; Group 4 genes encode acute-phase reactants such as haptoglobin and are induced during adipogenesis, but are inhibited by the thiazolidinedione family of insulin sensitizers. The goal of these studies is to define the mechanisms by which PPAR? regulates such a physiologically important and diverse program of adipogenic gene expression. The specific aims are: 1. Define the role of SIRT1, HDAC3 and PGC-1a in regulating PPAR? target gene expression during adipogenesis and in mature adipocytes. 2: Identify the transcriptional complexes associating with PPAR? on the promoters/enhancers of select genes in mature adipocytes. 3: Define the role of helix 7 within the ligand- binding domain of PPAR? in controlling adipocyte gene expression. 4: To determine the role of posttranslational modification of PPAR? in regulating expression of adipocyte genes. PUBLIC HEALTH RELEVANCE: The modern world is in the midst of an obesity epidemic that is growing to the extent that, in 2003-2004, 32% of US adults were obese and >50% were overweight and this increase in adiposity has led to a significant increase in the number of individuals with obesity-related disorders including type 2-diabetes. It is well accepted that the adipocyte is a central player in the development of insulin resistance that leads to type 2 diabetes; consequently, it is important to define the mechanisms by which adipocytes regulate insulin responsive processes in the body. To this end, the studies are designed to define the mechanisms by which the `master regulator' of adipocyte formation, PPAR?, regulates expression of the genes coding for select proteins involved in metabolic homeostasis and energy balance including FGF21, ¿Klotho and adiponectin.

描述（由申请人提供）：现代世界正处于肥胖流行之中，这种流行趋势日益严重，2003-2004 年，32% 的美国成年人肥胖，超过 50% 的人超重。肥胖人数的增加导致患有肥胖相关疾病（包括 2 型糖尿病）的人数显着增加。人们普遍认为，脂肪细胞是导致 2 型糖尿病的胰岛素抵抗发展的核心因素。因此，确定脂肪细胞调节体内胰岛素反应过程的机制非常重要。为此，我们将注意力集中在了解脂肪形成转录因子（尤其是 C/EBP 和 PPAR？）在调节脂肪细胞的形成和功能中的作用。在这些研究中，我们确定了 PPAR? 中的一个域？促进 Wnt 信号通路的抑制，从而促进脂肪生成。这些研究产生了一系列新颖且令人兴奋的数据，代表了我们未来目标的核心。具体来说，我们已经证明螺旋 7 在 PPAR? 的配体结合域内？是其对内源配体作出反应所必需的。我们还证明，螺旋 7 调节脂肪形成基因的新子集（第 2 组）的表达，包括 FGF21 和 Ero1-La，这些基因对 NAD 依赖性脱乙酰酶 SIRT1 的活性做出反应。我们发现脂联素分泌受 Ero1-La 和 PPAR? 变化的调节？和 SIRT1 活性。我们还鉴定了脂肪形成基因的另外两个子集：第 3 组基因编码 Ccl2/MCP-1 等炎症蛋白，并在脂肪形成过程中以 PPAR？相关方式下调；第 4 组基因编码急性期反应物，例如触珠蛋白，并在脂肪形成过程中被诱导，但受到胰岛素增敏剂噻唑烷二酮家族的抑制。这些研究的目标是确定 PPAR 的作用机制？调节这样一个生理上重要且多样化的脂肪形成基因表达程序。具体目标是： 1. 明确SIRT1、HDAC3和PGC-1a在调节PPAR中的作用？脂肪生成期间和成熟脂肪细胞中的靶基因表达。 2：确定与 PPAR 相关的转录复合物？成熟脂肪细胞中选择基因的启动子/增强子。 3：定义螺旋 7 在 PPAR 配体结合域中的作用？控制脂肪细胞基因表达。 4：确定PPAR翻译后修饰的作用？调节脂肪细胞基因的表达。公共健康相关性：现代世界正处于肥胖流行之中，2003-2004 年，美国成年人中有 32% 肥胖，超过 50% 超重，肥胖人数的增加导致患有肥胖相关疾病（包括 2 型糖尿病）的人数显着增加。人们普遍认为，脂肪细胞是导致 2 型糖尿病的胰岛素抵抗发展的核心因素。因此，确定脂肪细胞调节体内胰岛素反应过程的机制非常重要。为此，这些研究旨在明确脂肪细胞形成的“主调节器”PPAR？调节编码参与代谢稳态和能量平衡的选定蛋白质（包括 FGF21、Klotho 和脂联素）的基因表达的机制。