NR4A Orphan Receptors And Insulin Resistance

NR4A 孤儿受体和胰岛素抵抗

基本信息

批准号：
8116981
负责人：
W Timothy GARVEY
金额：
$ 46.68万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8116981
关键词：
2,4-thiazolidinedione 9-deoxy-delta-9-prostaglandin D2 Address Adipocytes Adipose tissue Adverse effects Affect Agonist Animals Biopsy Blood Glucose Blood Plasma Volume Body Composition Body Weight Body Weight decreased Cell Culture System Cell Differentiation process Cell Line Cells Cellular Stress Clinical Cultured Cells Data Development Diabetes Mellitus Diabetes prevention Diet Disease Drug Delivery Systems Drug effect disorder Exhibits Family Family member Fatty acid glycerol esters GLUT4 gene Gene Expression Genes Goals Health Heart Heart failure Human Individual Infusion procedures Insulin Insulin Resistance Investigation Isoprostanes Laboratories Ligands Lipids Liver Measures Mediating Mediator of activation protein Metabolic Metabolic Diseases Metabolic syndrome Metabolism Molecular Monitor Mus Muscle Muscle Cells NR4A1 gene Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Orphan Receptor Obesity Orphan Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphorylation Prediabetes syndrome Prevention Process Proteins Research Resistance Rodent Rodent Model Role Signal Transduction Signaling Molecule Skeletal Muscle Small Interfering RNA Subgroup Testing Therapeutic Therapeutic Intervention Thiazolidinediones Time Tissue-Specific Gene Expression Tissues Trans-Activators Transgenic Mice Translational Research Weight Gain Work adipocyte-specific fatty acid-binding protein adipokines base biological adaptation to stress cDNA Arrays cardiovascular disorder risk cyclopentenone diabetes control effective therapy feeding glucose tolerance glucose transport glucose uptake in vivo insulin sensitivity insulin signaling lifestyle intervention lipid mediator lipid metabolism macrophage metabolic abnormality assessment novel osmotic minipump prevent promoter prostaglandin A2 receptor small hairpin RNA subcutaneous therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): Insulin resistance is central to the pathogenesis of Type 2 Diabetes (T2DM) and the Metabolic Syndrome, and drugs or lifestyle interventions that increase insulin sensitivity constitute effective therapy and prevention. Thiazolidinedione drugs (TZDs) act through agonism of nuclear transcription factors (i.e., PPAR3) to enhance insulin sensitivity; however, TZD therapy is associated with adverse effects, including weight gain and heart failure. These untoward effects limit clinical utility, and highlight the need for alternative insulin-sensitizing medications that can act directly on muscle. We will study the NR4A family of orphan nuclear receptors, which were identified as differentially expressed genes on our human muscle cDNA microarrays. Extensive preliminary data indicate that: (i) NR4A3 is expressed at lower levels in insulin-resistant humans and rodents; (ii) TZDs induce NR4A3 suggesting that NR4A3 may be downstream of TZD action; (iii) MCK-NR4A3 transgenic mice exhibit an insulin sensitive phenotype; (iv) an increase in NR4A3 receptors can augment insulin signaling and stimulation of glucose transport; (v) PGA2 acts to increase insulin sensitivity in a NR4A3 dependent manner. To pursue these novel observations, our overall goal is to increase our understanding of the role of NR4A receptors in modulating insulin action, their role in human insulin resistance, and their rationale as a therapeutic drug target. To achieve this goal, we will apply our laboratory's capacity for translational research including human metabolism, human muscle and adipose tissue biopsies, transgenic mice, and cultured cell systems. Based on extensive preliminary data, the specific aims are: (1) Assess expression of NR4A receptors in muscle and fat in insulin sensitive, insulin resistant, and T2DM humans, before and after weight loss and TZD treatment, and in insulin resistant rodent models. (2) Establish metabolic role of NR4A3 by phenotyping transgenic mice with specific hyperexpression of NR4A3 in skeletal muscle. In both human and mouse, NR4A expression will be assessed for its ability to affect insulin sensitivity and substrate metabolism at the level of whole body and individual cells and tissues. (3) Determine mechanisms by which NR4A3 regulates insulin action by studying stable hyperexpression and shRNA- mediated suppression of NR4A3 in cultured muscle and adipose cells. These studies will address our preliminary data indicating that NR4A3 modulates insulin-stimulated glucose transport, GLUT4 translocation, and insulin-mediated phosphorylation of signaling molecules. (4) Identify lipid mediator agonists of NR4A3 based on preliminary data indicating that PGA2 increases insulin sensitivity in a NR4A3 dependent manner. Thus, this work will elucidate novel molecules and pathophysiologic processes contributing to insulin resistance, and develop new potential drug targets for the treatment and prevention of diabetes and cardiometabolic disease. PUBLIC HEALTH RELEVANCE: Insulin resistance is a critical factor causing Type 2 Diabetes and the Metabolic Syndrome. Treatment of insulin resistance can prevent diabetes and control blood sugars in patients who already have the disease; however, the available medications have serious side effects which limit their use. This research will elucidate, for the first time, the role of a novel family of orphan nuclear transcription factors (NR4A) in the cause of insulin resistance, and their potential as targets for new drugs to treat and prevent Type 2 Diabetes.

描述（由申请人提供）：胰岛素抵抗是 2 型糖尿病 (T2DM) 和代谢综合征发病机制的核心，增加胰岛素敏感性的药物或生活方式干预构成有效的治疗和预防。噻唑烷二酮类药物 (TZD) 通过激动核转录因子（即 PPAR3）发挥作用，增强胰岛素敏感性；然而，TZD 疗法会产生不良反应，包括体重增加和心力衰竭。这些不良影响限制了临床实用性，并凸显了对可直接作用于肌肉的替代胰岛素增敏药物的需求。我们将研究孤儿核受体 NR4A 家族，这些受体在我们的人类肌肉 cDNA 微阵列上被鉴定为差异表达基因。大量初步数据表明： (i) NR4A3 在胰岛素抵抗人类和啮齿动物中表达水平较低； (ii) TZD 诱导 NR4A3，表明 NR4A3 可能是 TZD 作用的下游； (iii) MCK-NR4A3转基因小鼠表现出胰岛素敏感表型； (iv) NR4A3 受体的增加可以增强胰岛素信号传导和葡萄糖转运的刺激； (v) PGA2 以 NR4A3 依赖性方式增加胰岛素敏感性。为了进行这些新的观察，我们的总体目标是增加我们对 NR4A 受体在调节胰岛素作用中的作用、它们在人类胰岛素抵抗中的作用以及它们作为治疗药物靶点的基本原理的理解。为了实现这一目标，我们将运用实验室的能力进行转化研究，包括人类新陈代谢、人类肌肉和脂肪组织活检、转基因小鼠和培养细胞系统。基于广泛的初步数据，具体目标是：（1）评估胰岛素敏感、胰岛素抵抗和 T2DM 人类、减肥和 TZD 治疗前后以及胰岛素抵抗啮齿动物模型中肌肉和脂肪中 NR4A 受体的表达。 (2) 通过对骨骼肌中 NR4A3 特异性超表达的转基因小鼠进行表型分析，确定 NR4A3 的代谢作用。在人和小鼠中，将评估 NR4A 表达在全身以及单个细胞和组织水平上影响胰岛素敏感性和底物代谢的能力。 (3) 通过研究培养的肌肉和脂肪细胞中 NR4A3 的稳定超表达和 shRNA 介导的抑制，确定 NR4A3 调节胰岛素作用的机制。这些研究将解决我们的初步数据，表明 NR4A3 调节胰岛素刺激的葡萄糖转运、GLUT4 易位和胰岛素介导的信号分子磷酸化。 (4)基于表明PGA2以NR4A3依赖性方式增加胰岛素敏感性的初步数据鉴定NR4A3的脂质介质激动剂。因此，这项工作将阐明导致胰岛素抵抗的新分子和病理生理过程，并开发用于治疗和预防糖尿病和心脏代谢疾病的新的潜在药物靶点。公共卫生相关性：胰岛素抵抗是导致 2 型糖尿病和代谢综合征的关键因素。治疗胰岛素抵抗可以预防糖尿病并控制已患有糖尿病的患者的血糖；然而，现有的药物有严重的副作用，限制了它们的使用。这项研究将首次阐明孤儿核转录因子 (NR4A) 的新家族在胰岛素抵抗中的作用，以及它们作为治疗和预防 2 型糖尿病新药靶点的潜力。