ROLE OF RESISTIN IN INSULIN RESISTANCE

抵抗素在胰岛素抵抗中的作用

• 批准号: 7486267
• 负责人: MITCHELL A. LAZAR
• 金额: $ 30.55万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486267
• 关键词: 2,4-thiazolidinedione; Address; Adipocytes; Adipose tissue; Affect; Area; Atherosclerosis; Attenuated; Biochemical; Blood Vessels; Cardiovascular Diseases; Cells; Cellular Assay; Cessation of life; Conflict (Psychology); Cysteine; Data; Diabetes Mellitus; Diet; Dimerization; Disease; Epidemic; Family; Functional disorder; Funding; Genes; Genetic; Genetic Models; Glucose; Goals; Hormones; Human; Hyperglycemia; Insulin; Insulin Resistance; Intervention; Knockout Mice; Leptin; Leptin deficiency; Link; Liver; Low Density Lipoprotein Receptor; Mediating; Mediator of activation protein; Metabolic; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Peroxisome Proliferator-Activated Receptors; Physiological; Physiology; Play; Production; Program Research Project Grants; Proteins; Research Personnel; Resistance; Risk Factors; Role; Signal Transduction; Small Interfering RNA; Societies; Source; Standards of Weights and Measures; System; Techniques; Testing; Thiazolidinediones; Tissues; Transgenes; Transgenic Mice; Translating; Translations; United States; Work; atherogenesis; base; cell type; cysteine-rich secreted protein FIZZ3; cytokine; disulfide bond; glucose metabolism; impaired glucose tolerance; improved; in vivo; insight; interest; lipid metabolism; low density lipoprotein inhibitor; macrophage; member; mouse model; mutant; novel; novel therapeutics; programs; promoter; research study; resistin

Diabetes is a leading cause of morbidity and death in the United States. Obesity is a major risk factor for the most common form of diabetes, type 2 diabetes, which is characterized by resistance to the actions of insulin. We have discovered a novel, secreted protein called resistin that is adipocyte-specific and circulates at elevated levels in obesity. Hyperresistinemia impairs glucose tolerance, and lack of resistin improves hyperglycemia and insulin resistance in mice with diet induced obesity. We hypothesize that 1) resistin will alter insulin action and cardiovascular disease in genetic models of obesity and atherosclerosis; 2) cellular actions of resistin involve induction of SOCS-3 and/or inhibition of AMPK, mediated by discrete biochemical forms of resistin; and 3) that the effects of mouse resistin are translatable to the human. These hypotheses will be directly tested in the experiments proposed in this project. Specific Aim 1 is to determine the effects of resistin deficiency in genetic models of obesity and atherosclerosis. We hypothesize that mice lacking resistin will be protected from obesity-associated diabetes and atherosclerosis, and will test this by crossing resistin knockout mice with leptin-deficient ob/ob mice and LDL-receptor null mice, respectively. Specific Aim 2 is to understand the molecular and cellular determinants of resistin signaling. We will systematically test the importance of resistin dimerization in a variety of cell types, focusing on potential mechanisms by which resistin influences glucose metabolism that were cellular assays in different cell types, focusing on the inhibition of AMPK, as well as the activation of SOCS-3 in several cell types. Specific Aim 3 is to derive and characterize humanized mouse models of resistin expression and physiology. One of the major questions about resistin concerns the translation of the insights from mouse models to humans. Mouse resistin is derived exclusively from adipose tissue, whereas macrophages are a major source of resistin in humans. Preliminary data suggest that human and mouse resistin signal similarly in mouse cells. Human resistin will be expressed in transgenic mice from a liver specific-transgene as well as the human promoter which, in humans, expresses resistin primarily in macrophages. These studies will test the hypothesis that human resistin functions in the mouse, and will provide novel in vivo systems to determine whether human resistin is a potential mediator of insulin resistance. Together, the proposed studies will address critical questions about the role of resistin as a link between obesity, insulin resistance, and diabetes, and a potential target for intervention in these devastating diseases. These studies have important implications for our society in which diabetes and obesity are rampant.

糖尿病是美国发病和死亡的主要原因。肥胖症是一个主要的危险因素， 糖尿病的最常见形式，2型糖尿病，其特征在于对以下作用的抵抗： 胰岛素我们已经发现了一种新的分泌蛋白，称为脂肪细胞特异性蛋白， 肥胖症的发病率也在上升。高抵抗素血症损害葡萄糖耐量，而缺乏β-葡聚糖可改善 高血糖和胰岛素抵抗。我们假设1）如果 在肥胖和动脉粥样硬化的遗传模型中改变胰岛素作用和心血管疾病; 2）细胞 Bcln的作用涉及SOCS-3的诱导和/或AMPK的抑制，由离散的生物化学物质介导。 3）小鼠的β-淀粉样蛋白的作用可以翻译给人类。这些假设 将在本项目中提出的实验中直接进行测试。具体目标1是确定 肥胖症和动脉粥样硬化遗传模型中β-半胱氨酸缺乏的影响。我们假设 缺乏β-淀粉样蛋白的小鼠将免受肥胖相关的糖尿病和动脉粥样硬化的影响， 通过分别将Leptin敲除小鼠与瘦素缺乏的ob/ob小鼠和LDL受体缺失小鼠杂交。 具体目标2是了解的分子和细胞的决定因素的信号转导。我们将 系统地测试在各种类型的细胞中，BRN二聚化的重要性，重点是潜在的 在不同细胞类型的细胞试验中， 集中于AMPK的抑制以及几种细胞类型中SOCS-3的激活。具体目标3 目的是获得和表征人源化小鼠模型中的GSTN表达和生理学。之一 关于生物进化的主要问题是如何将小鼠模型的见解转化为人类。 小鼠巨噬细胞仅来源于脂肪组织，而巨噬细胞是其主要来源。 人体抵抗素。初步数据表明，人类和小鼠的cDNAn在小鼠细胞中的信号相似。 人Bcln将在转基因小鼠中从肝特异性转基因以及人Bcln中表达。 启动子，在人类中主要在巨噬细胞中表达cDNAn。这些研究将测试 假设人的BcN在小鼠中起作用，并将提供新的体内系统来确定 人β-氨基丁酸是否是胰岛素抵抗的潜在介质。拟议的研究将共同 解决关键问题的作用，作为肥胖，胰岛素抵抗， 糖尿病，以及对这些毁灭性疾病进行干预的潜在目标。这些研究具有重要意义 对我们这个糖尿病和肥胖症猖獗的社会的影响。