ROLE OF RESISTIN IN INSULIN RESISTANCE

在美国，糖尿病是导致发病和死亡的主要原因。肥胖是老年人的一个主要风险因素 最常见的糖尿病形式是2型糖尿病，其特征是对 胰岛素。我们发现了一种名为抵抗素的新的分泌性蛋白质，它是脂肪细胞特有的，可以在体内循环 在肥胖症的高水平。高抵抗素血症损害糖耐量，抵抗素缺乏改善 饮食诱导肥胖小鼠的高血糖和胰岛素抵抗。我们假设抵抗素会 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 抵抗素的作用涉及离散生化介导的SOCS-3诱导和/或AMPK抑制 抵抗素的形式；以及3)小鼠抵抗素的作用是可以翻译给人类的。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 抵抗素缺乏在肥胖和动脉粥样硬化遗传模型中的作用。我们假设 缺乏抵抗素的小鼠将被保护，免受肥胖相关的糖尿病和动脉粥样硬化的影响，并将对此进行测试 通过将抵抗素基因敲除小鼠分别与瘦素缺陷ob/ob小鼠和低密度脂蛋白受体缺失小鼠杂交。 具体目标2是了解抵抗素信号的分子和细胞决定因素。我们会 系统地测试抵抗素二聚化在各种细胞类型中的重要性，重点是潜在的 抵抗素影响葡萄糖代谢的机制是不同细胞类型的细胞分析， 重点是AMPK的抑制，以及SOCS-3在几种细胞类型中的激活。具体目标3 是推导和表征抵抗素表达和生理学的人源化小鼠模型。其中之一 关于抵抗素的主要问题涉及从老鼠模型到人类的洞察力的转换。 小鼠抵抗素完全来自脂肪组织，而巨噬细胞是主要来源 人类体内的抵抗素。初步数据表明，人类和小鼠的抵抗素信号在小鼠细胞中相似。 人类抵抗素将在肝脏特异转基因的转基因小鼠中表达，与人类一样 启动子，在人类中主要在巨噬细胞中表达抵抗素。这些研究将测试 假设人类抵抗素在小鼠中起作用，并将提供新的体内系统来确定 人类抵抗素是否是胰岛素抵抗的潜在介体。总而言之，拟议的研究将 解决有关抵抗素作为肥胖、胰岛素抵抗和 糖尿病，以及干预这些毁灭性疾病的潜在目标。这些研究具有重要的意义 对糖尿病和肥胖症猖獗的社会的影响。

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.