Molecular Mechanisms of Obesity and Insulin Resistance

肥胖和胰岛素抵抗的分子机制

• 批准号: 6420299
• 负责人: GREGORY L. FLORANT
• 金额: $ 14.38万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6420299
• 关键词: biological signal transduction; ceramides; diabetes mellitus; free fatty acids; glucose metabolism; glucose tolerance; guanine nucleotide binding protein; hibernation; hyperinsulinism; immunoprecipitation; insulin receptor; insulin sensitivity /resistance; leptin; lipid metabolism; marmots; noninsulin dependent diabetes mellitus; northern blottings; obesity; polymerase chain reaction; protein kinase; thin layer chromatography; tumor necrosis factor alpha; weight control; western blottings

DESCRIPTION (provided by applicant): Obesity is associated with insulin resistance and type II diabetes, but the molecular events linking increased adiposity to these pathological conditions remains unclear. We intend to utilize a novel mammalian model of obesity and insulin resistance, the pre-hibernating marmot, to characterize the molecular defects underlying the development of these abnormal conditions. During the autumn, marmots undergo a doubling of body mass in the form of fat. This weight gain is associated with a profound hyperinsulinemia, and marmots display all of the characteristics of peripheral insulin resistance. Before this insulin resistance develops into frank diabetes, however, the animals begin hibernation, where they have suppressed appetite and rely almost exclusively on fat stores for energy. During this period, insulin resistance is apparently reversed, as the circulating insulin levels return to normal. None of the insulin signal transduction pathways have been evaluated during the astonishing period of weight gain, nor have they been investigated during the animal's subsequent conversion into this lipolytic state. In the studies described herein, we will characterize the effect of this rapid weight gain on insulin's ability to activate known signaling intermediates. We will obtain blood samples and tissue biopsies from these animals throughout the course of this pre-hibernation period, as well as following entry into hibernation. These studies could uncover important information about the molecular events associated with the development of insulin resistance. Moreover, by correlating the concentration of fat-derived circulating factors (e.g. free fatty acids, tumor necrosis factor-alpha, and resistin) with the degree of insulin resistance, we might uncover novel information about the contribution of these factors to the pathogenesis of type II diabetes mellitus. Ultimately, the exaggerated characteristics of hibernators could assist us in the identification of abnormalities relevant to the human condition.

描述（由申请人提供）：肥胖与胰岛素相关 抵抗和II型糖尿病，但分子事件连接增加 肥胖与这些病理状况的关系尚不清楚。我们打算 利用一种新的肥胖和胰岛素抵抗的哺乳动物模型， 冬眠前土拨鼠，以表征潜在的分子缺陷， 这些异常情况的发展。在秋天，土拨鼠经历了一个 以脂肪的形式使体重加倍。这种体重增加与 严重的高胰岛素血症，土拨鼠表现出所有的特征， 外周胰岛素抵抗在胰岛素抵抗发展成 然而，坦率的糖尿病，动物开始冬眠， 抑制食欲，几乎完全依赖脂肪储存来提供能量。 在此期间，胰岛素抵抗明显逆转， 循环胰岛素水平恢复正常。没有胰岛素信号 转导途径已经在惊人的时期进行了评估， 体重增加，也没有在动物随后的 转化为这种脂肪分解状态。在本文所述的研究中，我们将 描述这种快速体重增加对胰岛素能力的影响， 激活已知的信号传导中间体。我们将获取血液样本和组织 这些动物在冬眠前的活组织检查 进入休眠期后，也是如此。这些研究可以 揭示了有关与癌症相关的分子事件的重要信息， 胰岛素抵抗的发展。此外，通过将浓度 脂肪来源的循环因子（例如游离脂肪酸、肿瘤坏死 α因子和β-淀粉样蛋白）与胰岛素抵抗的程度，我们可能 发现新的信息，这些因素的贡献 II型糖尿病的发病机制。最终，被夸大的 冬眠动物的特征可以帮助我们识别 与人类状况相关的异常。