Molecular Mechanisms of Obesity and Insulin Resistance

描述(申请人提供)：肥胖与胰岛素有关 耐药性和II型糖尿病，但关联的分子事件增加 肥胖对这些病理条件的影响尚不清楚。我们打算 利用一种新的哺乳动物肥胖和胰岛素抵抗模型， 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，土拨鼠经历一次 以脂肪的形式使体重增加一倍。这种体重增加与 严重的高胰岛素血症，土拨鼠表现出 外周胰岛素抵抗。在这种胰岛素抵抗发展成 然而，弗兰克糖尿病，动物开始冬眠，在那里它们有 抑制食欲，几乎完全依赖脂肪储备提供能量。 在此期间，胰岛素抵抗明显逆转，因为 循环中的胰岛素水平恢复正常。没有胰岛素信号 转导通路已经在令人惊讶的时期进行了评估 体重增加，也没有在动物随后的研究中进行调查 转化为这种脂解状态。在这里描述的研究中，我们将 描述这种快速体重增加对胰岛素能力的影响 激活已知的信号中间产物。我们会获取血液样本和组织 这些动物在冬眠前的整个过程中的活组织检查 期间，以及在进入冬眠之后。这些研究可能 发现与分子事件相关的重要信息 胰岛素抵抗的发展。此外，通过将浓度关联起来 脂肪衍生的循环因子(如游离脂肪酸、肿瘤坏死 因子-α和抵抗素)与胰岛素抵抗的程度，我们可能 发现有关这些因素对 2型糖尿病的发病机制。最终，被夸大的 冬眠者的特征可以帮助我们识别 与人类状况相关的异常。

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.