Uncovering New Regulatory Mechanisms of Adiponectin Expression: Cooperation Between the Adipocyte and Adipose Tissue Microenv

项目摘要 发达国家肥胖率的上升并未显示出减弱的迹象， 社会承受着巨大的压力。这一负担既与金钱有关，也与健康有关，因为肥胖是一种 发生II型糖尿病及其相关并发症的强烈危险因素：冠状动脉 心脏病和中风。我们对该病的病理学认识已有很大进展。 肥胖相关的疾病，然而，越来越明显的是，需要新的方法来寻找 以更有效的方式和更少的副作用治疗代谢功能障碍的药理学目标 效果。一种这样的方法是针对脂肪组织的功能，脂肪组织是处于 肥胖症的代谢紊乱。脂肪组织产生许多分泌因子，这些因子具有 对全身新陈代谢有深远的影响。最值得注意的是脂联素(APN)，它已被证明 对肥胖小鼠的胰岛素敏感性和炎症有积极作用。事实上，血清脂联素 在肥胖状态下减少，这一效应已被证明有助于与肥胖相关 疾病。到目前为止，找到一种实用的方法来利用 脂联素。我们最近发现了一种限制脂联素的调节机制 在脂肪细胞中表达。在这个项目中，我提出，如果我们能够进一步了解这个机制， 我们可以找到新的治疗途径来恢复肥胖症患者降低的脂联素水平 如此一来，可以增强全身胰岛素敏感性，减少炎症。我们已经产生了第一个 转基因小鼠模型，允许我们在任何组织中诱导过表达脂联素。归纳 肝脏或肾脏APN基因的表达异常导致血清APN的预期升高。有趣的是， 脂肪组织中APN的诱导导致血清APN的降低。在这里，我将详细说明这一点 初步数据和实验设计来表征这种抑制APN的机制 在脂肪细胞中特异性表达，并确定APN发病后恢复的疗效 肥胖是为了增强胰岛素敏感性。

Project Summary The rising prevalence of obesity in developed countries has shown no signs of abating, putting society under monumental strain. The burden is both monetary and health-related, as obesity is a strong risk factor for the development of type II diabetes and its associated complications: coronary heart disease and stroke. Great progress has been made in our understanding of the pathology of obesity-related diseases, yet it is becoming clear that new approaches are needed to find pharmacological targets to treat metabolic dysfunction in a more effective way and with less side effects. One such approach is to target the function of adipose tissue, the organ at the forefront of metabolic disturbances in obesity. Adipose tissue produces a number of secreted factors that have profound effects on systemic metabolism. Most notably, adiponectin (Apn), which has been shown to have positive effects on insulin sensitivity and inflammation in obese mice. In fact, serum adiponectin is reduced in the obese state, an effect that has been shown to contribute to obesity-associated disease. To date, it has been challenging to find a practical way to harness the benefits of adiponectin. We have recently uncovered a regulatory mechanism that functions to limit adiponectin expression in adipocytes. In this project, I propose that if we can further understand this mechanism, we can find new therapeutic avenues to restore diminished adiponectin levels in obesity and, along with that, enhance systemic insulin sensitivity and reduce inflammation. We have generated the first transgenic mouse model that allows us to inducibly overexpress adiponectin in any tissue. Induction of Apn mRNA in liver or kidney resulted in the expected increase in serum Apn. Interestingly, induction of Apn in adipose tissue resulted in a decrease in serum Apn. Herein, I will detail this preliminary data and the experimental design to characterize this mechanism that restrains Apn expression specifically in the adipocyte and determine the efficacy of restoring Apn after the onset of obesity for enhancing insulin sensitivity.