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

项目摘要 发达国家肥胖症流行率的上升没有显示出减弱的迹象， 巨大压力下的社会这一负担既与金钱有关，也与健康有关，因为肥胖是一种 2型糖尿病及其相关并发症发生的强风险因素：冠状动脉 心脏病和中风。在我们对癌症病理学的理解上已经取得了很大的进展， 肥胖相关疾病，但越来越清楚的是，需要新的方法来找到 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靶点 方面的影响.一种这样的方法是针对脂肪组织的功能，脂肪组织是最前沿的器官。 肥胖症的代谢紊乱。脂肪组织产生许多分泌因子， 对全身代谢产生深远影响。最值得注意的是，脂联素（Apn），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，这种效应已被证明有助于肥胖相关的 疾病迄今为止，找到一种切实可行的方法来利用 脂联素。我们最近发现了一种限制脂联素的调节机制 在脂肪细胞中的表达。在这个项目中，我建议，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方法来恢复肥胖症患者减少的脂联素水平沿着 从而增强全身胰岛素敏感性并减少炎症。我们创造了第一个 转基因小鼠模型，使我们能够在任何组织中诱导过表达脂联素。感应 肝脏或肾脏Apn mRNA的表达增加可导致血清Apn水平升高。有趣的是， 在脂肪组织中诱导Apn导致血清Apn降低。在此，我将详细说明这一点 初步数据和实验设计，以表征这种机制，抑制Apn 在脂肪细胞中特异性表达，并确定在脂肪细胞中特异性表达后恢复Apn的功效。 提高胰岛素敏感性。

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.