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

揭示脂联素表达的新调控机制：脂肪细胞与脂肪组织微环境之间的合作

• 批准号: 9467119
• 负责人: Clair Crewe
• 金额: $ 5.71万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-05 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9467119
• 关键词: Abate; Adipocytes; Adipose tissue; Advanced Practice Nurse; Adverse effects; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Biochemical; Blood; Cell Nucleus; Cells; Coronary heart disease; Cues; Cytoplasm; Data; Developed Countries; Developing Countries; Development; Elements; Experimental Designs; Extracellular Space; Feedback; Functional disorder; Genes; Genetic Transcription; Goals; Health; Hepatocyte; Homeostasis; Hormones; Human; Immune system; Inflammation; Kidney; Length; Lipids; Liver; Mass Spectrum Analysis; Mediator of activation protein; Messenger RNA; Metabolic; Metabolism; MicroRNAs; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Obesity associated disease; Organ; Pathologic; Pathology; Pathway interactions; Peptide Sequence Determination; Pharmacology; Physiological; Prevalence; Production; Proteins; Public Health; Regulation; Reporting; Risk Factors; Role; Scientific Inquiry; Serum; Signal Transduction; Societies; Stroke; System; Testing; Time; Tissues; Transgenic Mice; Transgenic Organisms; Translations; adiponectin; base; combat; extracellular; gel electrophoresis; insulin sensitivity; insulin sensitizing drugs; insulin signaling; mouse model; nerve supply; novel strategies; novel therapeutics; overexpression; pleiotropism

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.

项目概要 发达国家肥胖患病率的上升没有显示出减弱的迹象， 社会承受着巨大的压力。这种负担既与金钱有关，又与健康有关，因为肥胖是一种 发生 II 型糖尿病及其相关并发症的强危险因素：冠状动脉 心脏病和中风。我们对病理学的认识取得了很大进展 肥胖相关疾病，但越来越明显的是，需要新的方法来发现 以更有效且副作用更少的方式治疗代谢功能障碍的药理靶点 影响。其中一种方法是针对脂肪组织的功能，脂肪组织是处于最前沿的器官。 肥胖中的代谢紊乱。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）已被证明可以 对肥胖小鼠的胰岛素敏感性和炎症有积极影响。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 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理解这个机制， 我们可以找到新的治疗途径来恢复肥胖症中降低的脂联素水平，并且 从而增强全身胰岛素敏感性并减少炎症。我们已经生成了第一个 转基因小鼠模型使我们能够在任何组织中诱导性过度表达脂联素。就职 肝脏或肾脏中 Apn mRNA 的减少导致血清 Apn 的预期增加。有趣的是， 脂肪组织中Apn 的诱导导致血清Apn 降低。在此，我将详细介绍这一点 初步数据和实验设计来表征这种抑制 Apn 的机制 特异性在脂肪细胞中表达并确定在 Apn 发作后恢复 Apn 的功效 肥胖可增强胰岛素敏感性。