A Novel Plasminogen Receptor Promotes Adipose Function and Metabolic Homeostasis

项目摘要 2016年，超过19亿成年人超重，其中超过6.5亿人肥胖。升腾 肥胖率对健康有重大影响，会增加代谢性疾病的发病率。 包括2型糖尿病、脂肪变性、高血压和心脏病。肥胖与胰岛素之间的关系 抵抗和糖尿病是复杂的，肥胖症的增加如何导致代谢和心血管疾病 并发症仍然是知识上的一个严重差距。我们令人兴奋的初步数据显示，这部小说 纤溶酶原受体PLG-RKT在瘦小鼠脂肪组织中高表达，并对高脂肪产生反应 饮食(HFD)后，PLG-RKT的脂肪表达显著降低。此外，高脂饲料喂养的PLG-RKT-/-小鼠增加了 与PLG-RKT/相比，更重的体重，更多的胰岛素抵抗/葡萄糖耐量，以及更多的肝脏脂肪变性 一窝产仔。这些代谢异常与脂肪组织巨噬细胞增多有关。 积聚和炎症，增加脂肪纤维化和降低标记物的表达 成脂作用。此外，PLG-RKT在前脂肪细胞中的表达很低，但在 脂肪生成：一种与促进脂肪生成的途径一致的表达模式。因此，令人惊讶的是， 除了维持抗纤维化、抗炎的脂肪环境外，PLG-RKT还协同 调节脂肪功能的多个方面，这些方面对维持有效的脂肪细胞功能也很重要 直接促进脂肪细胞成脂和直接促进脂肪细胞代谢动态平衡 胰岛素敏感性。我们的长期目标是了解PLG-RKT调节生理和 病理过程。！我们在本申请中的目标是确定PLG-RKT 调节脂肪功能和系统代谢，作为维持健康脂肪细胞的统一机制 以及限制慢性脂肪炎症和异位脂肪沉积。核心假设是 讨论的是PLG-RKT促进健康的脂肪细胞功能和维持全身代谢平衡 通过协调调节脂肪生成、胰岛素信号、炎症和纤维化。为了测试我们的假设，我们的 其具体目的是：1)阐明PLG-RKT在脂肪形成中的作用；2)确定PLG-RKT在 调节胰岛素敏感性；3)确定PLG-RKT抑制纤维化和 4)进行临床前研究，以测试PLG-RKT过表达对 活着。我们将采用一种饮食诱导的小鼠肥胖模型，该模型具有全局和组织特异性(脂肪和 巨噬细胞)缺失PLG-RKT、具有PLG-RKT全局和组织特异性过表达的小鼠以及小鼠 PLG-RKT和纤维蛋白原双重缺乏。创新在于研究一种新的纤溶酶原受体 作为调节脂肪功能的多个关键方面的重要焦点。建议进行的研究包括 重要是因为对脂肪功能和全身代谢的机制有了新的了解 动态平衡将被保持，具有翻译潜力的药物开发。

Project Summary In 2016 more than 1.9 billion adults were overweight and, of these, over 650 million were obese. Rising obesity rates have significant health consequences, contributing to increased rates of metabolic diseases including type 2 diabetes, steatosis, hypertension, and heart disease. Associations between obesity, insulin resistance and diabetes are complex, and how an increase in adiposity leads to metabolic and cardiovascular complications remains a critical gap in knowledge. Our exciting preliminary data show that the novel plasminogen receptor, Plg-RKT, is highly expressed in adipose tissue of lean mice and in response to a high fat diet (HFD), adipose expression of Plg-RKT is dramatically reduced. Furthermore, HFD-fed Plg-RKT-/- mice gain more weight, are more insulin resistant/glucose intolerant, and develop more hepatic steatosis than Plg-RKT+/+ littermates. These metabolic abnormalities are associated with increased adipose tissue macrophage accumulation and inflammation, increased adipose fibrosis and decreased expression of markers of adipogenesis. Furthermore, Plg-RKT expression is low in preadipocytes but dramatically increases during adipogenesis; an expression pattern consistent with pathways that promote adipogenesis. Thus, surprisingly, in addition to maintaining the anti-fibrotic, anti-inflammatory adipose environment, Plg-RKT coordinately regulates multiple aspects of adipose function that are also important to maintain efficient adipocyte function and metabolic homeostasis by directly promoting adipocyte adipogenesis and directly promoting adipocyte insulin sensitivity. Our long term goal to understand mechanisms by which Plg-RKT regulates physiologic and pathologic processes.! Our objective in this application is to determine mechanisms by which Plg-RKT regulates adipose function and systemic metabolism, as unifying mechanisms that maintain healthy adipocytes as well as limit chronic adipose inflammation and ectopic lipid deposition. The central hypothesis to be addressed is that Plg-RKT promotes healthy adipocyte function and maintains systemic metabolic homeostasis by coordinately regulating adipogenesis, insulin signaling, inflammation and fibrosis. To test our hypothesis our specific aims are: 1) To elucidate the role of Plg-RKT in adipogenesis; 2) To determine the role of Plg-RKT in regulation of insulin sensitivity; 3) To determine mechanisms by which Plg-RKT inhibits fibrosis and inflammation in obesity; and 4) To perform preclinical studies to test the effects of over-expression of Plg-RKT in vivo. We will employ a diet induced obesity model in mice with global and tissue specific (adipose and macrophage) deletion of Plg-RKT, mice with global and tissue specific overexpression of Plg-RKT, and mice doubly deficient for Plg-RKT and fibrinogen. Innovation lies in the investigation of a novel plasminogen receptor as a crucial focal point for regulation of multiple key aspects of adipose function. The studies proposed are significant because new knowledge of mechanisms by which adipose function and systemic metabolic homeostasis are maintained will be acquired, with translational potential for drug development.