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。上升 肥胖率有显著的健康后果，导致代谢性疾病的发病率增加 包括2型糖尿病、脂肪变性、高血压和心脏病。肥胖和胰岛素 抵抗和糖尿病是复杂的，以及肥胖的增加如何导致代谢和心血管疾病 并发症仍然是知识方面的一个关键空白。我们令人兴奋的初步数据显示， 纤溶酶原受体Plg-RKT在瘦小鼠的脂肪组织中高度表达，并响应于高脂肪 在高脂饮食（HFD）中，Plg-RKT的脂肪表达显著降低。此外，HFD喂养的Plg-RKT-/-小鼠获得 与Plg-RKT +/+相比，体重更高，胰岛素抵抗/葡萄糖不耐受更严重，肝脂肪变性更严重 同窝出生的这些代谢异常与脂肪组织巨噬细胞增多有关 积累和炎症，增加脂肪纤维化和减少的标志物的表达， 脂肪生成此外，Plg-RKT在前脂肪细胞中表达较低，但在生长过程中显著增加。 脂肪形成;与促进脂肪形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协调地 调节脂肪功能的多个方面，这些方面对于维持有效的脂肪细胞功能也很重要 通过直接促进脂肪细胞脂肪生成和直接促进脂肪细胞 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的是确定Plg-RKT 调节脂肪功能和全身代谢，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质沉积。核心假设是 Plg-RKT促进健康的脂肪细胞功能并维持全身代谢稳态 通过协调调节脂肪生成、胰岛素信号、炎症和纤维化。为了验证我们的假设， 具体的目的是：1）阐明Plg-RKT在脂肪形成中的作用; 2）确定Plg-RKT在脂肪形成中的作用。 调节胰岛素敏感性; 3）确定Plg-RKT抑制纤维化的机制， 4）进行临床前研究以测试Plg-RKT在肥胖症中的过表达的作用。 vivo.我们将在小鼠中采用饮食诱导的肥胖模型，其具有整体和组织特异性（脂肪和组织特异性）。 具有Plg-RKT的整体和组织特异性过表达的小鼠，以及具有Plg-RKT的整体和组织特异性过表达的小鼠。 Plg-RKT和纤维蛋白原双重缺陷。创新在于对新型纤溶酶原受体的研究 作为调节脂肪功能的多个关键方面的关键焦点。拟议的研究包括 重要的是，新的知识的机制，脂肪的功能和全身代谢 将获得维持体内平衡的药物，具有药物开发的转化潜力。

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.