A Novel Role of IEX-1 in High Fat Diet-induced Obesity and Insulin Resistance

描述(申请人提供)：本申请的中心主题是演示IEX-1缺陷如何保护小鼠免受HFD饮食诱导的肥胖和胰岛素抵抗的影响。通过使用相互适应转移技术从造血细胞中特异性地删除IEX-1，我们将阐明IEX-1在调节巨噬细胞表型和高热量消耗时的炎症中的决定性作用。这一操作将帮助我们描述造血细胞中的IEX-1是否在肥胖或胰岛素抵抗的发生中起重要作用。此外，IEX-1在线粒体中高表达，它通过促进线粒体F1F0-ATPase抑制剂IF1蛋白的降解来调节线粒体的呼吸。因此，我们推测IEX-1可能在新陈代谢和能量动态平衡中起直接作用。我们将分别使用高胰岛素-正常血糖钳和间接量热法评估单个组织中的葡萄糖代谢和在没有IEX-1的情况下的能量消耗。最后，为了从机制上了解IEX-1缺乏如何阻止饮食诱导的ATM表型转换，我们将在没有或存在原代脂肪细胞的情况下，对骨髓来源的巨噬细胞进行体外强制M1极化技术。这项研究将为IEX-1和代谢功能以及肥胖之间的机械联系提供新的见解。

DESCRIPTION (provided by applicant): The central theme of this application is to demonstrate how IEX-1 deficiency protects mice against HFD diet-induced obesity and insulin resistance. By employing a reciprocal adaptive transfer technique to specifically delete IEX-1 from hematopoietically derived cells, we will elucidate a decisive role of IEX-1 in regulation of macrophages phenotype and inflammation during high calorie consumption. This maneuver will help us delineate if IEX-1 in hematopoietically derived cells is important for development of obesity or insulin resistance. Furthermore, IEX-1 is highly expressed in mitochondria where it regulates mitochondrial respiration by promoting degradation of mitochondrial F1F0-ATPase inhibitor IF1 protein. Therefore, we suspect that IEX- 1 may have a direct role in metabolism and energy homeostasis. We will assess glucose metabolism in individual tissues and energy expenditure in the absence of IEX-1 using hyperinsulinemic-euglycemic clamp and indirect calorimetry, respectively. Lastly, to gain a mechanistic insight into how IEX-1 deficiency prevents diet-induced switch in ATM phenotype, we will employ an in-vitro forced M1 polarization techniques in bone marrow-derived macrophages co-cultured in the absence or presence of primary adipocytes. The study will provide novel insights into a mechanistic linkage between IEX-1 and metabolic function, and obesity.