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

描述（由申请人提供）：本申请的中心主题是证明IEX-1缺乏如何保护小鼠免受HFD饮食诱导的肥胖和胰岛素抵抗。通过采用一种相互适应的转移技术，专门删除IEX-1造血衍生细胞，我们将阐明IEX-1在调节巨噬细胞表型和炎症在高热量消耗的决定性作用。这种方法将帮助我们确定造血细胞中的IEX-1是否对肥胖或胰岛素抵抗的发展很重要。此外，IEX-1在线粒体中高度表达，通过促进线粒体F1 F0-ATP酶抑制剂IF 1蛋白的降解来调节线粒体呼吸。因此，我们怀疑IEX- 1可能在代谢和能量稳态中起直接作用。我们将分别使用高胰岛素-正葡萄糖钳夹和间接量热法评估个体组织中的葡萄糖代谢和不存在IEX-1时的能量消耗。最后，为了获得IEX-1缺陷如何阻止饮食诱导的ATM表型转换的机制性见解，我们将在不存在或存在原代脂肪细胞的情况下共培养的骨髓源性巨噬细胞中采用体外强制M1极化技术。这项研究将为IEX-1与代谢功能和肥胖之间的机制联系提供新的见解。

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.