Adipose Tissue Macrophage Iron Metabolism in Obesity

描述（由申请人提供）：自第一次报道巨噬细胞浸润脂肪组织（AT）并导致胰岛素抵抗（IR）以来，只有10年的时间。从那时起，该领域的新进展包括：1)巨噬细胞在死亡的脂肪细胞周围形成冠状结构；2)其他白细胞，如T淋巴细胞、B细胞、肥大细胞和中性粒细胞也被招募到AT； 3) AT巨噬细胞可以向M1或M2表型极化。迄今为止，atm的极化已被用作它们是常驻和抗炎（M2）还是招募和炎症（M1）的指示。ATM极化的主流模型认为，“常驻”ATM表现出“选择性激活”的M2表型，而在肥胖发病期间招募到脂肪组织的巨噬细胞则表现出主要的M1“经典激活”状态。M2巨噬细胞被认为在其他器官的组织重塑和修复中发挥作用。然而，M2巨噬细胞在AT中的生理功能尚不清楚。在这项应用中，我们提出M2 AT巨噬细胞在局部铁循环和稳态中的作用，从而为AT微环境中的这些细胞提供了一种特定的功能。此外，我们提出肥胖降低了M2巨噬细胞正确处理铁的能力，从而导致脂肪组织功能障碍。在其他器官，特别是肝脏和脾脏，巨噬细胞在铁稳态中起关键作用。已知M1和M2巨噬细胞都能隔离铁。M1固铁的作用是抑菌；然而，M2铁固存的作用尚不清楚。我们有令人兴奋的初步数据表明，约5%的AT巨噬细胞是顺磁性和隔离铁的。这些巨噬细胞具有反映M2极化的基因表达模式，铁代谢相关基因如血氧合酶-1、铁转运蛋白、转铁蛋白受体和铁蛋白多肽的表达升高。此后，我们将这些细胞称为MFehi细胞。低脂（LF）和高脂（HF）喂养小鼠的AT中均存在MFehi细胞。在细胞基础上，MFehi细胞比MFelo细胞含有更少的铁，它们的基因表达谱表明，与LF饮食小鼠的MFehi细胞相比，它们在铁循环方面存在缺陷。这项探索性/发现性R21应用的总体目标是表征这些AT MFehi细胞，并确定它们在肥胖AT功能障碍中的作用。我们将采用无偏见的方法来表征MFehi细胞，并评估它们如何与周围的脂肪细胞和MFelo细胞相互作用。

DESCRIPTION (provided by applicant): It has been only 10 years since the first reports that macrophages infiltrate adipose tissue (AT) in obesity and contribute to insulin resistance (IR). Since then, new advances in the field have included demonstration that 1) macrophages form crown-like structures around dead adipocytes, 2) other leukocytes such as T lymphocytes, B cells, mast cells, and neutrophils are also recruited to AT, and 3) the AT macrophages can be polarized toward an M1 or M2 phenotype. To date, the polarization of ATMs has been used as an indication of whether they are resident and anti-inflammatory (M2) or recruited and inflammatory (M1). The prevailing model of ATM polarization holds that 'resident' ATMs display an 'alternatively activated' M2 phenotype, whereas macrophages recruited to adipose tissue during the onset of obesity exhibit a predominantly M1 'classical activation' state. The M2 macrophages are thought to play a role in tissue remodeling and repair in other organs. However, the physiologic function of M2 macrophages in AT is not known. In this application, we propose a role for M2 AT macrophages in local iron recycling and homeostasis, thus providing a specific function for these cells within the AT microenvironment. Furthermore, we propose that obesity reduces the ability of M2 macrophages to handle iron properly, thus contributing to adipose tissue dysfunction. In other organs, liver and spleen in particular, macrophages play a key role in iron homeostasis. Both M1 and M2 macrophages are known to sequester iron. The role of M1 iron sequestration is in bacteriostasis; however, the role of M2 iron sequestration is unknown. We have exciting preliminary data demonstrating that about 5% of AT macrophages are paramagnetic and sequester iron. These macrophages have gene expression patterns reflective of an M2 polarization with elevated expression of iron metabolism-related genes such as hemoxygenase-1, ferroportin, transferrin receptor, and the ferritin polypeptides. Hereafter, we refer to these cells as MFehi cells. The MFehi cells are present in the AT of both low fat (LF) and high fat (HF) fed mice. On a cellular basis, the MFehi cells contain less iron than the MFelo cells and their gene expression profiles indicate that they are defective in iron recycling compared to MFehi cells from the LF diet-fed mice. The overall goal of this Exploratory/Discovery R21 application is to characterize these AT MFehi cells and to determine their contribution to AT dysfunction in obesity. We will take an unbiased approach to characterizing the MFehi cells and will evaluate how they interact with their surrounding adipocytes and MFelo cells. PUBLIC HEALTH RELEVANCE: Obesity has become a worldwide epidemic resulting in increased incidence of many different diseases. Expanded and inflammatory adipose tissue is likely one of the primary contributors to the pathological consequences of obesity. Identification and characterization of how iron handling in these adipose tissue macrophage influences adipose tissue expansion is important for understanding the metabolic consequences of obesity.