Adipose Tissue Macrophage Iron Metabolism in Obesity

描述(申请人提供)：自首次报道肥胖症患者巨噬细胞渗入脂肪组织(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巨噬细胞可以极化为M1或M2表型。到目前为止，ATM的极化一直被用来指示它们是常驻的和抗炎的(M2)还是招募的和炎症的(M1)。ATM极化的流行模型认为，“常驻”ATM表现为“交替激活”的M2表型，而在肥胖开始时招募到脂肪组织的巨噬细胞则表现为主要的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。在这一应用中，我们提出了M2 AT巨噬细胞在局部铁循环和动态平衡中的作用，从而为这些细胞在AT微环境中提供了特定的功能。此外，我们认为肥胖降低了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，巨噬细胞在铁稳态中起着关键作用。众所周知，M1和M2巨噬细胞都能隔离铁。M1铁的固存作用是抑菌的；然而，M2的铁固存的作用尚不清楚。我们有令人兴奋的初步数据表明，大约5%的AT巨噬细胞是顺磁性和隔离铁。这些巨噬细胞的基因表达模式反映了M2极化，铁代谢相关基因如血红氧合酶-1、铁蛋白、转铁蛋白受体和铁蛋白多肽的表达增加。此后，我们将这些细胞称为MFehi细胞。在低脂(LF)和高脂(HF)饲养的小鼠的AT中都存在MFeHI细胞。在细胞基础上，MFehi细胞含有的铁少于MFelo细胞，它们的基因表达谱表明，与来自LF饮食喂养的小鼠的MFehi细胞相比，它们在铁循环方面存在缺陷。这项探索性/Discovery R21应用的总体目标是表征这些AT MFehi细胞，并确定它们在肥胖症AT功能障碍中的作用。我们将采取一种公正的方法来描述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.