Adipose Tissue Macrophage Phenotype and Function

描述(申请人提供)：肥胖会引起炎症反应，导致重要的医学并发症，包括动脉粥样硬化、胰岛素抵抗、非酒精性脂肪性肝病和癌症。由这笔赠款支持的研究揭示了肥胖症引起的炎症中一种以前未被认识到的成分：脂肪组织巨噬细胞(ATM)。我们的工作已经证明，在啮齿类动物和人类中，ATM在脂肪组织中的积聚与肥胖成比例。我们还表明，ATM负责阐述与肥胖引起的并发症有关的促炎、促凝和急性期蛋白。通过使用缺乏趋化受体的小鼠，我们减少了脂肪组织中巨噬细胞的含量，同时改善了肥胖小鼠的代谢状况。由我们的发现刺激的研究表明，人类ATM的含量与肥胖、胰岛素敏感性密切相关，并被噻唑烷酮类药物显著降低。更详细地描述调节脂肪组织中巨噬细胞聚集和激活的过程将为肥胖症及其并发症的病理生理学提供重要的见解，并提供候选的治疗靶点。两个基本假设激发了本申请中描述的实验：(A)在肥胖中，脂肪组织中巨噬细胞的积累是一个多步骤的过程，包括三个步骤：招募、成熟/分化和激活。(B)激活的脂肪组织巨噬细胞有助于肥胖引起的局部和全身不良炎症效应。在其他生物环境中，巨噬细胞的招募、分化和激活已经得到了很好的表征。我们的具体目标是：(1)表征肥胖引起的单核细胞向脂肪组织的募集。(2)探讨M-CSF/CSF-1对脂肪组织巨噬细胞分化的调节作用。(3)确定肥胖诱导的脂肪组织炎症是否依赖于巨噬细胞核因子-kB的激活。目前应用的具体目的是确定巨噬细胞聚集的每一步所涉及的机制，并衡量每一步对肥胖引起的局部和全身炎症的贡献。在这项提案中，我们利用描述巨噬细胞生理学的丰富文献和我们的初步数据来提出ATM招募、分化和激活所需的分子机制。实现这项提案的这些具体目标将确定ATM积累所需的关键过程和分子。成功还将为脂肪组织生理学提供重要的见解，并通过确定调节脂肪组织中巨噬细胞聚集和激活的分子机制，确定潜在的新策略，以减少肥胖引发的炎症及其伴随的并发症。

DESCRIPTION (provided by applicant): Obesity induces an inflammatory response that has been implicated in the development of medically important complications, including atherosclerosis, insulin resistance, non-alcoholic fatty liver disease and cancer. Studies supported by this grant have revealed a previously unrecognized component of obesity- induced inflammation: adipose tissue macrophages (ATMs). Our work has demonstrated that ATMs accumulate in adipose tissue in proportion to adiposity in both rodents and humans. We have also shown that ATMs are responsible for elaborating proinflammatory, pro-coagulant and acute phase proteins implicated in obesity-induced complications. Through use of mice deficient in a chemoattractant receptor, we have decreased macrophage content in adipose tissue and concomitantly improved the metabolic profile of obese mice. Studies stimulated by our findings have demonstrated that ATM content in humans is tightly correlated with adiposity, insulin sensitivity and powerfully decreased by thiazolidiniones. A more detailed characterization of the process that regulates macrophage accumulation and activation in adipose tissue will provide important insights into the pathophysiology of obesity and its complications, and also provide candidate therapeutic targets. Two basic hypotheses motivate the experiments described in this application: (A) In obesity macrophage accumulation in adipose tissue is a multi-step process that consists of three steps: recruitment, maturation/differentiation and activation. (B) Activated adipose tissue macrophages contribute to the adverse local and systemic inflammatory effects of obesity . In other biological settings the recruitment, differentiation and activation of macrophages have been well characterized. Our specific aims are: (1) To characterize obesity-induced recruitment of monocytes to adipose tissue. (2) To determine whether M-CSF/CSF-1 regulates adipose tissue macrophage differentiation. (3) To determine whether obesity-induced adipose tissue inflammation is dependent upon macrophage NF-kB activation. The specific aims of the current application are designed to identify mechanisms involved in eacg step of macrophage accumulation, and measure the contribution of each to the local and systemic inflammation induced by obesity. In this proposal we have taken advantage of the rich literature that describes macrophage physiology and our preliminary data to propose molecular mechanisms required for recruitment, differentiation and activation of ATMs. Achieving these specific aims of this proposal will identify critical processes and molecules required for ATM accumulation. Success also will provide important insights into adipose tissue physiology, and by identifying the molecular mechanisms that regulate macrophage accumulation and activation in adipose tissue, identify potential novel strategies to reduce obesity-induced inflammation and its attendant complications.