Adipose Tissue Macrophage Phenotype and Function

描述（由申请人提供）：肥胖引起炎症反应，涉及医学上重要并发症的发展，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。该基金支持的研究揭示了肥胖诱导炎症的一个以前未被认识到的成分：脂肪组织巨噬细胞（ATMs）。我们的研究表明，在啮齿类动物和人类中，atm在脂肪组织中的积累与肥胖成正比。我们还表明，atm负责形成与肥胖引起的并发症有关的促炎、促凝和急性期蛋白。通过使用缺乏化学引诱剂受体的小鼠，我们降低了脂肪组织中的巨噬细胞含量，并同时改善了肥胖小鼠的代谢谱。我们的发现激发的研究表明，人类ATM含量与肥胖、胰岛素敏感性密切相关，噻唑烷酮类药物能有效降低ATM含量。更详细地描述脂肪组织中巨噬细胞积聚和激活的调节过程将为肥胖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应用中描述的实验：(A)在肥胖中，巨噬细胞在脂肪组织中的积累是一个多步骤的过程，包括三个步骤：募集、成熟/分化和激活。(B)活化的脂肪组织巨噬细胞有助于肥胖的局部和全身炎症反应。在其他生物学环境中，巨噬细胞的募集、分化和激活已经得到了很好的表征。我们的具体目标是：(1)表征肥胖诱导的单核细胞向脂肪组织的募集。(2)确定M-CSF/CSF-1是否调节脂肪组织巨噬细胞分化。(3)确定肥胖诱导的脂肪组织炎症是否依赖于巨噬细胞NF-kB的激活。当前应用的具体目的是确定巨噬细胞积累的每个步骤所涉及的机制，并测量每个步骤对肥胖引起的局部和全身性炎症的贡献。在本提案中，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募集、分化和激活所需的分子机制。实现本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。成功也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积聚和激活的分子机制，确定减少肥胖引起的炎症及其并发症的潜在新策略。

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.