CD11b调控巨噬细胞状态对肥胖及其相关的胰岛素抵抗的影响及机制

High fat diet-induced obesity is related to a chronic state of low-grade inflammation and prone to insulin resistance and subsequent progression to metabolic disorder diseases. During the development of obesity, adipose tissue remodeling is an ongoing process, featured by adipose tissue expansion, immune cell infiltration and subsequent pro-inflammatory responses. Among the infiltrated immune cells, a heterogeneous population of macrophages often initiates a chronic low level of innate immune responses. In our preliminary study, we found that adipose tissue macrophages in obesity showed enhanced cell proliferation. Both of macrophage proliferation in early stage and monocyte infiltration in late stage work together to decide the macrophage accumulation in adipose tissue during obesity. The deficiency of CD11b supposedly inhibit high fat diet-induced insulin resistance and monocyte/macrophage infiltration to the adipose tissues, however, we observed that high levels of macrophage accumulation in the obese-adipose tissues in CD11b -/- mice. Further analysis showed that macrophages in the inflamed adipose tissue were in high proliferation and are characterized as high percentage of type II macrophages. Thus, we hypotheses that during the development of obesity and its related insulin resistance, CD11b can regulate adipose tissue macrophage proliferation and subtype switching, thereby deciding the adipose tissue immune microenvironment and regulating the development of obesity and its related insulin resistance. We propose the following aims to test this hypothesis. We will investigate the properties of adipose tissue macrophage accumulation in obesity. Based on this, we will illustrate the mechanisms of CD11b in regulating higher levels of adipose tissue macrophage accumulation in high fat diet induced obesity. We will explain the potential mechanisms of CD11b in switching type 1 macrophages and type 2 macrophages. We will explore the new strategies that specifically regulate CD11b and macrophage accumulation in adipose tissue and effectively improve obesity and its related insulin resistance. We believe that the completion of this study will provide not only the critical information for understanding of the pathogenesis of high fat diet induced obesity and its comorbidities, but also for finding new targets to prevent and treat obesity and its related insulin resistance.

高脂诱导肥胖及其相关的胰岛素抵抗是一种慢性、低程度炎症性疾病，是由脂肪组织病理性重塑引起的代谢紊乱性疾病，与巨噬细胞异常浸润关系密切。我们的初步研究发现，肥胖脂肪组织中巨噬细胞的增加与巨噬细胞增殖和单核细胞向炎症脂肪组织浸润紧密相关。以调控单核细胞迁移的CD11b为靶标，研究发现CD11b缺失促进高脂诱导肥胖，但是显著改善肥胖相关的胰岛素抵抗和葡萄糖耐受，主要表现在小鼠脂肪组织中巨噬细胞增殖增加，并且M2型巨噬细胞比例上升。迄今为止，关于CD11b调控巨噬细胞增殖及亚型转化在肥胖和胰岛素抵抗中的作用尚无报道。研究将利用不同基因缺陷小鼠，多层次、多角度地研究肥胖脂肪组织中巨噬细胞增多的机制，阐明CD11b对巨噬细胞活性状态的调控及机制，并探讨这种调控作用对脂肪免疫微环境的调节和脂肪病理性重塑的影响，拓展我们对肥胖及其诱导胰岛素抵抗致病机制的认识，以便寻求更有效的治疗及预防措施。

高脂饮食诱导的胰岛素抵抗与巨噬细胞的浸润及其向经典活化巨噬细胞的转变密切相关。靶向性阻断巨噬细胞浸润和它向经典活化巨噬细胞的分化，或促进交替活化巨噬细胞的演变有助于对抗胰岛素抵抗、糖尿病等代谢类疾病。本项目围绕科学假设“CD11b调控脂肪组织中巨噬细胞的增殖和亚型转化，进而决定脂肪组织的免疫状态，调控肥胖乃至其相关的胰岛素抵抗”进行研究，并按原计划完成。研究发现：①肥胖过程中脂肪组织中巨噬细胞存在增殖现象，其调控依赖于IL-4—STAT6信号通路。②巨噬细胞的原位增殖和单核细胞迁移共同参与肥胖脂肪组织中巨噬细胞积聚过程。③调控单核巨噬细胞细胞迁移的CD11b受体分子可以负向调控巨噬细胞增殖及其向交替活化巨噬细胞的转变。④CD11b借以SHP1抑制STAT6信号通路，抑制巨噬细胞增殖和向交替活化巨噬细胞的转变。⑤阻断CD11b可以通过抑制单核细胞迁移和促进巨噬细胞向交替活化巨噬细胞的转变，改善高脂诱导的胰岛素抵抗。研究不仅首次揭示肥胖脂肪组织巨噬细胞积聚的动态演变规律，并且证明介导阻断CD11b信号不仅抑制单核细胞迁移，更重要的是促进交替活化巨噬细胞在脂肪组织部位的增多，以抵抗胰岛素抵抗、糖尿病等代谢类疾病。相关成果发表在PNAS、Cell Reports、Cell Death and Disease等杂志上。本项目的研究拓展了我们对肥胖脂肪组织中巨噬细胞特征和特性调控的认识，也为胰岛素抵抗和相关代谢类疾病的临床治疗提供有价值的新靶标。