巨噬细胞M1/M2极化对脂肪组织胰岛素抵抗具有重要调控作用，成为干预胰岛素抵抗的重要切入点。胰岛素抵抗中巨噬细胞极化改变的详细机制不明，基于前期工作，首次发现核不均一核糖核蛋白（hnRNP A1，以下称A1）介导的细胞自噬参与其中。本项目拟进一步明确自噬参与调控饱和游离脂肪酸诱导巨噬细胞极化改变、影响炎症因子分泌和脂肪细胞胰岛素信号的分子机制。研究A1与自噬相关基因结合并调控其mRNA稳定性和转录活性的功能；观察A1的核-浆定位、磷酸化修饰对上述自噬基因调控的影响；构建巨噬细胞条件敲除A1的小鼠，比较条件敲除型和野生型巨噬细胞在自噬、极化表型、炎症因子分泌上的差异和脂肪细胞功能的改变，发现A1调控自噬和炎症、改变胰岛素信号转导的分子基础；建立药物评价体系，研究药物靶向A1对胰岛素抵抗的改善作用，确立巨噬细胞"A1-自噬-极化-炎症"轴对胰岛素抵抗病理机制的重要贡献，为新型药物治疗打下基础。

M1/M2 macrophage polarization plays an important role in insulin resistance of adipose tissue, which can be a check point for disease therapy. But the underlying mechanisms are not very clear, based on the previous researches, we first found that hnRNP A1-induced autophagy is involved in the M1/M2 polarization. Then, we will continue to identify effects of autophagy on saturated free fatty acid-induced macrophage polarization, and following in inflammatory cytokines secretion and insulin resistance of adipocytes; Furthermore, we will elucidate the functions of hnRNP A1 on mRNA stability and transcription of autophagy genes; and evaluate whether these functions of hnRNP A1 can be modified by phosphorylation and translocation in nuclear-cytosol. Use hnRNP A1-conditional knockout mice, we examine deficiency of hnRNP A1 on autophagy, phenotype and inflammatory cytokines in macrophages, and the insulin signaling transduction in adipose tissues, from that, we want to find the molecular mechanisms of hnRNP A1-induced autophagy, inflammation and following effects in adipocytes. We will setup the drug evaluation system targeting hnRNP A1 and detect the improvement in insulin resistance of candidate compounds. By this project, we will evaluate the contribution of macrophage "hnRNP A1-autophage-polarization-inflammation" axis to insulin resistance which maybe the base of drug treatment.