肥胖相关的胰岛素抵抗可诱发糖尿病、高血压、脂肪肝等代谢综合征相关疾病，迄今仍缺乏对肥胖胰岛素抵抗的充分认识和有效防治。申请人前期发现：抑制脾脏酪氨酸激酶Syk可改善肥胖小鼠血糖、胰岛素、葡糖糖耐受、炎症因子、脂肪肝的情况，提示Syk可促进肥胖胰岛素抵抗；然而，其调控机制尚未明确。基于此，本项目拟结合临床相关性研究，利用Syk基因敲除模型鼠、C57模型鼠、ob/ob模型鼠和胰岛素抵抗细胞模型深入研究Syk对肥胖胰岛素抵抗的作用；采用差异蛋白质谱分析、转录组高通量测序和生物信息学分析等手段深入解析其调控肥胖炎症信号及胰岛素信号通路的靶基因，进一步确定其调控肥胖胰岛素抵抗的分子机制。本项目的实施，将完善肥胖胰岛素抵抗的理论，并为Syk成为治疗肥胖胰岛素抵抗的靶点和用于临床诊断、评估预后的标志物的可能性提供理论支持。

Obesity has become a global epidemic with complications contributing substantially to health care costs and mortality. Obesity can lead to insulin resistance, diabetes, hypertension, cardiovascular and other diseases. Previous studies showed that B lymphocyte regulate obesity related insulin resistance. Syk is an important signal transduction molecule of the BCR signaling pathway and has been demonstrated to be critical for the survival and maintenance of malignant B cells. However, there has been no study showed the pathogenesis of Syk in obesity related insulin resistance. Our previous study showed that Syk inhibitor could improve the body weight, blood lipid, blood glucose and glucose tolerance of obese mice. Hepatic histopathological analysis also showed that fatty liver was alleviated. All these results suggested that Syk may modulate obesity-related insulin resistance. In this study, we will use Syk knockout mice, obesity mice and insulin resistant cells to investigate the effect and the mechanism of Syk on obesity related insulin resistance. Meanwhile, we will use proteomics, genomics, bioinformatics and other methods to study the molecular mechanism of Syk signaling pathway in the obesity related insulin resistance. Then we will further study the correlation between Syk expression and BMI, triglycerides and total cholesterol levels in obese patients. This research could yield new insights into mechanism and targeted therapy of obesity related insulin resistance in the future.