TRAF3在调节肥胖小鼠肝脏胰岛素抵抗中的分子机制研究

Insulin resistance is a main contributor to type 2 diabetes. To restore insulin sensitivity in the liver of obesity is a hot research area in type 2 diabetes field. Chronic inflammation is a major cause of insulin resistance, but its detailed mechanisms are largely unknown. We have reported that hepatic specific deletion of TRAF2, a member of TRAF family, ameliorated high fat diet induced hyperglycemia (Diabetes,2012). In our preliminary studies, hepatic TRAF3 is abnormally overexpressed in high fat diet induced obesity and type 2 diabetes mouse model ob/ob mice. Liver specific deletion of TRAF3 improved glucose tolerance and insulin sensitivity in obesity, while liver specific overexpression of TRAF3 could induce insulin resistance. So our hypothesis is that hepatic TRAF3 expression level is regulated by glucose, and hepatic TRAF3 regulates insulin resistance in obesity. In this proposal, we will further elucidate how TRAF3 is regulated by glucose, and the mechansims of hepatic TRAF3 in the regulation of insulin resistance in the obesity. This study will provide a new drug target for the treatment of type 2 diabetes.

胰岛素抵抗是2型糖尿病的重要诱因。研究肝脏胰岛素抵抗的产生机制，进而恢复肝脏胰岛素敏感性是2型糖尿病研究热点和难点。慢性炎症是引起胰岛素抵抗的重要原因，但是其具体分子机制还不清楚。我们以往的工作发现TRAF家族成员TRAF2在肝脏中特异敲除后抑制了高脂饮食诱导的高血糖（Diabetes,2012）。本课题组未发表的工作显示：TRAF3在肥胖小鼠肝脏中异常高表达，肝脏特异敲除TRAF3提高了葡萄糖耐受和胰岛素敏感性，而肝脏特异的过表达TRAF3引起胰岛素抵抗。因此本项目的科学假设为：TRAF3的表达水平受葡萄糖浓度的调控，并且对肥胖小鼠肝脏胰岛素抵抗有调节作用。本项目拟在前期工作基础上，通过肝脏组织特异性基因敲除、蛋白相互作用、泛素化检测、胰岛素信号通路的磷酸化检测，研究TRAF3如何应答葡萄糖浓度，研究TRAF3调节肥胖小鼠肝脏胰岛素抵抗的分子机制，为2型糖尿病的诊治提供理论依据。

本课题阐明TRAF3以及下游分子NIK在胰岛素抵抗、葡萄糖代谢和肝脏损伤中的分子机制。TRAF3在肥胖小鼠肝脏中异常高表达，其高表达受到葡萄糖调控；肝脏特异敲除TRAF3提高了葡萄糖耐受和胰岛素敏感性，并且降低了高脂诱导的脂肪肝，而肝脏特异的过表达TRAF3引起胰岛素抵抗和葡萄糖耐量水平降低，TRAF3直接抑制了胰岛素诱导的p-AKT。我们还发现小分子化合物B022可以抑制TRAF3下游靶蛋白NIK激酶活性，进而缓解肝炎和肝损伤。我们还发现TRAF3下游分子NIK蛋白激酶在胰岛α细胞中的功能和分子机制。我们对TRAF3等接头蛋白在胰岛素抵抗、葡萄糖代谢和心脏疾病中的作用和调控机制做了总结和展望。TRAF3/NIK有望成为治疗代谢类疾病的新靶点。