LRP6交联Wnt与mTOR 信号网络对追赶生长IUGR大鼠胰岛素抵抗的作用机制

Intrauterine growth restriction (IUGR) followed by postnatal catch-up growth (CG-IUGR) is associated with long-term adverse metabolic consequences, and the underlying mechanism is still unclear. Our previous studies found that the insulin sensitivity and the expression/activity of the key components of insulin sigling pathway was decreased in CG-IUGR rats. Recent reports reveal that Wnt/β-Catenin signaling plays an essential role in growth and development as well as energy metabolism, interacting with multiple metabolic signaling pathways. mTORC1 is a key regulator in insulin signaling and nutrient-sensing signaling networks. LRP6 is probably a key node that crosslinks the abovementioned pathways to act on the insulin signaling. We hypothesized that, the intrauterine and postnatal nutrition programs the insulin-resistant phenotype in IUGR/CG-IUGR rats through altering the Wnt/β-Catenin signaling, mTOR signaling and the insulin signaling networks interaction, and LRP6 is an essential node in this complex networks. In this study, the expression and activity of the key components of Wnt/β-Catenin signaling and mTOR signaling in the liver, muscle and adipose tissue in IUGR/CG-IUGR rats will be determined. Moreover, using LRP6 as an entry point, the interaction mechanism between Wnt sigling, mTOR signaling and insulin signaling networks will be further investigated. This study will reveal the new molecular mechanism through which the intrauterine and postnatal nutrient milieu causes metabolic programming, and will probably provide potential therapeutic targets for insulin resistance and its related disorders in IUGR/CG-IUGR.

宫内发育迟缓（IUGR）尤其是生后早期出现追赶生长者（CG-IUGR），后期发生胰岛素抵抗相关疾病风险显著增高，而其机制仍不甚明了。我们前期研究发现CG-IUGR大鼠有明显的胰岛素抵抗表型，其肝脏、脂肪、骨骼肌中胰岛素信号受损。研究表明经典Wnt及mTORC1信号通路在能量代谢过程起重要作用，而LRP6可能是交联这两大通路作用于胰岛素信号的关键节点。我们推测，LRP6交联Wnt与mTORC1信号网络作用于胰岛素信号，从而编程IUGR/CG-IUGR后期胰岛素抵抗的发生发展。本课题拟研究IUGR/CG-IUGR大鼠肝脏、骨骼肌及脂肪的Wnt与mTOR 信号通路关键因子的表达及活性，并以LRP6为切入点，进一步研究Wnt及mTOR信号网络与胰岛素信号间的作用机制，从而深入探索宫内及生后营养环境致生长发育及代谢异常程序化改变的分子机制，为干预治疗IUGR/CG-IUGR胰岛素抵抗提供新的可能靶点