Elucidation of pathophysiological roles of Wnt5b gene susceptible to type 2 diabetes in glucose metabolism in liver

据报道，Wnt/β-catenin信号通路与胰岛素分泌和脂肪细胞分化有关。然而，在肝脏中的生理作用尚不清楚。最近有报道称Wnt家族中的Wnt5b基因对2型糖尿病易感，并负向调控9-catenin信号传导。为了研究Wnt/β-catenin信号通路和Wnt5b基因在肝脏中的作用，我们利用原代大鼠肝细胞检测了β-catenin信号通路的激活是否会影响糖代谢。氯化锂磷酸化GSK-3f3，降低与糖异生相关的PEPCK和G6Pase的基因表达水平。此外，我们对小鼠进行ipGTT，检测Wnt5b基因在db/db小鼠肝脏中的表达水平。ipGTT结果显示，葡萄糖负荷后Wnt5b基因表达量瞬间升高，db/db小鼠活体中Wnt5b基因表达量较对照小鼠升高。根据这些结果，可以推测Wnt/β-catenin信号在肝脏糖代谢中具有病理生理作用。因此，我们利用腺病毒载体在小鼠肝脏中过表达小鼠Wnt5b基因，但与对照小鼠相比，在空腹葡萄糖和葡萄糖负荷后，Wnt5b过表达小鼠均未发现显著变化，在体内模型中，我们未发现Wnt5b基因对肝脏糖代谢的直接影响。然而，先前的报道表明，Wnt/β-catenin信号通路与肝脏脂质代谢有关。因此，Wnt/β-catenin信号可能通过调节脂质代谢间接影响糖尿病的发病或/和进展，明确Wnt5b基因在脂质代谢中的病理生理作用具有重要意义。

Wnt/β-catenin signaling is reported to be associated with insulin secretion and adipocyte differentiation. However physiological roles in liver have remained unknown. Recently, it has been reported that Wnt5b gene, one of the Wnt family, is susceptible to type2 diabetes and regulates 9-catenin signaling negatively. In order to investigate some roles of Wnt/β-catenin signaling and Wnt5b gene in liver we examined whether activation of β-catenin signaling can affect glucose metabolism using primary rat hepatocytes. lithium chloride phosphorylated GSK-3f3 and reduced the gene expression levels of PEPCK and G6Pase that are associated with gluconeogenesis. Additionally, we did ipGTT in mice and examined the expression level of Wnt5b gene in liver of db/db mice. The result of ipGTT showed that the expression level of Wnt5b gene was transiently increased after glucose loading and Wnt5b gene expression in live of db/db mice was increased compared with control mice. From these results, it could be hypothesized that Wnt/β-catenin signaling has pathophyisological roles in hepatic glucose metabolism. Therefore, we overexpressed mouse Wnt5b gene in mouse liver using adenovirus vector However no remarkable changes in Wnt5b-overexpressed mice were found in both fasting glucose and after glucose loading compared with control mice and we did not find direct effects of Wnt5b gene on hepatic glucose metabolism in vivo model However, previous reports showed that Wnt/β-catenin signaling was associated with lipid metabolism in liver. Therefore Wnt/β-catenin signaling may have indirect effects on onset or/and progression of diabetes by regulating lipid metabolism and it is important to clear pathophyisological roles of Wnt5b gene in lipid metabolism.