Hubrecht Institute, KNAW and University Medical Center Utrecht, 3584CT Utrecht, The Netherlands.
Cell. 2012 Dec 21;151(7):1595-607. doi: 10.1016/j.cell.2012.10.053.
Most studies on TCF7L2 SNP variants in the pathogenesis of type 2 diabetes (T2D) focus on a role of the encoded transcription factor TCF4 in β cells. Here, a mouse genetics approach shows that removal of TCF4 from β cells does not affect their function, whereas manipulating TCF4 levels in the liver has major effects on metabolism. In Tcf7l2(-/-) mice, the immediate postnatal surge in liver metabolism does not occur. Consequently, pups die due to hypoglycemia. By combining chromatin immunoprecipitation with gene expression profiling, we identify a TCF4-controlled metabolic gene program that is acutely activated in the postnatal liver. In concordance, adult liver-specific Tcf7l2 knockout mice show reduced hepatic glucose production during fasting and display improved glucose homeostasis when maintained on high-fat diet. Furthermore, liver-specific TCF4 overexpression increases hepatic glucose production. These observations imply that TCF4 directly activates metabolic genes and that inhibition of Wnt signaling may be beneficial in metabolic disease.
大多数关于 TCF7L2 SNP 变异在 2 型糖尿病 (T2D) 发病机制中的研究都集中在编码转录因子 TCF4 在β细胞中的作用。在这里，一种小鼠遗传学方法表明，从β细胞中去除 TCF4 不会影响其功能，而在肝脏中操纵 TCF4 水平对代谢有重大影响。在 Tcf7l2(-/-) 小鼠中，肝脏代谢的出生后即刻激增不会发生。因此，幼鼠因低血糖而死亡。通过将染色质免疫沉淀与基因表达谱分析相结合，我们确定了 TCF4 控制的代谢基因程序，该程序在出生后肝脏中被急性激活。一致地，成年肝脏特异性 Tcf7l2 敲除小鼠在禁食期间显示出肝葡萄糖产生减少，并在高脂肪饮食时显示出改善的葡萄糖稳态。此外，肝脏特异性 TCF4 过表达增加肝葡萄糖产生。这些观察结果表明 TCF4 直接激活代谢基因，抑制 Wnt 信号可能对代谢疾病有益。
