Diabetes Risk Gene and Wnt Effector Tcf7l2/TCF4 Controls Hepatic Response to Perinatal and Adult Metabolic Demand

作者：Boj Sylvia F; van Es Johan H; Huch Meritxell; Li Vivian S W; Jose Anabel; Hatzis Pantelis; Mokry Michal; Haegebarth Andrea; van den Born Maaike; Chambon Pierre; Voshol Peter; Dor Yuval; Cuppen Edwin; Fillat Cristina; Clevers Hans^*

来源：Cell, 2012, 151(7): 1595-1607.

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 beta cells. Here, a mouse genetics approach shows that removal of TCF4 from beta 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.

• 出版日期2012-12-21
• 单位河北医科大学