Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / metabolism*
  • Diet, High-Fat
  • Fasting / metabolism
  • Glucose / metabolism*
  • Islets of Langerhans / metabolism
  • Liver / metabolism*
  • Metabolic Networks and Pathways*
  • Mice
  • Mice, Knockout
  • Transcription Factor 7-Like 2 Protein / genetics
  • Transcription Factor 7-Like 2 Protein / metabolism*
  • Transcriptional Activation


  • Tcf7l2 protein, mouse
  • Transcription Factor 7-Like 2 Protein
  • Glucose

Associated data

  • GEO/GSE41284