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.
Bibliographical noteFunding Information:
We thank H. Begthel, J. Korving, L. van Gurp, C. Kroon-Veenboer, and B. El Haddouti for technical assistance and T. Mahmoudi and J.D. Mul for their helpful discussions. This work was supported by Stichting Diabetes Onderzoek Nederland and the Diabetes Fonds. S.F.B. is supported by EMBO long-term fellowship (ALT-835-2007) and by EU/232814-stemcellmark; J.H.E. is supported by EU/232814-stemcellmark; V.S.W.L. is supported by KWF/PF HUBR 2007-3956; P.H. was supported by CGCII; A.H. was supported by KWF/PF HUBR 2007-3956; M.H. is supported by long-term Marie Curie fellowship and EU/236954-ICSC LGR5; M.B. is supported by Ti Pharm/T3-106; and A.J. and C.F. are supported by BIO2011-30299-C02-02 from MINECO and IIS10/00014 from Instituto de Salud Carlos III.