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

TY - JOUR

T1 - Diabetes Risk Gene and Wnt Effector Tcf7l2/TCF4 Controls Hepatic Response to Perinatal and Adult Metabolic Demand

AU - Boj, S.F.

AU - van Es, J.H.

AU - Huch, M.

AU - Li, V.S.

AU - Jose, A.

AU - Hatzis, P.

AU - Mokry, M.

AU - Haegebarth, A.

AU - van den Born, M.

AU - Chambon, P.

AU - Voshol, P.

AU - Dor, Y.

AU - Cuppen, E.

AU - Fillat, C.

AU - Clevers, H.

N1 - Reporting year: 2012

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

U2 - 10.1016/j.cell.2012.10.053

DO - 10.1016/j.cell.2012.10.053

M3 - Article

SN - 0092-8674

VL - 151

SP - 1595

EP - 1607

JO - Cell

JF - Cell

IS - 7

ER -