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

Sylvia F. Boj; Johan H. Van Es; Meritxell Huch; Vivian S.W. Li; Anabel José; Pantelis Hatzis; Michal Mokry; Andrea Haegebarth; Maaike Van Den Born; Pierre Chambon; Peter Voshol; Yuval Dor; Edwin Cuppen; Cristina Fillat; Hans Clevers

doi:10.1016/j.cell.2012.10.053

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

Sylvia F. Boj, Johan H. Van Es, Meritxell Huch, Vivian S.W. Li, Anabel José, Pantelis Hatzis, Michal Mokry, Andrea Haegebarth, Maaike Van Den Born, Pierre Chambon, Peter Voshol, Yuval Dor, Edwin Cuppen, Cristina Fillat, Hans Clevers^*

^*Corresponding author for this work

Department of Developmental Biology and Cancer Research

Research output: Contribution to journal › Article › peer-review

182 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1595-1607
Number of pages	13
Journal	Cell
Volume	151
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2012.10.053
State	Published - 21 Dec 2012

Bibliographical note

Funding 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.

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Boj, S. F., Van Es, J. H., Huch, M., Li, V. S. W., José, A., Hatzis, P., Mokry, M., Haegebarth, A., Van Den Born, M., Chambon, P., Voshol, P., Dor, Y., Cuppen, E., Fillat, C., & Clevers, H. (2012). Diabetes risk gene and wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand. Cell, 151(7), 1595-1607. https://doi.org/10.1016/j.cell.2012.10.053

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title = "Diabetes risk gene and wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand",

abstract = "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.",

author = "Boj, {Sylvia F.} and {Van Es}, {Johan H.} and Meritxell Huch and Li, {Vivian S.W.} and Anabel Jos{\'e} and Pantelis Hatzis and Michal Mokry and Andrea Haegebarth and {Van Den Born}, Maaike and Pierre Chambon and Peter Voshol and Yuval Dor and Edwin Cuppen and Cristina Fillat and Hans Clevers",

note = "Funding 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. ",

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month = dec,

day = "21",

doi = "10.1016/j.cell.2012.10.053",

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Boj, SF, Van Es, JH, Huch, M, Li, VSW, José, A, Hatzis, P, Mokry, M, Haegebarth, A, Van Den Born, M, Chambon, P, Voshol, P, Dor, Y, Cuppen, E, Fillat, C & Clevers, H 2012, 'Diabetes risk gene and wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand', Cell, vol. 151, no. 7, pp. 1595-1607. https://doi.org/10.1016/j.cell.2012.10.053

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T1 - Diabetes risk gene and wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand

AU - Boj, Sylvia F.

AU - Van Es, Johan H.

AU - Huch, Meritxell

AU - Li, Vivian S.W.

AU - José, Anabel

AU - Hatzis, Pantelis

AU - Mokry, Michal

AU - Haegebarth, Andrea

AU - Van Den Born, Maaike

AU - Chambon, Pierre

AU - Voshol, Peter

AU - Dor, Yuval

AU - Cuppen, Edwin

AU - Fillat, Cristina

AU - Clevers, Hans

N1 - Funding 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.

PY - 2012/12/21

Y1 - 2012/12/21

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 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.

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 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.

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

Abstract

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