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Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand.
- Source :
-
Cell [Cell] 2012 Dec 21; Vol. 151 (7), pp. 1595-607. - Publication Year :
- 2012
-
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.<br /> (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Animals, Newborn
Diet, High-Fat
Fasting metabolism
Islets of Langerhans metabolism
Mice
Mice, Knockout
Transcription Factor 7-Like 2 Protein genetics
Transcriptional Activation
Diabetes Mellitus genetics
Diabetes Mellitus metabolism
Glucose metabolism
Liver metabolism
Metabolic Networks and Pathways
Transcription Factor 7-Like 2 Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4172
- Volume :
- 151
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 23260145
- Full Text :
- https://doi.org/10.1016/j.cell.2012.10.053