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.
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, 3584CT Utrecht, The Netherlands.
authors.forename: Sylvia F
authors.initials: SF
authors.lastname: Boj
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Es
authors.forename: Meritxell
authors.initials: M
authors.lastname: Huch
authors.forename: Vivian S W
authors.initials: VS
authors.lastname: Li
authors.forename: Anabel
authors.initials: A
authors.lastname: José
authors.forename: Pantelis
authors.initials: P
authors.lastname: Hatzis
authors.forename: Michal
authors.initials: M
authors.lastname: Mokry
authors.forename: Andrea
authors.initials: A
authors.lastname: Haegebarth
authors.forename: Maaike
authors.initials: M
authors.lastname: van den Born
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Peter
authors.initials: P
authors.lastname: Voshol
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.forename: Cristina
authors.initials: C
authors.lastname: Fillat
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism*; D059305:Diet, High-Fat; D005215:Fasting / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D051379:Mice; D018345:Mice, Knockout; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D005947:Glucose