title: Wnt signaling regulates hepatic metabolism.
abstract: The contribution of the Wnt pathway has been extensively characterized in embryogenesis, differentiation, and stem cell biology but not in mammalian metabolism. Here, using in vivo gain- and loss-of-function models, we demonstrate an important role for Wnt signaling in hepatic metabolism. In particular, β-catenin, the downstream mediator of canonical Wnt signaling, altered serum glucose concentrations and regulated hepatic glucose production. β-Catenin also modulated hepatic insulin signaling. Furthermore, β-catenin interacted with the transcription factor FoxO1 in livers from mice under starved conditions. The interaction of FoxO1 with β-catenin regulated the transcriptional activation of the genes encoding glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), the two rate-limiting enzymes in hepatic gluconeogenesis. Moreover, starvation induced the hepatic expression of mRNAs encoding different Wnt isoforms. In addition, nutrient deprivation appeared to favor the association of β-catenin with FoxO family members, rather than with members of the T cell factor of transcriptional activators. Notably, in a model of diet-induced obesity, hepatic deletion of β-catenin improved overall metabolic homeostasis. These observations implicate Wnt signaling in the modulation of hepatic metabolism and raise the possibility that Wnt signaling may play a similar role in the metabolic regulation of other tissues.
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Liu
authors.forename: Maria M
authors.initials: MM
authors.lastname: Fergusson
authors.forename: J Julie
authors.initials: JJ
authors.lastname: Wu
authors.forename: Ilsa I
authors.initials: II
authors.lastname: Rovira
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.forename: Teng
authors.initials: T
authors.lastname: Lu
authors.forename: Jianjun
authors.initials: J
authors.lastname: Bao
authors.forename: Donghe
authors.initials: D
authors.lastname: Han
authors.forename: Michael N
authors.initials: MN
authors.lastname: Sack
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D010730:Phosphoenolpyruvate Carboxylase / Q000235:genetics; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013217:Starvation / Q000378:metabolism / Q000503:physiopathology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D020033:Protein Isoforms; D051153:Wnt Proteins; D051176:beta Catenin; D005952:Glucose-6-Phosphatase; D010730:Phosphoenolpyruvate Carboxylase; D005947:Glucose