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Sci. Signal., 1 February 2011
Vol. 4, Issue 158, p. ra6
[DOI: 10.1126/scisignal.2001249]

RESEARCH ARTICLES

Wnt Signaling Regulates Hepatic Metabolism

Hongjun Liu1*, Maria M. Fergusson1, J. Julie Wu1, Ilsa I. Rovira1, Jie Liu1, Oksana Gavrilova2, Teng Lu1,3, Jianjun Bao1, Donghe Han4, Michael N. Sack1, and Toren Finkel1{dagger}

1 Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
2 Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD 20892, USA.
3 Emory University School of Medicine, Atlanta, GA 30322, USA.
4 Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.

* Present address: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.

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.

{dagger} To whom correspondence should be addressed. E-mail: finkelt{at}nih.gov

Citation: H. Liu, M. M. Fergusson, J. J. Wu, I. I. Rovira, J. Liu, O. Gavrilova, T. Lu, J. Bao, D. Han, M. N. Sack, T. Finkel, Wnt Signaling Regulates Hepatic Metabolism. Sci. Signal. 4, ra6 (2011).

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