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Significance The lobules are the functional units of the liver. They consist of 15–25 layers of hepatocytes with specialized metabolic functions and gene expression patterns relative to their position along the lobule, a phenomenon referred to as metabolic zonation. The Wnt/β-catenin pathway regulates hepatocyte function but how the zonation is controlled to meet the metabolic demands of the liver is unclear. Glucagon regulates hepatic function. We now demonstrate that glucagon contributes to liver zonation by interacting and opposing the actions of the Wnt/β-catenin pathway., Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal function. Wnt/β-catenin signaling controls metabolic zonation by activating genes in the perivenous hepatocytes, while suppressing genes in the periportal counterparts. We now demonstrate that glucagon opposes the actions of Wnt/β-catenin signaling on gene expression and metabolic zonation pattern. The effects were more pronounced in the periportal hepatocytes where 28% of all genes were activated by glucagon and inhibited by Wnt/β-catenin. The glucagon and Wnt/β-catenin receptors and their signaling pathways are uniformly distributed in periportal and perivenous hepatocytes and the expression is not regulated by the opposing signal. Collectively, our results show that glucagon controls gene expression and metabolic zonation in the liver through a counterplay with the Wnt/β-catenin signaling pathway.