The homeodomain transcription factor Pdx1 is essential for pancreas formation and functions in pancreatic islets cells to regulate genes involved in maintenance of glucose homeostasis. In order to investigate a role for Pdx1 in intestinal cells, we analyzed the functions and networks associated with genes differentially expressed by Pdx1 overexpression in human Caco-2 cells. In agreement with previous results for intestine isolated from mice with Pdx1 inactivation, functional analysis of genes differentially expressed with Pdx1 overexpression revealed functions significantly associated with nutrient metabolism. Similarly, network analysis examining the interactions among the differentially expressed genes revealed gene networks involved in lipid metabolism. Consistent with defects in maternal nutrient metabolism, mouse pups born to dams with intestine-specific Pdx1 inactivation are underweight and fail to thrive in the neonatal period compared to pups born to control dams. We conclude that Pdx1 mediates lipid metabolism gene networks in intestinal cells and that maternal expression is essential for perinatal growth in mice.