Foxo1 links insulin signaling to C/EBPα and regulates gluconeogenesis during liver development

C/EBP alpha is a key transcription factor indispensable for the onset of gluconeogenesis in perinatal liver. However, C/EBP alpha was already expressed in fetal liver, suggesting that the expression of C/EBP alpha alone does not account for the dramatic increase of the expression of metabolic genes, and hence an additional factor(s) is expected to function cooperatively with C/EBP alpha in perinatal liver. We show here that expression of Foxo1 was sharply increased in the perinatal liver and augmented C/EBP alpha-dependent transcription. Foxo1 bound C/EBP alpha via its forkhead domain, and Foxo1 bound to the promoter of a gluconeogenic gene, phosphoenolpyruvate carboxykinase (PEPCK), in a C/ EBP alpha-dependent manner in vivo. Insulin inhibited the expression of PEPCK in a culture of fetal liver cells, and also the C/EBP alpha-dependent transcription enhanced by Foxo1. These results indicate that Foxo1 regulates gluconeogenesis cooperatively with C/EBP alpha, and also links insulin signaling to C/EBP alpha during liver development.