Foxo1 and the insulin resistance of cultured kidney cells
As a normal aspect of energy metabolism, cells in the kidney, much like those in the liver, respond to insulin by suppressing the metabolic pathways by which glucose is generated and released. In the healthy kidney, expression of the enzyme glucose 6-phosphatase (G6P), which controls a key step in glycogen breakdown, is suppressed by insulin. Curiously, this and other aspects of the transcriptional control by insulin are lacking in cultured kidney cells. In hopes of uncovering a general mechanism by which insulin sensitivity could be gained or lost, Nakae et al. have now studied insulin responses in kidney epithelial cell lines. They show here that the transcription factor Foxo1, which is present in the normal tissue but only weakly expressed in the cell line, is sufficient to restore insulin regulation of transcripts that are sensitive to glucose levels. Previous work had suggested that Foxo1 binding to the G6P promoter accounts for activation of gene expression by glucose and the corresponding silencing of expression following insulin treatment. The present work shows that he transcription factor becomes phosphorylated and is excluded from the nucleus following insulin treatment, which may explain at least some of the suppressive effect of this hormone on G6P and related genes. Whether reduced expression or increased phosphorylation of Foxo1 contribute to the loss of insulin sensitivity seen in the kidney or other organs in vivo remains to be tested.