In the canonical insulin signaling pathway in the liver, insulin leads to activation of the kinase Akt, which phosphorylates and inhibits the transcription factor Foxo1, thus resulting in decreased expression of genes involved in glucose production (gluconeogenesis). Accordingly, Lu et al. found that mice with a hepatic-specific deletion of Akt1 and Akt2 (double-knockout mice) showed metabolic defects such as hyperglycemia after feeding, glucose intolerance, and fasting hyperinsulinemia. These mice also showed decreased insulin signaling (as indicated by decreased phosphorylation of the ribosomal protein S6 and increased abundance of Igfbp1 (insulin-like growth factor binding protein 1) and increased expression of various Foxo1 target genes. Mice with hepatic deletions of Akt1, Akt2, and Foxo1 (triple-knockout mice) did not show the metabolic defects exhibited by the double-knockout mice; however, insulin signaling remained impaired in the livers of triple-knockout mice. These results led the authors to propose that after feeding, Foxo1 can suppress an Akt-independent, insulin-responsive noncanonical pathway and that the main function of Akt is to inhibit Foxo1 through a parallel pathway. Similar to wild-type mice, the expression of genes encoding gluconeogenic enzymes decreased after feeding in Foxo1–/– and double-knockout mice, findings that supported the proposed noncanonical pathway. In contrast, basal expression of genes encoding gluconeogenic enzymes was lower in hepatocytes isolated from Foxo1–/– and triple-knockout mice and was nonresponsive to insulin stimulation, suggesting that the isolated hepatocytes were responding to insulin through the canonical pathway. In the associated commentary, Cheng and White discuss reports that suggest that the kinases PDPK1 (3-phosphoinositide dependent protein kinase-1) and atypical PKC (protein kinase C) could be involved in the noncanonical pathway.
M. Lu, M. Wan, K. F. Leavens, Q. Chu, B. R. Monks, S. Fernandez, R. S. Ahima, K. Ueki, C. R. Kahn, M. J. Birnbaum, Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat. Med. 18, 388–395 (2012). [PubMed]
Z. Cheng, M. F. White, The AKTion in non-canonical insulin signaling. Nat. Med. 18, 351–353 (2012). [PubMed]