Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1

The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nature medicine (Impact Factor: 27.36). 02/2012; 18(3):388-95. DOI: 10.1038/nm.2686
Source: PubMed


Considerable data support the idea that forkhead box O1 (Foxo1) drives the liver transcriptional program during fasting and is then inhibited by thymoma viral proto-oncogene 1 (Akt) after feeding. Here we show that mice with hepatic deletion of Akt1 and Akt2 were glucose intolerant, insulin resistant and defective in their transcriptional response to feeding in the liver. These defects were normalized with concomitant liver-specific deletion of Foxo1. Notably, in the absence of both Akt and Foxo1, mice adapted appropriately to both the fasted and fed state, and insulin suppressed hepatic glucose production normally. A gene expression analysis revealed that deletion of Akt in liver led to the constitutive activation of Foxo1-dependent gene expression, but again, concomitant ablation of Foxo1 restored postprandial regulation, preventing the inhibition of the metabolic response to nutrient intake caused by deletion of Akt. These results are inconsistent with the canonical model of hepatic metabolism in which Akt is an obligate intermediate for proper insulin signaling. Rather, they show that a major role of hepatic Akt is to restrain the activity of Foxo1 and that in the absence of Foxo1, Akt is largely dispensable for insulin- and nutrient-mediated hepatic metabolic regulation in vivo.

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Available from: Kohjiro Ueki
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    • "Thus, any defects in the PI3 kinase/Akt/AS160 transduction pathway would ultimately reduce glucose uptake in skeletal muscle. Similarly, hepatic deletion of the Akt1 and Akt2 isoform causes glucose intolerance, insulin resistance, and a defective insulin transcriptional response to feeding in hepatocytes.55 "
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    • "Basal hepatic glucose production (HGP) was the same between the two groups, but suppression of HGP by insulin was significantly blunted in Akt2 (lox/lox) ; AFP > CRE mice (Figure 1A). The mildness of the defect is due to functional rescue by Akt1, which represents about 15% of the Akt protein in hepatocytes, the remainder being Akt2 (Lu et al., 2012). Surprisingly, the rate of glucose disposal (Rd) was also significantly reduced, indicating that peripheral insulin resistance developed upon deletion of Akt2 exclusively in liver (Leavens et al., 2009) (Figure 1A, left). "
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    • "Improper FOXO1 activation and regulation may contribute to increased GPR and gluconeogenic gene expression. The phosphorylation and nuclear exclusion of FOXO1 is one well-characterized mechanism for insulin-mediated suppression of gluconeogenic gene expression, and recent studies indicate the importance of proper FOXO1 regulation for hepatic metabolism (40–43). Basal phosphorylation of FOXO1 is higher in the IUGR liver and is not increased further with insulin, nor is nuclear localization reduced, despite normal AKT activation. "
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