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

Nature Medicine volume 18, pages 388–395 (2012)Cite this article

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Abstract

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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Figure 1: Liver-specific deletion of Akt1 in Akt2 whole-body knockout mice resulted in severe hyperglycemia and the disruption of Foxo1-regulated gene expression.
Figure 2: Aberrant insulin signaling and disrupted expression of Foxo1-regulated genes in DLKO but not 2LKO livers.
Figure 3: Deletion of both Akt1 and Akt2 in liver results in hyperglycemia, glucose intolerance and insulin resistance.
Figure 4: Deletion of Foxo1 normalizes hyperglycemia, glucose intolerance and hyperinsulinemia in DLKO livers despite defective insulin signaling.
Figure 5: Nutritional regulation of hepatic gene expression in the absence of Foxo1 alone and in the absence of both Akt and Foxo1.
Figure 6: Insulin-regulated expression of Foxo1 target genes was compromised in the Foxo1−/− and TLKO primary hepatocytes.

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Acknowledgements

The authors would like to thank M. Magnuson (Vanderbilt University) for providing the antibody to Gck and D. Accili (Columbia University) for sharing the Foxo1loxP/loxP mice. We are grateful to J. Schug, who helped with the microarray data analysis and generated the heat map and the density plot. The Functional Genomics Core and the Transgenic, Knockout, Mouse Phenotyping and Biomarker Cores of the University of Pennsylvania Diabetes and Endocrinology Research Center (NIH grant P30 DK19525) were instrumental in this work. This work was supported by the US National Institutes of Health grant RO1 DK56886 (M.J.B.) and the diabetes training grant T32 DK007314 (M.L.).

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Authors and Affiliations

  1. The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Mingjian Lu, Min Wan, Karla F Leavens, Qingwei Chu, Bobby R Monks, Sully Fernandez, Rexford S Ahima & Morris J Birnbaum

  2. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Kohjiro Ueki

  3. Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA

    C Ronald Kahn

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  1. Mingjian Lu
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Contributions

M.L. conceived of the hypothesis, designed and performed the experiments and analyzed the data. M.W. and K.F.L. performed experiments. Q.C., B.R.M. and S.F. provided technical assistance. The R.S.A. lab performed the hyperinsulinemic-euglycemic clamps experiments. K.U. and C.R.K. generated the Akt1loxP/loxP mice. M.J.B. conceived the hypothesis and directed the project. M.L. and M.J.B. prepared the manuscript.

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Correspondence to Morris J Birnbaum.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 (PDF 3499 kb)

Supplementary Table 1

Metabolic responsive genes in the control livers (XLS 423 kb)

Supplementary Table 2

Metabolic responsive genes that respond to the loss of Akt in the fed livers (XLS 220 kb)

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Lu, M., Wan, M., Leavens, K. et al. Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat Med 18, 388–395 (2012). https://doi.org/10.1038/nm.2686

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