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Foxo1 integrates insulin signaling with mitochondrial function in the liver

Nature Medicine volume 15, pages 1307–1311 (2009)Cite this article

Abstract

Type 2 diabetes is a complex disease that is marked by the dysfunction of glucose and lipid metabolism. Hepatic insulin resistance is especially pathogenic in type 2 diabetes, as it dysregulates fasting and postprandial glucose tolerance and promotes systemic dyslipidemia and nonalcoholic fatty liver disease1,2. Mitochondrial dysfunction is closely associated with insulin resistance and might contribute to the progression of diabetes3,4. Here we used previously generated mice5 with hepatic insulin resistance owing to the deletion of the genes encoding insulin receptor substrate-1 (Irs-1) and Irs-2 (referred to here as double-knockout (DKO) mice) to establish the molecular link between dysregulated insulin action and mitochondrial function. The expression of several forkhead box O1 (Foxo1) target genes increased in the DKO liver, including heme oxygenase-1 (Hmox1), which disrupts complex III and IV of the respiratory chain and lowers the NAD+/NADH ratio and ATP production. Although peroxisome proliferator–activated receptor-γ coactivator-1α (Ppargc-1α) was also upregulated in DKO liver, it was acetylated and failed to promote compensatory mitochondrial biogenesis or function. Deletion of hepatic Foxo1 in DKO liver normalized the expression of Hmox1 and the NAD+/NADH ratio, reduced Ppargc-1α acetylation and restored mitochondrial oxidative metabolism and biogenesis. Thus, Foxo1 integrates insulin signaling with mitochondrial function, and inhibition of Foxo1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome.

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Figure 1: Mitochondrial morphology and biogenesis in the insulin-resistant livers.
Figure 2: Evaluation of mitochondrial function.
Figure 3: Ppargc-1α inactivation in liver.
Figure 4: Foxo1 regulates electron transport chain via Hmox1.

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Acknowledgements

We thank B. Spiegelman and L.M. Rohas for help with respiration assays, S. Orkin for help with fluorescent assays and R. de Cabo for the communication on flow cytometric assay. We are also grateful to Y. Long for his valuable comments and discussion. This project was supported by US National Institutes of Health grants DK38712 and DK55326 (M.F.W.), American Diabetes Association Mentor-Based Postdoctoral Fellowship 7-08-MN-63 (M.F.W. and Z.C.) and American Diabetes Association Junior Faculty Grant JF-7-07-27 (S.G.).

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  1. Xiaochen Dong

    Present address: Present address: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.,

Authors and Affiliations

  1. Division of Endocrinology, Howard Hughes Medical Institute, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA

    Zhiyong Cheng, Shaodong Guo, Kyle Copps, Xiaochen Dong & Morris F White

  2. Department of Medical Oncology, Departments of Medicine and Genetics, Belfer Institute for Applied Cancer Science, Harvard Medical School, Boston, Massachusetts, USA

    Ramya Kollipara & Ronald A Depinho

  3. Department of Cancer Biology, Department of Cell Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Joseph T Rodgers & Pere Puigserver

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Contributions

Z.C. and M.F.W. designed this study. Z.C., S.G., K.C., X.D., R.K. and J.T.R. performed the experiments. Z.C. and M.F.W. analyzed the data. Z.C. and M.F.W. communicated with R.A.D. and P.P. about data interpretation and wrote the manuscript.

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Correspondence to Morris F White.

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Cheng, Z., Guo, S., Copps, K. et al. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nat Med 15, 1307–1311 (2009). https://doi.org/10.1038/nm.2049

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