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Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction

Nature volume 423, pages 550–555 (2003)Cite this article

Abstract

Hepatic gluconeogenesis is absolutely required for survival during prolonged fasting or starvation, but is inappropriately activated in diabetes mellitus. Glucocorticoids and glucagon have strong gluconeogenic actions on the liver. In contrast, insulin suppresses hepatic gluconeogenesis1,2,3. Two components known to have important physiological roles in this process are the forkhead transcription factor FOXO1 (also known as FKHR) and peroxisome proliferative activated receptor-γ co-activator 1 (PGC-1α; also known as PPARGC1), a transcriptional co-activator; whether and how these factors collaborate has not been clear. Using wild-type and mutant alleles of FOXO1, here we show that PGC-1α binds and co-activates FOXO1 in a manner inhibited by Akt-mediated phosphorylation. Furthermore, FOXO1 function is required for the robust activation of gluconeogenic gene expression in hepatic cells and in mouse liver by PGC-1α. Insulin suppresses gluconeogenesis stimulated by PGC-1α but co-expression of a mutant allele of FOXO1 insensitive to insulin completely reverses this suppression in hepatocytes or transgenic mice. We conclude that FOXO1 and PGC-1α interact in the execution of a programme of powerful, insulin-regulated gluconeogenesis.

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Figure 1: Insulin regulates PGC-1α action but not PGC-1α gene expression.
Figure 2: Co-activation of FOXO1 by PGC-1α is required for gluconeogenic gene expression.
Figure 3: Insulin regulation of PGC-1α action on gluconeogenesis depends on FOXO1 function in hepatocyte cells.
Figure 4: Insulin regulation of PGC-1α action on gluconeogenic genes depends on FOXO1 function in live mice.

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Acknowledgements

We acknowledge members of the Spiegelman laboratory for helpful discussions on the project. We also thank P. Vazquez for discussions on the project. Some constructs and reagents used in this work were obtained from W. Sellers, D. Schmoll, Y. Inoue and F. Gonzalez. We also thank the Vector Core of the Institute for Human Gene Therapy at Mount Sinai School of Medicine for virus preparation and help with injections. P.P. was supported by a Lee Career Award. This work was supported by grants to B.M.S. from the National Institutes of Health.

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  1. Pere Puigserver

    Present address: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA

Authors and Affiliations

  1. Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Pere Puigserver, James Rhee, Jerry Donovan, Christopher J. Walkey, J. Cliff Yoon & Bruce M. Spiegelman

  2. Naomi Berrie Diabetes Center and Department of Medicine, College of Physicians & Surgeons of Columbia University, New York, New York, 10032, USA

    Francesco Oriente, Yukari Kitamura & Domenico Accili

  3. Institute for Human Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York, 10029, USA

    Jennifer Altomonte & Hengjiang Dong

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  1. Pere Puigserver
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Correspondence to Bruce M. Spiegelman.

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Puigserver, P., Rhee, J., Donovan, J. et al. Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction. Nature 423, 550–555 (2003). https://doi.org/10.1038/nature01667

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