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Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1

Nature volume 413, pages 131–138 (2001)Cite this article

Abstract

Blood glucose levels are maintained by the balance between glucose uptake by peripheral tissues and glucose secretion by the liver. Gluconeogenesis is strongly stimulated during fasting and is aberrantly activated in diabetes mellitus. Here we show that the transcriptional coactivator PGC-1 is strongly induced in liver in fasting mice and in three mouse models of insulin action deficiency: streptozotocin-induced diabetes, ob/ob genotype and liver insulin-receptor knockout. PGC-1 is induced synergistically in primary liver cultures by cyclic AMP and glucocorticoids. Adenoviral-mediated expression of PGC-1 in hepatocytes in culture or in vivo strongly activates an entire programme of key gluconeogenic enzymes, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, leading to increased glucose output. Full transcriptional activation of the PEPCK promoter requires coactivation of the glucocorticoid receptor and the liver-enriched transcription factor HNF-4α (hepatic nuclear factor-4α) by PGC-1. These results implicate PGC-1 as a key modulator of hepatic gluconeogenesis and as a central target of the insulin–cAMP axis in liver.

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Figure 1: PGC-1 gene expression is regulated by nutritional status.
Figure 2: PGC-1 gene expression is induced in cultured hepatocytes by treatment with gluconeogenic hormones.
Figure 3: PGC-1 gene expression is increased in the livers of insulin-deficient animals.
Figure 4: Adenovirus-mediated expression of PGC-1 induces multiple genes of the gluconeogenic pathway in hepatocytes.
Figure 5: Expression of PGC-1 enhances glucose production in hepatocytes in the absence of hormonal treatment.
Figure 6: PGC-1 activates the PEPCK promoter through a functional interaction with HNF-4α.
Figure 7: PGC-1 physically interacts with HNF-4α in cells and in vitro.
Figure 8: PGC-1 activates gluconeogenesis in vivo.

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Acknowledgements

We gratefully acknowledge E. Park for the pGL3 PEPCK-Luc constructs; F. Sladek for the HNF-4α constructs; V. Yechoor for the tissue samples from the streptozotocin-treated animals; S. Curtis for help with the LIRKO animals; and C.Y. Zhang for help with the fasting experiments. We also thank the members of the Spiegelman laboratory for helpful discussions. P.P. and Z.W. were supported by fellowships from the Juvenile Diabetes Foundation. This work was supported by grants to B.M.S., D.K.G., C.R.K. and C.B.N. from the National Institutes of Health.

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Authors and Affiliations

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

    J. Cliff Yoon, Pere Puigserver, Jerry Donovan, Zhidan Wu, James Rhee, Guillaume Adelmant & Bruce M. Spiegelman

  2. Departments of Biochemistry and Internal Medicine, Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Guoxun Chen & Christopher B. Newgard

  3. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, 37232, Tennessee, USA

    John Stafford & Daryl K. Granner

  4. Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, 02115, Massachusetts, USA

    C. Ronald Kahn

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Correspondence to Bruce M. Spiegelman.

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Yoon, J., Puigserver, P., Chen, G. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131–138 (2001). https://doi.org/10.1038/35093050

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