[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Nordlie, R. C. & Foster, J. D. Regulation of glucose production by the liver. Annu. Rev. Nutr. 19, 379–406 (1999).

    Article  CAS  Google Scholar 

  2. Pilkis, S. J. & Granner, D. K. Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis. Annu. Rev. Physiol. 54, 885–909 (1992).

    Article  CAS  Google Scholar 

  3. DeFronzo, R. A. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev. 5, 177–269 (1997).

    Google Scholar 

  4. Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).

    Article  CAS  Google Scholar 

  5. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999).

    Article  CAS  Google Scholar 

  6. Boss, O. et al. Role of the β3-adrenergic receptor and/or a putatibe β4-adrenergic receptor on the expression of uncoupling proteins and peroxisome proliferator activated receptor-γ coactivator-1. Biochem. Biophys. Res. Commun. 261, 870–876 (1999).

    Article  CAS  Google Scholar 

  7. Gomez-Ambrosi, J., Fruhbeck, G. & Alfredo-Martinez, J. Rapid in vivo PGC-1 mRNA upregulation in brown adipose tissue of Wistar rats by a β3-adrenergic agonist and lack of effect of leptin. Mol. Cell. Endocrinol. 176, 85–90 (2001).

    Article  CAS  Google Scholar 

  8. Hall, R. K., Sladek, F. & Granner, D. K. The orphan receptors COUP-TF and HNF-4 serve as accessory factors required for phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. Proc. Natl Acad. Sci. 92, 412–416 (1995).

    Article  ADS  CAS  Google Scholar 

  9. McNeill, J. H. Experimental Models of Diabetes (CRC, Boca Raton, 1999).

    Google Scholar 

  10. Michael, M. D. et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol. Cell 6, 87–97 (2000).

    Article  CAS  Google Scholar 

  11. Hanson, R. W. & Reshef, L. Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annu. Rev. Biochem. 66, 581–611 (1997).

    Article  CAS  Google Scholar 

  12. Mitchell, J. et al. Integration of multiple signals through a complex hormone response unit in the phosphoenolpyruvate carboxykinase gene promoter. Mol. Endocrinol. 8, 585–594 (1994).

    CAS  PubMed  Google Scholar 

  13. Park, E. A., Song, S., Vinson, C. & Roesler, W. J. Role of CCAAT enhancer-binding protein β in the thyroid hormone and cAMP induction of phosphoenolpyruvate caroboxykinase gene transcription. J. Biol. Chem. 274, 211–217 (1999).

    Article  CAS  Google Scholar 

  14. Roesler, W. J., Simard, J., Graham, J. G. & McFie, P. J. Characterization of the liver-specific component of the cAMP response unit in the phosphoenolpyruvate carboxykinase (GTP) gene promoter. J. Biol. Chem. 269, 14276–14283 (1994).

    CAS  PubMed  Google Scholar 

  15. Scott, D. K., Mitchell, J. A. & Granner, D. K. The orphan receptor COUP-TF binds to a third glucocorticoids accessory factor element within the phosphoenolpyruvate carboxykinase gene promoter. J. Biol. Chem. 271, 31909–31904 (1996).

    Article  CAS  Google Scholar 

  16. Yeagley, D., Agati, J. M. & Quinn, P. G. A tripartite array of transcription factor binding sites mediates cAMP induction of phosphoenolpyruvate carboxykinase gene transcription and its inhibition by insulin. J. Biol. Chem. 273, 18743–18750 (1998).

    Article  CAS  Google Scholar 

  17. Sugiyama, T., Wang, J. C., Scott, D. K. & Granner, D. K. Transcriptional activation by the orphan nuclear receptor, chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI). J. Biol. Chem. 275, 3446–3454 (2000).

    Article  CAS  Google Scholar 

  18. Wang, J. C., Stromstedt, P. I., Sugiyama, T. & Granner, D. K. The phosphoenolpyruvate carboxykinase gene glucocorticoid response unit: identification of the functional domains of accessory factors HNF3β (hepatic nuclear factor-3β) and HNF4 and the necessity of proper alignment of their cognate binding sites. Mol. Endocrinol. 13, 604–618 (1999).

    CAS  PubMed  Google Scholar 

  19. Knutti, D., Kaul, A. & Kralli, A. A tissue-specific coactivator of steroid receptors, identified in a functional genetic screen. Mol. Cell. Biol. 20, 2411–2422 (2000).

    Article  CAS  Google Scholar 

  20. Tcherepanova, I., Puigserver, P., Norris, J. D., Spiegelman, B. M. & McDonnell, D. P. Modulation of estrogen receptor-α transcriptional activity by the coactivator PGC-1. J. Biol. Chem. 275, 16302–16308 (2000).

    Article  CAS  Google Scholar 

  21. Vega, R. B., Huss, J. M. & Kelly, D. P. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor α in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol. Cell. Biol. 20, 1868–1876 (2000).

    Article  CAS  Google Scholar 

  22. Puigserver, P. et al. Activation of PPARγ coactivator-1 through transcription factor docking. Science 286, 1368–1371 (1999).

    Article  CAS  Google Scholar 

  23. Trinh, K., O'Doherty, R. M., Anderson, P., Lange, A. J. & Newgard, C. B. Perturbations of fuel homeostasis caused by overexpression of the glucose-6-phosphatase catalytic subunit in liver of normal rats. J. Biol. Chem. 273, 31615–31620 (1998).

    Article  CAS  Google Scholar 

  24. O'Doherty, R. M., Lehman, D., Telemaque-Potts, S. & Newgard, C. B. Metabolic impact of glucokinase overexpression in liver: Lowering of blood glucose in fed rats is accompanied by hyperlipidemia. Diabetes 48, 2022–2027 (1999).

    Article  CAS  Google Scholar 

  25. Valera, A., Pujol, A., Pelegrin, M. & Bosch, F. Transgenic mice overexpressing phosphoenolpyruvate carboxykinase gene develop non-insulin-dependent diabetes mellitus. Proc. Natl Acad. Sci. USA 91, 9151–9154 (1994).

    Article  ADS  CAS  Google Scholar 

  26. Seoane, J. K. et al. Metabolic impact of adenovirus-mediated overexpression of the glucose-6-phosphatase catalytic subunit in hepatocytes. J. Biol. Chem. 272, 26972–26977 (1997).

    Article  CAS  Google Scholar 

  27. Cho, H. et al. Insulin resistance and diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ). Science 292, 1728–1731 (2001).

    Article  ADS  CAS  Google Scholar 

  28. Nakae, J., Barr, V. & Accili, D. Differential regulation of gene expression by insulin and IGF-1 receptors correlates with phosphorylation of a single amino acid residue in the forkhead transcription factor FKHR. EMBO J. 19, 989–996 (2000).

    Article  CAS  Google Scholar 

  29. Antinozzi, P. A., Berman, H. K., O'Doherty, R. M. & Newgard, C. B. Metabolic engineering with recombinant adenoviruses. Annu. Rev. Nutr. 19, 511–544 (1999).

    Article  CAS  Google Scholar 

  30. Becker, T. et al. Use of recombinant adenovirus for metabolic engineering. Methods Cell Biol. 43, 161–189 (1994).

    Article  CAS  Google Scholar 

  31. Glass, C. K. & Rosenfeld, M. D. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 14, 121–141 (2000).

    CAS  PubMed  Google Scholar 

  32. Wiernsperger, N. F. & Bailey, C. J. The antihyperglycaemic effect of metformin: Therapeutic and cellular mechanisms. Drugs 58, 31–39 (1999).

    Article  CAS  Google Scholar 

  33. Lehman, J. J. et al. Peroxisome proliferator-activated receptor γ promotes cardiac mitochondrial biogenesis. J. Clin. Invest. 106, 847–856 (2000).

    Article  CAS  Google Scholar 

Download references

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.

Author information

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

Authors
  1. J. Cliff Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pere Puigserver
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guoxun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jerry Donovan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhidan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. James Rhee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guillaume Adelmant
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John Stafford
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C. Ronald Kahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Daryl K. Granner
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christopher B. Newgard
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Bruce M. Spiegelman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bruce M. Spiegelman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35093050

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing