[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:

The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism

Nature volume 437, pages 1109–1114 (2005)Cite this article

Abstract

Glucose homeostasis is regulated systemically by hormones such as insulin and glucagon, and at the cellular level by energy status. Glucagon enhances glucose output from the liver during fasting by stimulating the transcription of gluconeogenic genes via the cyclic AMP-inducible factor CREB (CRE binding protein). When cellular ATP levels are low, however, the energy-sensing kinase AMPK inhibits hepatic gluconeogenesis through an unknown mechanism. Here we show that hormonal and energy-sensing pathways converge on the coactivator TORC2 (transducer of regulated CREB activity 2) to modulate glucose output. Sequestered in the cytoplasm under feeding conditions, TORC2 is dephosphorylated and transported to the nucleus where it enhances CREB-dependent transcription in response to fasting stimuli. Conversely, signals that activate AMPK attenuate the gluconeogenic programme by promoting TORC2 phosphorylation and blocking its nuclear accumulation. Individuals with type 2 diabetes often exhibit fasting hyperglycaemia due to elevated gluconeogenesis; compounds that enhance TORC2 phosphorylation may offer therapeutic benefits in this setting.

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: Fasting hormones activate TORC2.
Figure 2: TORC2 is required for fasting hepatic gluconeogenesis.
Figure 3: Induction of SIK1 during fasting attenuates the gluconeogenic programme in primary hepatocytes.
Figure 4: SIKs inhibit hepatic gluconeogenesis via Ser 171 phosphorylation of TORC2.
Figure 5: AMPK inhibits activation of TORC2 by fasting signals.

Similar content being viewed by others

References

  1. Saltiel, A. & Kahn, C. R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  2. Saltiel, A. R. New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell 104, 517–529 (2001)

    Article  CAS  PubMed  Google Scholar 

  3. Phillips, C. A. & Molitch, M. E. The relationship between glucose control and the development and progression of diabetic nephropathy. Curr. Diab. Rep. 2, 523–529 (2002)

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Hall, R. K. & Granner, D. K. Insulin regulates expression of metabolic genes through divergent signalling pathways. J. Basic Clin. Physiol. Pharmacol. 10, 119–133 (1999)

    Article  CAS  PubMed  Google Scholar 

  6. Herzig, S. et al. CREB regulates hepatic gluconeogenesis via the co-activator PGC-1. Nature 413, 179–183 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Herzig, S. et al. CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ. Nature 426, 190–193 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Yoon, J. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131–138 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Koo, S. H. et al. PGC-1 promotes insulin resistance in liver through PPAR-α-dependent induction of TRB-3. Nature Med. 10, 530–534 (2004)

    Article  CAS  PubMed  Google Scholar 

  10. Lin, J. et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice. Cell 119, 121–135 (2004)

    Article  CAS  PubMed  Google Scholar 

  11. Leone, T. C. et al. PGC-1α deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol. 3, e101 (2005)

    Article  PubMed  PubMed Central  Google Scholar 

  12. Puigserver, P. et al. Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction. Nature 423, 550–555 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Banerjee, R. R. et al. Regulation of fasted blood glucose by resistin. Science 303, 1195–1198 (2004)

    Article  ADS  CAS  PubMed  Google Scholar 

  14. Yamauchi, T. et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nature Med. 8, 1288–1295 (2002)

    Article  CAS  PubMed  Google Scholar 

  15. Chrivia, J. C. et al. Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365, 855–859 (1993)

    Article  ADS  CAS  PubMed  Google Scholar 

  16. Arias, J. et al. Activation of cAMP and mitogen responsive genes relies on a common nuclear factor. Nature 370, 226–228 (1994)

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Conkright, M. D. et al. TORCs: transducers of regulated CREB activity. Mol. Cell 12, 413–423 (2003)

    Article  CAS  PubMed  Google Scholar 

  18. Iourgenko, V. et al. Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells. Proc. Natl Acad. Sci. USA 100, 12147–12152 (2003)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  19. Screaton, R. A. et al. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 119, 61–74 (2004)

    Article  CAS  PubMed  Google Scholar 

  20. Bittinger, M. A. et al. Activation of cAMP response element-mediated gene expression by regulated nuclear transport of TORC proteins. Curr. Biol. 14, 2156–2161 (2004)

    Article  CAS  PubMed  Google Scholar 

  21. Zhou, X. Y. et al. Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein. Nature Med. 10, 633–637 (2004)

    Article  CAS  PubMed  Google Scholar 

  22. Kasper, L. H. et al. A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis. Nature 419, 738–743 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Ahn, S. et al. A dominant negative inhibitor of CREB reveals that it is a general mediator stimulus-dependent transcription of c-fos. Mol. Cell. Biol. 18, 967–977 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sasaki, K. et al. Multihormonal regulation of phosphoenolpyruvate carboxykinase gene transcription. J. Biol. Chem. 259, 15242–15251 (1984)

    CAS  PubMed  Google Scholar 

  25. Lochhead, P. A., Coghlan, M., Rice, S. Q. & Sutherland, C. Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphatase and phosphoenolypyruvate carboxykinase gene expression. Diabetes 50, 937–946 (2001)

    Article  CAS  PubMed  Google Scholar 

  26. Kahn, B. B., Alquier, T., Carling, D. & Hardie, D. G. AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 1, 15–25 (2005)

    Article  CAS  PubMed  Google Scholar 

  27. Lizcano, J. M. et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 23, 833–843 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sakamoto, K., Goransson, O., Hardie, D. G. & Alessi, D. R. Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR. Am. J. Physiol. Endocrinol. Metab. 287, E310–E317 (2004)

    Article  CAS  PubMed  Google Scholar 

  29. Radziuk, J., Bailey, C. J., Wiernsperger, N. F. & Yudkin, J. S. Metformin and its liver targets in the treatment of type 2 diabetes. Curr. Drug Targets Immune Endocr. Metab. Disord. 3, 151–169 (2003)

    Article  CAS  Google Scholar 

  30. Bergeron, R. et al. Effect of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats. Diabetes 50, 1076–1082 (2001)

    Article  CAS  PubMed  Google Scholar 

  31. Du, K., Herzig, S., Kulkarni, R. N. & Montminy, M. TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 300, 1574–1577 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  32. Katoh, Y. et al. Salt-inducible kinase-1 represses cAMP response element-binding protein activity both in the nucleus and in the cytoplasm. Eur. J. Biochem. 271, 4307–4319 (2004)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the NIH, the Keickhefer Foundation, the Hillblom Foundation, the American Diabetes Association, the Juvenile Diabetes Foundation and the Leukemia and Lymphoma Society. We thank L. Vera for mouse injections and ProteinExpress Co. Ltd for the gift of p-TORC2 antiserum.

Author information

Author notes

  1. Seung-Hoi Koo and Lawrence Flechner: *These authors contributed equally to this work

Authors and Affiliations

  1. Peptide Biology Laboratories, Salk Institute for Biological Studies, 10010 N Torrey Pines Rd, California, 92037-1002, La Jolla, USA

    Seung-Hoi Koo, Lawrence Flechner, Ling Qi, Xinmin Zhang, Robert A. Screaton, Shawn Jeffries, Susan Hedrick & Marc Montminy

  2. Department of Biochemistry, St Jude Children's Research Hospital, 332 N. Lauderdale, Tennessee, 38105, Memphis, USA

    Wu Xu, Fayçal Boussouar & Paul Brindle

  3. Department of Biochemistry and Molecular Biology, Graduate School of Medicine (H-1), Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Hiroshi Takemori

Authors
  1. Seung-Hoi Koo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lawrence Flechner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ling Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xinmin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert A. Screaton
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shawn Jeffries
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Susan Hedrick
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wu Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Fayçal Boussouar
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Paul Brindle
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hiroshi Takemori
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Marc Montminy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marc Montminy.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures S1–S19. (PDF 1540 kb)

Supplementary Figure Legends

This file contains text descriptions to accompany the above Supplementary Figures. (DOC 24 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Koo, SH., Flechner, L., Qi, L. et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109–1114 (2005). https://doi.org/10.1038/nature03967

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03967

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