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:

Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo

Abstract

The transcription factor, signal transducer and activator of transcription-3 (STAT-3) contributes to various physiological processes. Here we show that mice with liver-specific deficiency in STAT-3, achieved using the Cre-loxP system, show insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT-3 expression in these mice, using adenovirus-mediated gene transfer, corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Overexpression of STAT-3 in cultured hepatocytes inhibited gluconeogenic gene expression independently of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), an upstream regulator of gluconeogenic genes. Liver-specific expression of a constitutively active form of STAT-3, achieved by infection with an adenovirus vector, markedly reduced blood glucose, plasma insulin concentrations and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT-3 signaling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes mellitus.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Metabolic phenotypes of mice with liver-specific STAT-3 deficiency (L-ST3KO mice).
Figure 2: Euglycemic, hyperinsulinemic clamp analyses, effects of high-fat diet and changes in hepatic gene expression in L-ST3KO mice.
Figure 3: Restoration of STAT-3 expression in livers of L-ST3KO mice.
Figure 4: Effects of IL-6, Ly294002 and dominant-negative or wild-type STAT-3 on gluconeogenic genes, FOXO-1 phosphorylation and Pck1 promoter activity.
Figure 5: Effects of wild-type STAT-3 on PGC-1α-induced expression of PCK-1 and G6PC.
Figure 6: Effects of constitutively active STAT-3 (STAT-3C) on glucose intolerance, gene expression and lipid content in livers of Lepr−/− mice.

Similar content being viewed by others

References

  1. Taylor, S.I. Deconstructing type 2 diabetes. Cell 97, 9–12 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Radziuk, J. & Pye, S. Hepatic glucose uptake, gluconeogenesis and the regulation of glycogen synthesis. Diabet. Metab. Res. Rev. 17, 250–272 (2001).

    Article  CAS  Google Scholar 

  3. Shimomura, I. et al. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol. Cell 6, 77–86 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. 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  PubMed  Google Scholar 

  5. Trinh, K.Y., O'Doherty, R.M., Anderson, P., Lange, A.J. & Newgard, C.B. Perturbation 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rosella, G. et al. Impaired glucose tolerance and increased weight gain in transgenic rats overexpressing a non-insulin-responsive phosphoenolpyruvate carboxykinase gene. Mol. Endocrinol. 9, 1396–1404 (1995).

    CAS  PubMed  Google Scholar 

  8. Sun, Y. et al. Phosphoenolpyruvate carboxykinase overexpression selectively attenuates insulin signaling and hepatic insulin sensitivity in transgenic mice. J. Biol. Chem. 277, 23301–23307 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. O'Brien, R.M. & Granner, D.K. Regulation of gene expression by insulin. Physiol. Rev. 76, 1109–1161 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Christ, B., Yazici, E. & Nath, A. Phosphatidylinositol 3-kinase and protein kinase C contribute to the inhibition by interleukin 6 of phosphoenolpyruvate carboxykinase gene expression in cultured rat hepatocytes. Hepatology 31, 461–468 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Metzger, S. et al. Interleukin-6 secretion in mice is associated with reduced glucose-6-phosphatase and liver glycogen levels. Am. J. Physiol. 273, E262–E267 (1997).

    CAS  PubMed  Google Scholar 

  12. Akira, S., Taga, T. & Kishimoto, T. Interleukin-6 in biology and medicine. Adv. Immunol. 54, 1–78 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Febbraio, M.A. & Pedersen, B.K. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. FASEB J. 16, 1335–1347 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Vgontzas, A.N., Papanicolaou, D.A., Bixler, E.O., Kales, A., Tyson, K. & Chrousos, G.P. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J. Clin. Endocrinol. Metab. 82, 1313–1316 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Levy, D.E. & Lee, C.-K. What does Stat3 do? J. Clin. Invest. 109, 1143–1148 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Takeda, K. et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl. Acad. Sci. USA 94, 3801–3804 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yaker, S. et al. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc. Natl. Acad. Sci. USA 96, 7324–7329 (1999).

    Article  Google Scholar 

  18. Takeda, K. et al. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J. Immunol. 161, 4652–4560 (1998).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Horton, J.D., Goldstein, J.L. & Brown, M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Miyake, K. et al. Hyperinsulinemia, glucose intolerance, and dyslipidemia induced by acute inhibition of phosphoinositide 3-kinase signaling in the liver. J. Clin. Invest. 110, 1483–1491 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Minami, M. et al. STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line. Proc. Natl. Acad. Sci. USA 93, 3963–3966 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nakae, J., Kitamura, T., Silver, D.L. & Accili, D. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity. onto glucose-6-phosphatase expression. J. Clin. Invest. 108, 1359–67 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Scott, D.K., O'Doherty, R.M., Stafford, J.M., Newgard, C.B. & Granner, D.K. Therepression of hormone-activated PEPCK gene expression by glucose is insulin-independent but requires glucose metabolism. J. Biol. Chem. 273, 24145–24151 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Kotani, K et al. Dominant negative forms of Akt (protein kinase B) and atypical protein kinase Cλ do not prevent insulin inhibition of phosphoenolpyruvate carboxykinase gene transcription. J. Biol. Chem. 274, 21305–21312 (1998).

    Article  Google Scholar 

  27. Herzig, S et al. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413, 179–183 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Lee, G.-H. et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Bromberg, J.F. et al. Stat3 as an oncogene. Cell 98, 295–303 (1999).

    CAS  PubMed  Google Scholar 

  30. Strassmann, G., Fong, M., Windsor, S. & Neta, R. The role of interleukin-6 in lipopolysaccharide-induced weight loss, hypoglycemia and fibrinogen production in vivo. Cytokine 5, 285–290 (1993).

    Article  CAS  PubMed  Google Scholar 

  31. Wallenius, V. et al. Interleukin-6-deficient mice develop mature-onset obesity. Nature Med. 8, 75–79 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Bluher, M et al. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev. Cell. 3, 25–38 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Kitamura, T. et al. Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt. Mol. Cell. Biol. 19, 6286–6296 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ozaki, M. et al. Inhibition of the Rac1 GTPase protects against nonlethal ischemia/reperfusion-induced necrosis and apoptosis in vivo. FASEB J. 14, 418–429 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Ren, J.M., Marshall, B.A., Mueckler, M.M., McCaleb, M., Amatruda, J.M., & Shulman, G.I. Overexpression of Glut4 protein in muscle increases basal and insulin-stimulated whole body glucose disposal in conscious mice. J. Clin. Invest. 95, 429–432 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Matsumoto, M. et al. PKCλ in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity. J. Clin. Invest. 112, 935–944 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Matsumoto, M. et al. Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. Diabetes 51, 1672–1680 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank J.E. Darnell Jr. for the STAT-3C-encoding cDNA, T. Noguchi for the Gck probe, H. Shimano for the Srebf1 probe, H. Nakajima for the G6pc probe, N. Iritani for the Fasn probe, D. Accili for the adenovirus encoding hemagglutinin-tagged, wild-type FOXO-1, and D.K. Granner for the HL1C cells. This work was supported by a grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to M.K. and W.O.) and a grant from the Cooperative Link of Unique Science and Technology for Economy Revitalization (to M.K.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Masato Kasuga.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Inoue, H., Ogawa, W., Ozaki, M. et al. Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. Nat Med 10, 168–174 (2004). https://doi.org/10.1038/nm980

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm980

This article is cited by

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