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:

TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes

Nature Medicine volume 12, pages 107–113 (2006)Cite this article

Abstract

Using an expression cloning strategy, we have identified TFE3, a basic helix-loop-helix protein, as a transactivator of metabolic genes that are regulated through an E-box in their promoters. Adenovirus-mediated expression of TFE3 in hepatocytes in culture and in vivo strongly activated expression of IRS-2 and Akt and enhanced phosphorylation of insulin-signaling kinases such as Akt, glycogen synthase kinase 3β and p70S6 kinase. TFE3 also induced hexokinase II (HK2) and insulin-induced gene 1 (INSIG1). These changes led to metabolic consequences, such as activation of glycogen and protein synthesis, but not lipogenesis, in liver. Collectively, plasma glucose levels were markedly reduced both in normal mice and in different mouse models of diabetes, including streptozotocin-treated, db/db and KK mice. Promoter analyses showed that IRS2, HK2 and INSIG1 are direct targets of TFE3. Activation of insulin signals in both insulin depletion and resistance suggests that TFE3 could be a therapeutic target for diabetes.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Identification of TFE3 as a transactivator of E-box–containing promoters of genes involved in metabolism.
Figure 2: Effects of TFE3 on insulin signaling and glycogen synthesis in primary hepatocytes.
Figure 3: In vivo effects of TFE3 on livers of normal mice.
Figure 4: Changes in blood glucose and plasma insulin levels by TFE3 in diabetic mice.
Figure 5: Effects of TFE3 on gene expression and insulin signaling in livers of diabetic mice.
Figure 6: IRS2 promoter is a direct target of TFE3.

Similar content being viewed by others

References

  1. White, M.F. The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol. Cell. Biochem. 182, 3–11 (1998).

    Article  CAS  Google Scholar 

  2. Virkamaki, A., Ueki, K. & Kahn, C.R. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J. Clin. Invest. 103, 931–943 (1999).

    Article  CAS  Google Scholar 

  3. Withers, D.J. et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391, 900–904 (1998).

    Article  CAS  Google Scholar 

  4. Kubota, N. et al. Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia. Diabetes 49, 1880–1889 (2000).

    Article  CAS  Google Scholar 

  5. Rother, K.I. et al. Evidence that IRS-2 phosphorylation is required for insulin action in hepatocytes. J. Biol. Chem. 273, 17491–17497 (1998).

    Article  CAS  Google Scholar 

  6. Kido, Y. et al. Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. J. Clin. Invest. 105, 199–205 (2000).

    Article  CAS  Google Scholar 

  7. Rawson, R.B. The SREBP pathway–insights from Insigs and insects. Nat. Rev. Mol. Cell Biol. 4, 631–640 (2003).

    Article  CAS  Google Scholar 

  8. Shimano, H. Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Prog. Lipid Res. 40, 439–452 (2001).

    Article  CAS  Google Scholar 

  9. 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  Google Scholar 

  10. Osborne, T.F. Sterol regulatory element-binding proteins (SREBPs): key regulators of nutritional homeostasis and insulin action. J. Biol. Chem. 275, 32379–32382 (2000).

    Article  CAS  Google Scholar 

  11. Matsuzaka, T. et al. Insulin-independent induction of sterol regulatory element-binding protein-1c expression in the livers of streptozotocin-treated mice. Diabetes 53, 560–569 (2004).

    Article  CAS  Google Scholar 

  12. Kerouz, N.J., Horsch, D., Pons, S. & Kahn, C.R. Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. J. Clin. Invest. 100, 3164–3172 (1997).

    Article  CAS  Google Scholar 

  13. 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  Google Scholar 

  14. Yahagi, N. et al. Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice. J. Biol. Chem. 277, 19353–19357 (2002).

    Article  CAS  Google Scholar 

  15. Ide, T. et al. SREBPs suppress IRS-2-mediated insulin signalling in the liver. Nat. Cell Biol. 6, 351–357 (2004).

    Article  CAS  Google Scholar 

  16. Vallet, V.S. et al. Glucose-dependent liver gene expression in upstream stimulatory factor 2 −/− mice. J. Biol. Chem. 272, 21944–21949 (1997).

    Article  CAS  Google Scholar 

  17. Casado, M., Vallet, V.S., Kahn, A. & Vaulont, S. Essential role in vivo of upstream stimulatory factors for a normal dietary response of the fatty acid synthase gene in the liver. J. Biol. Chem. 274, 2009–2013 (1999).

    Article  CAS  Google Scholar 

  18. Riu, E., Bosch, F. & Valera, A. Prevention of diabetic alterations in transgenic mice overexpressing Myc in the liver. Proc. Natl. Acad. Sci. USA 93, 2198–2202 (1996).

    Article  CAS  Google Scholar 

  19. Shimano, H. et al. Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes. J. Biol. Chem. 274, 35832–35839 (1999).

    Article  CAS  Google Scholar 

  20. Uyeda, K., Yamashita, H. & Kawaguchi, T. Carbohydrate responsive element-binding protein (ChREBP): a key regulator of glucose metabolism and fat storage. Biochem. Pharmacol. 63, 2075–2080 (2002).

    Article  CAS  Google Scholar 

  21. Beckmann, H., Su, L.K. & Kadesch, T. TFE3: a helix-loop-helix protein that activates transcription through the immunoglobulin enhancer muE3 motif. Genes Dev. 4, 167–179 (1990).

    Article  CAS  Google Scholar 

  22. Giangrande, P.H., Hallstrom, T.C., Tunyaplin, C., Calame, K. & Nevins, J.R. Identification of E-box factor TFE3 as a functional partner for the E2F3 transcription factor. Mol. Cell. Biol. 23, 3707–3720 (2003).

    Article  CAS  Google Scholar 

  23. Grinberg, A.V. & Kerppola, T. Both Max and TFE3 cooperate with Smad proteins to bind the plasminogen activator inhibitor-1 promoter, but they have opposite effects on transcriptional activity. J. Biol. Chem. 278, 11227–11236 (2003).

    Article  CAS  Google Scholar 

  24. Feinman, R. et al. PU.1 and an HLH family member contribute to the myeloid-specific transcription of the Fc gamma RIIIA promoter. EMBO J. 13, 3852–3860 (1994).

    Article  CAS  Google Scholar 

  25. Zhao, G.Q., Zhao, Q., Zhou, X., Mattei, M.G. & de Crombrugghe, B. TFEC, a basic helix-loop-helix protein, forms heterodimers with TFE3 and inhibits TFE3-dependent transcription activation. Mol. Cell. Biol. 13, 4505–4512 (1993).

    Article  CAS  Google Scholar 

  26. Osawa, H., Sutherland, C., Robey, R.B., Printz, R.L. & Granner, D.K. Analysis of the signaling pathway involved in the regulation of hexokinase II gene transcription by insulin. J. Biol. Chem. 271, 16690–16694 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Daitoku, H., Yamagata, K., Matsuzaki, H., Hatta, M. & Fukamizu, A. regulation of PGC-1 promoter activity by protein kinase B and the forkhead transcription factor FKHR. Diabetes 52, 642–649 (2003).

    Article  CAS  Google Scholar 

  30. Riu, E. et al. Overexpression of c-myc in the liver prevents obesity and insulin resistance. FASEB J. 17, 1715–1717 (2003).

    Article  CAS  Google Scholar 

  31. Yoshikawa, T. et al. Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol. Cell. Biol. 21, 2991–3000 (2001).

    Article  CAS  Google Scholar 

  32. Amemiya-Kudo, M. et al. Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes. J. Lipid Res. 43, 1220–1235 (2002).

    CAS  PubMed  Google Scholar 

  33. Murakami, K. et al. A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats. Diabetes 47, 1841–1847 (1998).

    Article  CAS  Google Scholar 

  34. He, T.C. et al. A simplified system for generating recombinant adenoviruses. Proc. Natl. Acad. Sci. USA 95, 2509–2514 (1998).

    Article  CAS  Google Scholar 

  35. Heikkinen, S. et al. Mouse hexokinase II gene: structure, cDNA, promoter analysis, and expression pattern. Mamm. Genome 11, 91–96 (2000).

    Article  CAS  Google Scholar 

  36. Peng, Y. et al. Cloning, human chromosomal assignment, and adipose and hepatic expression of the CL-6/INSIG1 gene. Genomics 43, 278–284 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants-in-aid from the Ministry of Science, Education, Culture, and Technology of Japan (to Y.N., H.S., A.T. and N.Y.).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Metabolism and Endocrinology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Yoshimi Nakagawa, Hitoshi Shimano, Tomohiro Yoshikawa, Tomohiro Ide, Mariko Tamura, Mika Furusawa, Takashi Yamamoto, Noriyuki Inoue, Takashi Matsuzaka, Akimitsu Takahashi, Hiroaki Suzuki, Hirohito Sone, Hideo Toyoshima & Nobuhiro Yamada

  2. Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Yoshimi Nakagawa, Hitoshi Shimano, Takashi Matsuzaka, Akimitsu Takahashi, Hirohito Sone & Naoya Yahagi

  3. Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 21st Avenue South and Garland Avenue, Nashville, 37232, Tennessee, USA

    Alyssa H Hasty

Authors
  1. Yoshimi Nakagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hitoshi Shimano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomohiro Yoshikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomohiro Ide
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mariko Tamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mika Furusawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takashi Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Noriyuki Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takashi Matsuzaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Akimitsu Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Alyssa H Hasty
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hiroaki Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hirohito Sone
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hideo Toyoshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Naoya Yahagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Nobuhiro Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hitoshi Shimano.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

The multiple products of TFE3 are derived from different ATG sites. The Tcfe3 cDNA contains four potential start (ATG) sites. (PDF 309 kb)

Supplementary Fig. 2

The effects of dominant negative form of TFE3 (dnTFE3) on insulin signaling and glycogen synthesis in rat primary hepatocytes. (PDF 512 kb)

Supplementary Fig. 3

Dose-dependent effects of adenoviral TFE3 on hepatic gene expression as estimated by northern blotting. (PDF 320 kb)

Supplementary Fig. 4

HkII and INSIG1 promoters as targets of TFE3. (a) The mouse HkII promoter contains an E box which is responsible for induction of TFE3. (PDF 514 kb)

Supplementary Fig. 5

Physiological regulation of Irs2 expression in fasted and refed states, and effects of TFE3 over-expression on insulin-signaling. (PDF 351 kb)

Supplementary Table 1

Metabolic parameters in C57BL6 mice overexpressing GFP and wtTFE3. (PDF 296 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nakagawa, Y., Shimano, H., Yoshikawa, T. et al. TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes. Nat Med 12, 107–113 (2006). https://doi.org/10.1038/nm1334

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1334

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