Skip to main content
SpringerLink
Log in

Overactivation of NF-κB impairs insulin sensitivity and mediates palmitate-induced insulin resistance in C2C12 skeletal muscle cells

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Lipid-induced insulin resistance is associated with inflammatory state in epidemiological studies. However, it is still unclear whether the activation of NF-κB, a pivotal transcription factor of inflammation, plays a crucial role in mediating skeletal muscle insulin resistance. This study addressed what was the role of NF-κB in lipid-induced insulin resistance and whether NF-κB activation was sufficient to cause insulin resistance in C2C12 myotubes. A 16 h exposure of myotubes to palmitate reduced net insulin-stimulated glucose uptake by 48%, GLUT4 translocation by 52%, Akt phosphorylation by 54%, induced a 1.8-fold increase in insulin-stimulated insulin receptor substrate (IRS) phosphorylation, and doubled NF-κB activation. Myotubes transfected with NF-κB p65 siRNA for 24 h and followed by a treatment with palmitate for 16 h efficiently blocked NF-κB activation, and prevented the detrimental effects of palmitate on the metabolic actions of insulin. Transfection of myotubes with I-κBα siRNA for 24 h also led to a twofold induction of NF-κB activation, and reduced net insulin-stimulated glucose uptake by 30%, GLUT4 translocation by 35%, Akt phosphorylation by 31%, induced a 0.7-fold increase in insulin-stimulated IRS phosphorylation. These findings suggest that NF-κB overexpression per se is sufficient to impair insulin sensitivity and palmitate-induced insulin resistance is mediated by NF-κB in skeletal muscle cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. J.P. Wilding, Diabet. Med. 24, 934–945 (2007)

    Article  PubMed  CAS  Google Scholar 

  2. J.D. McGarry, Science 258, 766–770 (1992)

    Article  PubMed  CAS  Google Scholar 

  3. P. Brassard, F. Frisch, F. Lavoie, D. Cyr, A. Bourbonnais, S.C. Cunnane, B.W. Patterson, R. Drouin, J.P. Baillargeon, A.C. Carpentier, J. Clin. Endocrinol. Metab. 93, 837–844 (2008)

    Article  PubMed  CAS  Google Scholar 

  4. A. Carpentier, S.D. Mittelman, B. Lamarche, R.N. Bergman, A. Giacca, G.F. Lewis, Am. J. Physiol. 276, E1055–E1066 (1999)

    PubMed  CAS  Google Scholar 

  5. S.E. Shoelson, L. Herrero, A. Naaz, Gastroenterology 132, 2169–2180 (2007)

    Article  PubMed  CAS  Google Scholar 

  6. A. Festa Jr., R. D’Agostino, R.P. Tracy, S.M. Haffner, Diabetes 51, 1131–1137 (2002)

    Article  PubMed  CAS  Google Scholar 

  7. C. Winzer, O. Wagner, A. Festa, B. Schneider, M. Roden, D. Bancher-Todesca, G. Pacini, T. Funahashi, A. Kautzky-Willer, Diabetes Care 27, 1721–1727 (2004)

    Article  PubMed  CAS  Google Scholar 

  8. E. Park, V. Wong, X. Guan, A.I. Oprescu, A. Giacca, J. Endocrinol. 195, 323–331 (2007)

    Article  PubMed  CAS  Google Scholar 

  9. J. Reid, A.I. MacDougall, M.M. Andrews, Br. Med. J. 2, 1071–1074 (1957)

    Article  PubMed  CAS  Google Scholar 

  10. P.J. Barnes, M. Karin, N. Engl. J. Med. 336, 1066–1071 (1997)

    Article  PubMed  CAS  Google Scholar 

  11. S. Schreiber, Gut 44, 309–310 (1999)

    Article  PubMed  CAS  Google Scholar 

  12. M. Karin, Y. Ben-Neriah, Annu. Rev. Immunol. 18, 621–663 (2000)

    Article  PubMed  CAS  Google Scholar 

  13. U.J. Lee, S.R. Choung, K.V. Prakash, E.J. Lee, M.Y. Lee, Y.J. Kim, C.W. Han, Y.C. Choi, Mol. Biol. Rep. 35, 291–298 (2008)

    Article  PubMed  CAS  Google Scholar 

  14. S.I. Itani, N.B. Ruderman, F. Schmieder, G. Boden, Diabetes 51, 2005–2011 (2002)

    Article  PubMed  CAS  Google Scholar 

  15. S. Sinha, G. Perdomo, N.F. Brown, R.M. O’Doherty, J. Biol. Chem. 279, 41294–41301 (2004)

    Article  PubMed  CAS  Google Scholar 

  16. M. Jove, A. Planavila, J.C. Laguna, M. Vazquez-Carrera, Endocrinology 146, 3087–3095 (2005)

    Article  PubMed  CAS  Google Scholar 

  17. E. Polkinghorne, Q. Lau, G.J. Cooney, E.W. Kraegen, M.E. Cleasby, Am J. Physiol. Endocrinol. Metab. 294, E316–E325 (2008)

    Article  PubMed  CAS  Google Scholar 

  18. P. Barma, S. Bhattacharya, A. Bhattacharya, R. Kundu, S. Dasgupta, A. Biswas, S. Bhattacharya, S.S. Roy, S. Bhattacharya, Biochim. Biophys. Acta 1792, 190–200 (2009)

    PubMed  CAS  Google Scholar 

  19. Y. Wei, J.R. Sowers, S.E. Clark, W. Li, C.M. Ferrario, C.S. Stump, Am. J. Physiol. Endocrinol. Metab. 294, E345–E351 (2008)

    Article  PubMed  CAS  Google Scholar 

  20. T. Ogihara, T. Asano, H. Katagiri, H. Sakoda, M. Anai, N. Shojima, H. Ono, M. Fujishiro, A. Kushiyama, Y. Fukushima, M. Kikuchi, N. Noguchi, H. Aburatani, Y. Gotoh, I. Komuro, T. Fujita, Diabetologia 47, 794–805 (2004)

    Article  PubMed  CAS  Google Scholar 

  21. M. Yuan, N. Konstantopoulos, J. Lee, L. Hansen, Z.W. Li, M. Karin, S.E. Shoelson, Science 293, 1673–1677 (2001)

    Article  PubMed  CAS  Google Scholar 

  22. M.C. Arkan, A.L. Hevener, F.R. Greten, S. Maeda, Z.W. Li, J.M. Long, A. Wynshaw-Boris, G. Poli, J. Olefsky, M. Karin, Nat. Med. 11, 191–198 (2005)

    Article  PubMed  CAS  Google Scholar 

  23. P.P. Hommelberg, J. Plat, R.C. Langen, A.M. Schols, R.P. Mensink, Am. J. Physiol. Endocrinol. Metab. 296, E114–E120 (2009)

    Article  PubMed  CAS  Google Scholar 

  24. A.A. Beg, W.C. Sha, R.T. Bronson, D. Baltimore, Genes Dev. 9, 2736–2746 (1995)

    Article  PubMed  CAS  Google Scholar 

  25. M. Pasparakis, T. Luedde, M. Schmidt-Supprian, Cell Death Differ. 13, 861–872 (2006)

    Article  PubMed  CAS  Google Scholar 

  26. D. Cai, M. Yuan, D.F. Frantz, P.A. Melendez, L. Hansen, J. Lee, S.E. Shoelson, Nat. Med. 11, 183–190 (2005)

    Article  PubMed  CAS  Google Scholar 

  27. J.K. Kim, Y.J. Kim, J.J. Fillmore, Y. Chen, I. Moore, J. Lee, M. Yuan, Z.W. Li, M. Karin, P. Perret, S.E. Shoelson, G.I. Shulman, J. Clin. Invest. 108, 437–446 (2001)

    PubMed  CAS  Google Scholar 

  28. H.L. Pahl, Oncogene 18, 6853–6866 (1999)

    Article  PubMed  CAS  Google Scholar 

  29. P. Plomgaard, K. Bouzakri, R. Krogh-Madsen, B. Mittendorfer, J.R. Zierath, B.K. Pedersen, Diabetes 54, 2939–2945 (2005)

    Article  PubMed  CAS  Google Scholar 

  30. B. Feve, J.P. Bastard, Nat. Rev. Endocrinol. 5, 305–311 (2009)

    Article  PubMed  CAS  Google Scholar 

  31. J. Spranger, A. Kroke, M. Mohlig, K. Hoffmann, M.M. Bergmann, M. Ristow, H. Boeing, A.F. Pfeiffer, Diabetes 52, 812–817 (2003)

    Article  PubMed  CAS  Google Scholar 

  32. L. Osborn, S. Kunkel, G.J. Nabel, Proc. Natl Acad. Sci. USA 86, 2336–2340 (1989)

    Article  PubMed  CAS  Google Scholar 

  33. T. Bouwmeester, A. Bauch, H. Ruffner, P.O. Angrand, G. Bergamini, K. Croughton, C. Cruciat, D. Eberhard, J. Gagneur, S. Ghidelli, C. Hopf, B. Huhse, R. Mangano, A.M. Michon, M. Schirle, J. Schlegl, M. Schwab, M.A. Stein, A. Bauer, G. Casari, G. Drewes, A.C. Gavin, D.B. Jackson, G. Joberty, G. Neubauer, J. Rick, B. Kuster, G. Superti-Furga, Nat. Cell Biol. 6, 97–105 (2004)

    Article  PubMed  CAS  Google Scholar 

  34. D. Melisi, J. Niu, Z. Chang, Q. Xia, B. Peng, S. Ishiyama, D.B. Evans, P.J. Chiao, Mol. Cancer Res. 7, 624–633 (2009)

    Article  PubMed  CAS  Google Scholar 

  35. L. Pickersgill, G.J. Litherland, A.S. Greenberg, M. Walker, S.J. Yeaman, J. Biol. Chem. 282, 12583–12589 (2007)

    Article  PubMed  CAS  Google Scholar 

  36. N.C. Andrews, D.V. Faller, Nucleic Acids Res. 19, 2499 (1991)

    Article  PubMed  CAS  Google Scholar 

  37. X. Wu, H. Motoshima, K. Mahadev, T.J. Stalker, R. Scalia, B.J. Goldstein, Diabetes 52, 1355–1363 (2003)

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

The study was supported by the Natural science foundation of Guangdong Province, China (Grant No. 7001282).

Author information

Authors and Affiliations

  1. Department of Endocrinology, The Second Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China

    Jingwen Zhang, Ying Guo & Helin Ding

  2. Department of Endocrinology, Guangdong General Hospital, Guangzhou, 510080, China

    Wen Wu

  3. Research Centre, Guangdong General Hospital, Guangzhou, 510080, China

    Dongfeng Li

Authors
  1. Jingwen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wen Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dongfeng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Helin Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helin Ding.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, J., Wu, W., Li, D. et al. Overactivation of NF-κB impairs insulin sensitivity and mediates palmitate-induced insulin resistance in C2C12 skeletal muscle cells. Endocr 37, 157–166 (2010). https://doi.org/10.1007/s12020-009-9283-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-009-9283-y

Keywords

Search

Navigation