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.

  • Paper
  • Published:

Inhibitor κB kinase is involved in the paracrine crosstalk between human fat and muscle cells

International Journal of Obesity volume 28, pages 985–992 (2004)Cite this article

Abstract

OBJECTIVE: Adipose tissue is now considered as an endocrine and secretory organ, and some adipocyte factors are thought to play a major role in the induction of insulin resistance in skeletal muscle. Here we tested the hypothesis that the crosstalk between fat and muscle involves activation of inhibitor κB Kinase (IKK) in the myocytes.

MEASUREMENTS: Adipocyte-conditioned culture medium was added to the muscle cells overnight, or human fat and muscle cells were kept in co-culture. Insulin signalling was subsequently analysed in the myocytes. Involvement of IKK was assessed using I229, a highly specific inhibitor of the IKK complex.

RESULTS: Adipocyte-conditioned medium strongly inhibited insulin-induced serine phosphorylation of Akt in myocytes with a rapid parallel activation of the nuclear factor κB pathway in these cells. Conditioned medium lacking the perturbation of insulin signalling did not activate NF-κB. Insulin signalling to Akt was completely abrogated under co-culture conditions. The IKK inhibitor I229 did not affect protein expression of Akt, but fully restored insulin action in myocytes subjected to co-culture.

CONCLUSION: These data show that the release of fat cell factors may rapidly induce insulin resistance in human skeletal muscle cells. This process appears to be mediated by an IKK/NF-κB dependent pathway. We suggest that inhibitors of IKK would be of use to counteract the negative crosstalk between fat and muscle.

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
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Groop LC . Insulin resistance: the fundamental trigger of type 2 diabetes. Diabetes Obes Metab 1999; 1 (Suppl 1): 1–7.

    Article  Google Scholar 

  2. Ryder JW, Gilbert M, Zierath JR . Skeletal muscle and insulin sensitivity: pathophysiological alterations. Front Biosci 2001; 6: D154–D163.

    Article  CAS  Google Scholar 

  3. Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G . Insulin resistance and hypersecretion in obesity. J Clin Invest 1997; 100: 1166–1173.

    Article  CAS  Google Scholar 

  4. Goodpaster BH, Thaete FL, Kelley DE . Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus. Am J Clin Nutr 2000; 71: 885–892.

    Article  CAS  Google Scholar 

  5. Mohamed-Ali V, Pinkney JH, Coppack SW . Adipose tissue as an endocrine and paracrine organ. Int J Obes Relat Metab Disord 1998; 22: 1145–1158.

    Article  CAS  Google Scholar 

  6. Dietze D, Koenen M, Roehrig K, Horikoshi H, Hauner H, Eckel J . Impairment of insulin signaling in human skeletal muscle cells by co-culture with human adipocytes. Diabetes 2002; 51: 2369–2376.

    Article  CAS  Google Scholar 

  7. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM . IRS-1 mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 1996; 271: 665–668.

    Article  CAS  Google Scholar 

  8. Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, Goodyear LJ, Kraegen EW, White MF, Shulman GI . Free fatty acid induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 1999; 48: 1270–1274.

    Article  CAS  Google Scholar 

  9. Kolter T, Uphues I, Eckel J . Molecular analysis of insulin resistance in isolated ventricular cardiomyocytes of obese zucker rats. Am J Physiol 1997; 273: E59–E67.

    CAS  PubMed  Google Scholar 

  10. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE . Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001; 293: 1673–1677.

    Article  CAS  Google Scholar 

  11. Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI . Prevention of fat induced insulin resistance by salicylate. J Clin Invest 2001; 108: 437–446.

    Article  CAS  Google Scholar 

  12. Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J . Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 2002; 277: 48115–48121.

    Article  CAS  Google Scholar 

  13. Karin M . The beginning of the end: IκB Kinase (IKK) and NF-κB activation. J Biol Chem 1999; 274: 27339–27342.

    Article  CAS  Google Scholar 

  14. Ghosh S, Karin M . Missing pieces in the NF-kappaB puzzle. Cell 2002; 109: S81–S96.

    Article  CAS  Google Scholar 

  15. Das UN . Is metabolic syndrome X an inflammatory condition? Exp Biol Med 2002; 227: 989–997.

    Article  CAS  Google Scholar 

  16. Hauner H, Petruschke T, Russ M, Rohrig K, Eckel J . Effects of tumour necrosis factor alpha (TNF alpha) on glucose transport and lipid metabolism of newly-differentiated human fat cells in cell culture. Diabetologia 1995; 38: 764–771.

    Article  CAS  Google Scholar 

  17. Wichelhaus A, Russ M, Petersen S, Eckel J . G protein expression and adenylate cyclase regulation in ventricular cardiomyocytes from STZ-diabetic rats. Am J Physiol 1994; 267: H548–H555.

    CAS  PubMed  Google Scholar 

  18. Hajduch E, Litherland GJ, Hundal HS . Protein kinase B (PKB/Akt)—a key regulator of glucose transport? FEBS Lett 2001; 492: 199–203.

    Article  CAS  Google Scholar 

  19. Päth G, Bornstein SR, Gurniak M, Chrousos GP, Scherbaum WA, Hauner H . Human breast adipocytes express interleukin-6 (IL-6) and its receptor system: increased IL-6 production by beta-adrenergic activation and effects of IL-6 on adipocyte function. J Clin Endocrinol Metab 2001; 86: 2281–2288.

    PubMed  Google Scholar 

  20. Haffner SM . Insulin resistance, inflammation, and the prediabetic state. Am J Cardiol 2003; 92: 18J–26J.

    Article  CAS  Google Scholar 

  21. Lyon CJ, Law RE, Hsueh WA . Minireview: adiposity, inflammation, and atherogenesis. Endocrinology 2003; 144: 2195–2200.

    Article  CAS  Google Scholar 

  22. Festa A, D'Agostino Jr R, Tracy RP, Haffner SM . Insulin resistance atherosclerosis study. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes 2002; 51: 1131–1137.

    Article  CAS  Google Scholar 

  23. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM . C-reactive protein, interleukin-6, and risk of developing type 2 diabetes mellitus. JAMA 2001; 286: 327–334.

    Article  CAS  Google Scholar 

  24. Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW . C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999; 19: 972–978.

    Article  CAS  Google Scholar 

  25. Coppack SW . Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 2001; 60: 349–356.

    Article  CAS  Google Scholar 

  26. Kielstein JT, Becker B, Graf S, Brabant G, Haller H, Fliser D . Increased resistin blood levels are not associated with insulin resistance in patients with renal disease. Am J Kidney Dis 2003; 42: 62–66.

    Article  CAS  Google Scholar 

  27. Maebuchi M, Machidori M, Urade R, Ogawa T, Moriyama T . Low resistin levels in adipose tissues and serum in high-fat fed mice and genetically obese mice: development of an ELISA system for quantification of resistin. Arch Biochem Biophys 2003; 416: 164–170.

    Article  CAS  Google Scholar 

  28. Karin M, Ben-Neriah Y . Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 2000; 18: 621–663.

    Article  CAS  Google Scholar 

  29. Itani SI, Ruderman NB, Schmieder F, Boden G . Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002; 51: 2005–2011.

    Article  CAS  Google Scholar 

  30. Hotamisligil GS . The role of TNFalpha and TNF receptors in obesity and insulin resistance. J Intern Med 1999; 245: 621–625.

    Article  CAS  Google Scholar 

  31. Shulman GI . Cellular mechanisms of insulin resistance. J Clin Invest 2000; 106: 171–176.

    Article  CAS  Google Scholar 

  32. Feinstein R, Kanety H, Papa MZ, Lunenfeld B, Karasik A . Tumor necrosis factor-alpha suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J Biol Chem 1993; 268: 26055–26058.

    CAS  PubMed  Google Scholar 

  33. Gao Z, Zuberi A, Quon MJ, Dong Z, Ye J . Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. J Biol Chem 2003; 278: 24944–24950.

    Article  CAS  Google Scholar 

  34. Ruan H, Pownall HJ, Lodish HF . Troglitazone antagonizes tumor necrosis factor-alpha-induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF-kappaB. J Biol Chem 2003; 278: 28181–28192.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Ministerium für Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the Bundesministerium für Gesundheit, EU COST Action B 17, the Deutsche Forschungsgemeinschaft (FOR-441, TP7), the Deutsche Diabetes-Stiftung and in part by a grant from Aventis Pharma, Frankfurt, Germany. We wish to thank Professor R Olbrisch and his team, Department of Plastic Surgery, Florence-Nightingale-Hospital Düsseldorf, for support in obtaining adipose tissue samples. The secretarial assistance of Birgit Hurow is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry and Pathobiochemistry, German Diabetes Research Institute, Düsseldorf, Germany

    D Dietze, S Ramrath & J Eckel

  2. Aventis, Frankfurt, Germany

    O Ritzeler & N Tennagels

  3. Else-Kröner-Fresenius-Centre for Nutritional Medicine, Technical University of Munich, Germany

    H Hauner

Authors
  1. D Dietze
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Ramrath
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. O Ritzeler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N Tennagels
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Hauner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Eckel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Eckel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dietze, D., Ramrath, S., Ritzeler, O. et al. Inhibitor κB kinase is involved in the paracrine crosstalk between human fat and muscle cells. Int J Obes 28, 985–992 (2004). https://doi.org/10.1038/sj.ijo.0802701

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0802701

Keywords

This article is cited by

Search

Advanced search

Quick links