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Animal Models

Blocking CD40-TRAF6 interactions by small-molecule inhibitor 6860766 ameliorates the complications of diet-induced obesity in mice

International Journal of Obesity volume 39, pages 782–790 (2015)Cite this article

Subjects

Abstract

Background:

Immune processes contribute to the development of obesity and its complications, such as insulin resistance, type 2 diabetes mellitus and cardiovascular disease. Approaches that target the inflammatory response are promising therapeutic strategies for obesity. In this context, we recently demonstrated that the interaction between the costimulatory protein CD40 and its downstream adaptor protein tumor necrosis factor receptor-associated factor 6 (TRAF6) promotes adipose tissue inflammation, insulin resistance and hepatic steatosis in mice in the course of diet-induced obesity (DIO).

Methods:

Here we evaluated the effects of a small-molecule inhibitor (SMI) of the CD40-TRAF6 interaction, SMI 6860766, on the development of obesity and its complications in mice that were subjected to DIO.

Results:

Treatment with SMI 6860766 did not result in differences in weight gain, but improved glucose tolerance. Moreover, SMI 6860766 treatment reduced the amount of CD45+ leucocytes in the epididymal adipose tissue by 69%. Especially, the number of adipose tissue CD4+ and CD8+ T cells, as well as macrophages, was significantly decreased.

Conclusions:

Our results indicate that small-molecule-mediated inhibition of the CD40-TRAF6 interaction is a promising therapeutic strategy for the treatment of metabolic complications of obesity by improving glucose tolerance, by reducing the accumulation of immune cells to the adipose tissue and by skewing of the immune response towards a more anti-inflammatory profile.

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References

  1. Kanneganti T-D, Dixit VD . Immunological complications of obesity. Nat Immunol 2012; 13: 707–712.

    Article  CAS  Google Scholar 

  2. Wang YC, Colditz GA, Kuntz KM . Forecasting the obesity epidemic in the aging U.S. population. Obesity 2007; 15: 2855–2865.

    Article  Google Scholar 

  3. Ferrante AW . The immune cells in adipose tissue. Diabetes Obes Metab 2013; 15: 34–38.

    Article  CAS  Google Scholar 

  4. Winer S, Winer DA . The adaptive immune system as a fundamental regulator of adipose tissue inflammation and insulin resistance. Immunol Cell Biol 2012; 90: 755–762.

    Article  CAS  Google Scholar 

  5. Anderson EK, Gutierrez DA, Hasty AH . Adipose tissue recruitment of leukocytes. Curr Opin Lipidol 2010; 21: 172–177.

    Article  CAS  Google Scholar 

  6. Chatzigeorgiou A, Phieler J, Gebler J, Bornstein SR, Chavakis T . CD40L stimulates the crosstalk between adipocytes and inflammatory cells. Horm Metab Res 2013; 45: 741–747.

    Article  CAS  Google Scholar 

  7. Ouchi N, Parker JL, Lugus JJ, Walsh K . Adipokines in inflammation and metabolic disease. Nat Rev Immunol 2011; 11: 85–97.

    Article  CAS  Google Scholar 

  8. Surmi B, Hasty A . Macrophage infiltration into adipose tissue: initiation, propagation and remodeling. Fut Lipidol 2008; 3: 545–556.

    Article  CAS  Google Scholar 

  9. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112: 1821–1830.

    Article  CAS  Google Scholar 

  10. Seijkens T, Kusters P, Engel D, Lutgens E . CD40–CD40L: linking pancreatic, adipose tissue and vascular inflammation in type 2 diabetes and its complications. Diabetes Vasc Dis Res 2013; 10: 115–122.

    Article  Google Scholar 

  11. Engel D, Seijkens T, Poggi M, Sanati M, Thevissen L, Beckers L et al. The immunobiology of CD154–CD40–TRAF interactions in atherosclerosis. Semin Immunol 2009; 21: 308–312.

    Article  CAS  Google Scholar 

  12. Donners M, Beckers L, Lievens D, Munnix I, Heemskerk J, Janssen B et al. The CD40–TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling. Blood 2008; 111: 4596–4604.

    Article  CAS  Google Scholar 

  13. Lutgens E, Lievens D, Beckers L, Wijnands E, Soehnlein O, Zernecke A et al. Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile. J Exp Med 2010; 207: 391–404.

    Article  CAS  Google Scholar 

  14. Baena-Fustegueras JA, Pardina E, Balada E, Ferrer R, Catalán R, Rivero J et al. Soluble cd40 ligand in morbidly obese patients: effect of body mass index on recovery to normal levels after gastric bypass surgery. JAMA Surg 2013; 148: 151–156.

    Article  CAS  Google Scholar 

  15. Poggi M, Engel D, Christ A, Beckers L, Wijnands E, Boon L et al. CD40L deficiency ameliorates adipose tissue inflammation and metabolic manifestations of obesity in mice. Arterioscler Thromb Vasc Biol 2011; 31: 2251–2260.

    Article  CAS  Google Scholar 

  16. Poggi M, Jager J, Paulmyer-Lacroix O, Peiretti F, Gremeaux T, Verdier M et al. The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes. Diabetologia 2009; 52: 1152–1163.

    Article  CAS  Google Scholar 

  17. Seijkens T, Kusters P, Chatzigeorgiou A, Chavakis T, Lutgens E . Immune cell crosstalk in obesity: a key role for co-stimulation? Diabetes 2014; 63: 3982–3991.

    Article  CAS  Google Scholar 

  18. Guo C-A, Kogan S, Amano SU, Wang M, Dagdeviren S, Friedline RH et al. CD40 deficiency in mice exacerbates obesity-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance. Am J Physiol Endocrinol Metab 2013; 304: 951–963.

    Article  Google Scholar 

  19. Chatzigeorgiou A, Seijkens T, Zarzycka B, Engel D, Poggi M, van den Berg S et al. Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance. Proc Natl Acad Sci USA 2014; 111: 2686–2691.

    Article  CAS  Google Scholar 

  20. Wolf D, Jehle F, Michel NA, Bukosza EN, Rivera J, Chen YC et al. Coinhibitory suppression of T cell activation by CD40 protects against obesity and adipose tissue inflammation in mice. Circulation 2014; 129: 2414–2425.

    Article  CAS  Google Scholar 

  21. Kawabe T . The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1994; 1: 167–178.

    Article  CAS  Google Scholar 

  22. Ahonen C . The CD40-TRAF6 axis controls affinity maturation and the generation of long-lived plasma cells. Nat Immunol 2002; 3: 451–456.

    Article  CAS  Google Scholar 

  23. Lafontan M . Adipose tissue and adipocyte dysregulation. Diabetes Metab 2014; 40: 16–28.

    Article  CAS  Google Scholar 

  24. Osborn O, Olefsky JM . The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 2012; 18: 363–374.

    Article  CAS  Google Scholar 

  25. Chmelar J, Chung KJ, Chavakis T . The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance. Thromb Haemost 2013; 109: 399–406.

    Article  CAS  Google Scholar 

  26. Sell H, Habich C, Eckel J . Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol 2012; 8: 709–716.

    Article  CAS  Google Scholar 

  27. Wolf D, Jehle F, Ortiz Rodriguez A, Dufner B, Hoppe N, Colberg C et al. CD40L deficiency attenuates diet-induced adipose tissue inflammation by impairing immune cell accumulation and production of pathogenic IgG-antibodies. PLoS One 2012; 7: e33026.

    Article  CAS  Google Scholar 

  28. Yi Z, Stunz L, Bishop G . CD40-mediated maintenance of immune homeostasis in the adipose tissue microenvironment. Diabetes 2014; 63: 2751–2760.

    Article  CAS  Google Scholar 

  29. Zhong J, Rao X, Braunstein Z, Taylor A, Narula V, Hazey J et al. T-cell costimulation protects obesity-induced adipose inflammation and insulin resistance. Diabetes 2014; 63: 1289–1302.

    Article  CAS  Google Scholar 

  30. Chatzigeorgiou A, Chung K-J, Garcia-Martin R, Alexaki V-I, Klotzsche-von Ameln A, Phieler J et al. Dual role of B7 costimulation in obesity-related non-alcoholic steatohepatitis (NASH) and metabolic dysregulation. Hepatology 2014; 60: 1196–1210.

    Article  CAS  Google Scholar 

  31. Lagorce D, Sperandio O, Galons H, Miteva M, Villoutreix B . FAF-Drugs2: free ADME/tox filtering tool to assist drug discovery and chemical biology projects. BMC Bioinform 2008; 9: 396.

    Article  Google Scholar 

  32. Miteva MA, Violas S, Montes M, Gomez D, Tuffery P, Villoutreix BO . FAF-Drugs: free ADME/tox filtering of compound collections. Nucleic Acids Res 2006; 34: W738–W744.

    Article  CAS  Google Scholar 

  33. Nishimura S, Manabe I, Nagai R . Adipose tissue inflammation in obesity and metabolic syndrome. Discov Med 2009; 8: 55–60.

    PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the support from the Netherlands CardioVascular Research Initiative: ‘the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences’ for the GENIUS project ‘Generating the best evidence-based pharmaceutical targets for atherosclerosis’ (CVON2011-19). This work was supported by the Netherlands Organization for Scientific Research (NWO)(VICI grant to EL, and CW, medium investment grant to GN), the Netherlands Heart Foundation (Established investigator grant to EL, MW, Dr E Dekker grant to TS), the Rembrandt foundation (SB, MW, EL), the Deutsche Forschungsgemeinschaft (DFG FOR809: LU1643/1-2, SO876/3-1, WE1913/11-2, SFB914-B08 and SFB 1054 and SFB-1123 to EL, CW, CH279/5-1 to TC), European Research Council Grants (No. 281296 to TC and ERC AdG No. 249929 to CW), a grant from the Else-Kroner-Fresenius-Stiftung (to TC) and by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD eV) (to TC) and DZHK (German Centre for Cardiovascular Research, MHA VD1.2 to CW), the Cardiovascular Research Institute Maastricht (to GN), the EU (Grant No. KBBE-2011-5 289350 to GN), the Transnational University Limburg (to GN) and Cyttron II (FES0908 to GN).

Author information

Author notes

  1. S M van den Berg and T T P Seijkens: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands,

    S M van den Berg, T T P Seijkens, P J H Kusters, L Beckers, M den Toom, M J J Gijbels, M P J de Winther & E Lutgens

  2. Department of Biochemistry, University of Maastricht, Maastricht, The Netherlands

    B Zarzycka, C Weber & G A F Nicolaes

  3. Department of Pathology, Maastricht University, Maastricht, The Netherlands

    M J J Gijbels

  4. Department of Molecular Genetics, Maastricht University, Maastricht, The Netherlands

    M J J Gijbels

  5. Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany

    A Chatzigeorgiou & T Chavakis

  6. Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian’s University, Munich, Germany

    C Weber & E Lutgens

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  1. S M van den Berg
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Corresponding author

Correspondence to E Lutgens.

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van den Berg, S., Seijkens, T., Kusters, P. et al. Blocking CD40-TRAF6 interactions by small-molecule inhibitor 6860766 ameliorates the complications of diet-induced obesity in mice. Int J Obes 39, 782–790 (2015). https://doi.org/10.1038/ijo.2014.198

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