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

S. M. Van Den Berg, T. T.P. Seijkens, P. J.H. Kusters, B. Zarzycka, L. Beckers, M. Den Toom, M. J.J. Gijbels, A. Chatzigeorgiou, C. Weber, M. P.J. De Winther, T. Chavakis, G. A.F. Nicolaes, E. Lutgens*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)782-790
Number of pages9
JournalInternational Journal of Obesity
Volume39
Issue number5
DOIs
Publication statusPublished - 8 May 2015
Externally publishedYes

Funding

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).

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