Blocking CD40-TRAF6 interactions by small-molecule inhibitor 6860766 ameliorates the complications of diet-induced obesity in mice.
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.
Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
S M
SM
van den Berg
Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
T T P
TT
Seijkens
Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
P J H
PJ
Kusters
Department of Biochemistry, University of Maastricht, Maastricht, The Netherlands.
B
B
Zarzycka
Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
L
L
Beckers
Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
M
M
den Toom
1] Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands [2] Department of Pathology, Maastricht University, Maastricht, The Netherlands [3] Department of Molecular Genetics, Maastricht University, Maastricht,The Netherlands.
M J J
MJ
Gijbels
Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
A
A
Chatzigeorgiou
1] Department of Biochemistry, University of Maastricht, Maastricht, The Netherlands [2] Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian's University, Munich, Germany.
C
C
Weber
Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
M P J
MP
de Winther
Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
T
T
Chavakis
Department of Biochemistry, University of Maastricht, Maastricht, The Netherlands.
G A F
GA
Nicolaes
1] Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands [2] Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian's University, Munich, Germany.
E
E
Lutgens
D000273:Adipose Tissue / Q000378:metabolism*; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D019013:CD40 Antigens / Q000037:antagonists & inhibitors*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D059305:Diet, High-Fat; D005434:Flow Cytometry; D007249:Inflammation / Q000378:metabolism*; D007333:Insulin Resistance; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications* / Q000209:etiology / Q000378:metabolism; D011427:Propiophenones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors*
D000814:Aniline Compounds; D019013:CD40 Antigens; D011427:Propiophenones; C000605981:SMI 6860766; D048029:TNF Receptor-Associated Factor 6