Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 7; pp. 2686 - 2691
• Main Authors: Chatzigeorgiou, Antonios, Seijkens, Tom, Zarzycka, Barbara, Engel, David, Poggi, Marjorie, van den Berg, Susan, van den Berg, Sjoerd, Soehnlein, Oliver, Winkels, Holger, Beckers, Linda, Lievens, Dirk, Driessen, Ann, Kusters, Pascal, Biessen, Erik, Garcia-Martin, Ruben, Amelna, Anne Klotzsche-von, Gijbels, Marion, Noelle, Randolph, Boon, Louis, Hackeng, Tilman, Schulte, Klaus, Xu, Aimin, Vriend, Gert, Nabuurs, Sander, Chung, Kyoung-Jin, van Dijk, Ko Willems, Rensen, Patrick C. N., Gerdes, Norbert, de Winther, Menno, Block, Norman L., Schally, Andrew V., Webere, Christian, Bornstein, Stefan R., Nicolaes, Gerry, Chavakis, Triantafyllos, Lutgens, Esther
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18-02-2014; National Acad Sciences
• Subjects: Adipose Tissue - cytology; Adipose Tissue - immunology; Adipose Tissue - pathology; Analysis of Variance; Animals; Azo Compounds; Biological Sciences; Calorimetry; CD40 Antigens - antagonists & inhibitors; CD40 Antigens - genetics; CD40 Antigens - metabolism; CD8-Positive T-Lymphocytes - immunology; Cells; Fatty Liver - etiology; Fatty Liver - pathology; Flow Cytometry; Genotype & phenotype; Grants; Immune system; Inflammation; Insulin resistance; Insulin Resistance - immunology; Ligands; Liver; Macrophages; Magnetic Resonance Spectroscopy; Male; Medical research; Medical treatment; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecules; Obesity; Obesity - complications; Obesity - immunology; Real-Time Polymerase Chain Reaction; Rodents; Signal Transduction - drug effects; Signal Transduction - immunology; Surface Plasmon Resonance; T lymphocytes; TNF Receptor-Associated Factor 6 - antagonists & inhibitors; TNF Receptor-Associated Factor 6 - metabolism; metabolism; type 2 diabetes; immunity
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1400419111

The immune system plays an instrumental role in obesity and insulin resistance. Here, we unravel the role of the costimulatory molecule CD40 and its signaling intermediates, TNF receptor-associated factors (TRAFs), in diet-induced obesity (DIO). Although not exhibiting increased weight gain, male CD40 −/− mice in DIO displayed worsened insulin resistance, compared with wild-type mice. This worsening was associated with excessive inflammation of adipose tissue (AT), characterized by increased accumulation of CD8 + T cells and M1 macrophages, and enhanced hepatosteatosis. Mice with deficient CD40-TRAF2/3/5 signaling in MHCII + cells exhibited a similar phenotype in DIO as CD40 −/− mice. In contrast, mice with deficient CD40-TRAF6 signaling in MHCII + cells displayed no insulin resistance and showed a reduction in both AT inflammation and hepatosteatosis in DIO. To prove the therapeutic potential of inhibition of CD40-TRAF6 in obesity, DIO mice were treated with a small-molecule inhibitor that we designed to specifically block CD40-TRAF6 interactions; this compound improved insulin sensitivity, reduced AT inflammation, and decreased hepatosteatosis. Our study reveals that the CD40-TRAF2/3/5 signaling pathway in MHCII + cells protects against AT inflammation and metabolic complications associated with obesity whereas CD40-TRAF6 interactions in MHCII + cells aggravate these complications. Inhibition of CD40-TRAF6 signaling by our compound may provide a therapeutic option in obesity-associated insulin resistance.