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

2014; National Academy of Sciences; Volume: 111; Issue: 7 Linguagem: Inglês

10.1073/pnas.1400419111

1091-6490

Antonios Chatzigeorgiou, Tom Seijkens, Barbara Zarzycka, David Engel, Marjorie Poggi, Susan Berg, Sjoerd A.A. van den Berg, Oliver Soehnlein, Holger Winkels, Linda Beckers, Dirk Lievens, Ann Driessen, Pascal Kusters, Erik A.L. Biessen, Rubén García-Martín, Anne Klotzsche–von Ameln, Marion J. Gijbels, Randolph J. Noelle, Louis Boon, Tilman M. Hackeng, Klaus‐Martin Schulte, Aimin Xu, Gert Vriend, Sander B. Nabuurs, Kyoung‐Jin Chung, Ko Willems van Dijk, Patrick C.N. Rensen, Norbert Gerdes, Menno P.J. de Winther, Norman L. Block, Andrew V. Schally, Christian Weber, Stefan R. Bornstein, Gerry A. F. Nicolaes, Triantafyllos Chavakis, Esther Lutgens,

NF-κB Signaling Pathways

Significance Inflammation is a critical contributor to the pathogenesis of metabolic disorders associated with obesity. A group of molecules crucial in regulating the immune system are costimulatory molecules, including CD40. Our current study shows that CD40 acts as a double-edged sword in the metabolic syndrome through the initiation of differential signaling cascades. The CD40-TNF receptor-associated factor (TRAF) 2/3/5 signaling pathway protects against metabolic dysfunction and inflammation associated with obesity; conversely, the CD40-TRAF6 pathway contributes to the detrimental consequences of obesity. In the present study, we therefore designed, validated, and used a small-molecule inhibitor that blocks CD40-TRAF6 interactions. The improvement of insulin resistance by this specific CD40-TRAF6 inhibitor could represent a therapeutic breakthrough in the field of immunometabolism.