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

Antonios Chatzigeorgiou, Tom Seijkens, Barbara Zarzycka, David Engel, Marjorie Poggi, Susan Van Den Berg, Sjoerd Van Den Berg, Oliver Soehnlein, Holger Winkels, Linda Beckers, Dirk Lievens, Ann Driessen, Pascal Kusters, Erik Biessen, Ruben Garcia-Martin, Anne Klotzsche Von Ameln, Marion Gijbels, Randolph Noelle, Louis Boon, Tilman HackengKlaus Schulte, Aimin Xu, Gert Vriend, Sander Nabuurs, Kyoung Jin Chung, Ko Willems Van Dijk, Patrick C.N. Rensen, Norbert Gerdes, Menno De Winther, Norman L. Block, Andrew V. Schally, Christian Weber, Stefan R. Bornstein, Gerry Nicolaes, Triantafyllos Chavakis, Esther Lutgens

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2686-2691
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number7
DOIs
StatePublished - Feb 18 2014

Keywords

  • Immunity
  • Metabolism
  • Type 2 diabetes

ASJC Scopus subject areas

  • General

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    Chatzigeorgiou, A., Seijkens, T., Zarzycka, B., Engel, D., Poggi, M., Van Den Berg, S., Van Den Berg, S., Soehnlein, O., Winkels, H., Beckers, L., Lievens, D., Driessen, A., Kusters, P., Biessen, E., Garcia-Martin, R., Ameln, A. K. V., Gijbels, M., Noelle, R., Boon, L., ... Lutgens, E. (2014). Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance. Proceedings of the National Academy of Sciences of the United States of America, 111(7), 2686-2691. https://doi.org/10.1073/pnas.1400419111