Abstract 611: Blocking CD40-TRAF6 Signaling is a Novel Therapeutic Target in Obesity-Associated Insulin Resistance
The immune system plays an instrumental role in obesity and insulin resistance. Here we unravel the role of the co-stimulatory 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, as compared to wild type mice. This 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 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 newly developed compound may provide a novel therapeutic option in obesity-associated insulin resistance.
Author Disclosures: T. Seijkens: None. A. Chatzigeorgiou: None. B. Zarzycka: None. D. Engel: None. M. Poggi: None. S.M. van den Berg: None. S.A.A. van den Berg: None. O. Soehnlein: None. H. Winkels: None. L. Beckers: None. D. Lievens: None. A. Driessen: None. P. Kusters: None. E. Biessen: None. R. Garcia Martin: None. A. Klotzsche-von Ameln: None. M.J. Gijbels: None. R.J. Noelle: None. L. Boon: None. T.M. Hackeng: None. K. Martin Schulte: None. A. Xu: None. G. Vriend: None. S.B. Nabuurs: None. K. Chung: None. K. Willems van Dijk: None. P.C.N. Rensen: None. N. Gerdes: None. M.P.J. de Winther: None. N.L. Block: None. A.W. Schally: None. C. Weber: None. S.R. Bornstein: None. G.A.F. Nicolaes: None. T. Chavakis: None. E. Lutgens: None.
- © 2014 by American Heart Association, Inc.