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Chatzigeorgiou, A.* ; Seijkens, T.* ; Zarzycka, B.* ; Engel, D.* ; Poggi, M.* ; van den Berg, S.* ; Soehnlein, O.* ; Winkels, H.* ; Beckers, L.* ; Lievens, D.* ; Driessen, A.* ; Kusters, P.* ; Biessen, E.* ; Garcia-Martin, R.* ; Klotzsche-von Ameln, A.* ; Gijbels, M.J.* ; Noelle, R.* ; Boon, L.* ; Hackeng, T.M.* ; Schulte, K.M.* ; Schulte, K.* ; Xu, A.* ; Vriend, G.* ; Nabuurs, S.B.* ; Chung, K.-J.* ; van Dijk, K.W.* ; Rensen, P.C.* ; Gerdes, N.* ; de Winther, M.P.* ; Block, N.L.* ; Schally, A.V.* ; Weber, C.* ; Bornstein, S.R.* ; Nicolaes, G.A.F.* ; Chavakis, T.* ; Lutgens, E.*

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

Proc. Natl. Acad. Sci. U.S.A. 111, 2686-2691 (2014)

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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.

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