Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2014-02, Vol.111 (7), p.2686-2691

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.