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Título: | Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance |
Autor: | 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; García-Martín, Rubén; Klotzsche-von Ameln, Anne; Gijbels, Marion; Noelle, Randolph; Boon, Louis; Hackeng, Tilman; Schulte, Klaus-Martin; Xu, Aimin; Vriend, Gert; Nabuurs, Sander; Chung, Kyoung-Jin; Willems van Dijk, Ko; Rensen, Patrick C N; Gerdes, Norbert; de Winther, Menno; Block, Norman L; Schally, Andrew V; Weber, Christian; Bornstein, Stefan R.; Nicolaes, Gerry; Chavakis, Triantafyllos; Lutgens, Esther | Palabras clave: | Immunity Metabolism Type 2 diabetes |
Fecha de publicación: | 18-feb-2014 | Editor: | National Academy of Sciences (U.S.) | Citación: | Proceedings of the National Academy of Sciences 111(7): 2686-2691 (2014) | Resumen: | 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. | Versión del editor: | https://doi.org/10.1073/pnas.1400419111 | URI: | http://hdl.handle.net/10261/346556 | DOI: | 10.1073/pnas.1400419111 | ISSN: | 0027-8424 | E-ISSN: | 1091-6490 |
Aparece en las colecciones: | (CNB) Artículos |
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CD40_Chatzigeorgiou_Art_2014.pdf | 1,31 MB | Adobe PDF | Visualizar/Abrir |
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