TY - JOUR
T1 - Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance
AU - Chatzigeorgiou, Antonios
AU - Seijkens, Tom
AU - Zarzycka, Barbara
AU - Engel, David
AU - Poggi, Marjorie
AU - Van Den Berg, Susan
AU - Van Den Berg, Sjoerd
AU - Soehnlein, Oliver
AU - Winkels, Holger
AU - Beckers, Linda
AU - Lievens, Dirk
AU - Driessen, Ann
AU - Kusters, Pascal
AU - Biessen, Erik
AU - Garcia-Martin, Ruben
AU - Ameln, Anne Klotzsche Von
AU - Gijbels, Marion
AU - Noelle, Randolph
AU - Boon, Louis
AU - Hackeng, Tilman
AU - Schulte, Klaus
AU - Xu, Aimin
AU - Vriend, Gert
AU - Nabuurs, Sander
AU - Chung, Kyoung Jin
AU - Van Dijk, Ko Willems
AU - Rensen, Patrick C.N.
AU - Gerdes, Norbert
AU - De Winther, Menno
AU - Block, Norman L.
AU - Schally, Andrew V.
AU - Weber, Christian
AU - Bornstein, Stefan R.
AU - Nicolaes, Gerry
AU - Chavakis, Triantafyllos
AU - Lutgens, Esther
PY - 2014/2/18
Y1 - 2014/2/18
N2 - 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.
AB - 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.
KW - Immunity
KW - Metabolism
KW - Type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=84894377101&partnerID=8YFLogxK
U2 - 10.1073/pnas.1400419111
DO - 10.1073/pnas.1400419111
M3 - Article
SN - 0027-8424
VL - 111
SP - 2686
EP - 2691
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 7
ER -