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Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.
Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance.
Proc. Natl. Acad. Sci. U.S.A. 111, 2686-2691 (2014)
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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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Immunity ; Metabolism ; Type 2 Diabetes
Sprache
englisch
Veröffentlichungsjahr
2014
HGF-Berichtsjahr
0
ISSN (print) / ISBN
0027-8424
e-ISSN
1091-6490
Quellenangaben
Band: 111,
Heft: 7,
Seiten: 2686-2691
Verlag
National Academy of Sciences
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Pancreatic Islet Research (IPI)
German Center for Diabetes Reseach (DZD)
German Center for Diabetes Reseach (DZD)
PubMed ID
24492375
Erfassungsdatum
2014-12-31