Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance
Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance
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DOI：
10.1073/pnas.1400419111
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发表时间：
2014-02-18
影响因子：
11.1
通讯作者：
Lutgens, Esther
中科院分区：
文献类型：
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作者：
Chatzigeorgioua, Antonios;Seijkens, Tom;Lutgens, Esther
免疫系统在肥胖和胰岛素抵抗中起着重要作用。在这里，我们揭示了共刺激分子CD40及其信号中间产物，肿瘤坏死因子受体相关因子(TRAF)在饮食诱导肥胖(DIO)中的作用。虽然没有表现出体重增加，但与野生型小鼠相比，DIO中的雄性CD40(-/-)小鼠表现出更严重的胰岛素抵抗。这种恶化与脂肪组织(AT)的过度炎症有关，其特征是CD8(+)T细胞和M1巨噬细胞的聚集增加，并加剧了肝骨病。MHCII+细胞CD40-TRAF2/3/5信号缺陷小鼠的DIO表型与CD40(-/-)小鼠相似。相反，在MHCII+细胞中CD40-TRAF6信号缺陷的小鼠没有表现出胰岛素抵抗，并在DIO中显示出AT炎症和肝骨病的减少。为了证明抑制CD40-TRAF6在肥胖中的治疗潜力，DIO小鼠接受了我们设计的专门阻断CD40-TRAF6相互作用的小分子抑制剂的治疗；这种化合物提高了胰岛素敏感性，减少了AT炎症，并减少了肝脏骨质疏松症。我们的研究表明，MHCII+细胞中的CD40-TRAF2/3/5信号通路对肥胖相关的AT炎症和代谢并发症具有保护作用，而MHCII+细胞中的CD40-TRAF6相互作用则加剧了这些并发症。我们的化合物抑制CD40-TRAF6信号可能为肥胖相关的胰岛素抵抗提供了一种治疗选择。
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.