van den Berg S M, Seijkens T T P, Kusters P J H, Zarzycka B, Beckers L, den Toom M, Gijbels M J J, Chatzigeorgiou A, Weber C, de Winther M P J, Chavakis T, Nicolaes G A F, Lutgens E
Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
Department of Biochemistry, University of Maastricht, Maastricht, The Netherlands.
Int J Obes (Lond). 2015 May;39(5):782-90. doi: 10.1038/ijo.2014.198. Epub 2014 Nov 13.
Immune processes contribute to the development of obesity and its complications, such as insulin resistance, type 2 diabetes mellitus and cardiovascular disease. Approaches that target the inflammatory response are promising therapeutic strategies for obesity. In this context, we recently demonstrated that the interaction between the costimulatory protein CD40 and its downstream adaptor protein tumor necrosis factor receptor-associated factor 6 (TRAF6) promotes adipose tissue inflammation, insulin resistance and hepatic steatosis in mice in the course of diet-induced obesity (DIO).
Here we evaluated the effects of a small-molecule inhibitor (SMI) of the CD40-TRAF6 interaction, SMI 6860766, on the development of obesity and its complications in mice that were subjected to DIO.
Treatment with SMI 6860766 did not result in differences in weight gain, but improved glucose tolerance. Moreover, SMI 6860766 treatment reduced the amount of CD45(+) leucocytes in the epididymal adipose tissue by 69%. Especially, the number of adipose tissue CD4(+) and CD8(+) T cells, as well as macrophages, was significantly decreased.
Our results indicate that small-molecule-mediated inhibition of the CD40-TRAF6 interaction is a promising therapeutic strategy for the treatment of metabolic complications of obesity by improving glucose tolerance, by reducing the accumulation of immune cells to the adipose tissue and by skewing of the immune response towards a more anti-inflammatory profile.
免疫过程参与肥胖及其并发症的发生发展，如胰岛素抵抗、2型糖尿病和心血管疾病。针对炎症反应的方法是治疗肥胖的有前景的策略。在此背景下，我们最近证明，共刺激蛋白CD40与其下游衔接蛋白肿瘤坏死因子受体相关因子6（TRAF6）之间的相互作用在饮食诱导的肥胖（DIO）过程中促进小鼠脂肪组织炎症、胰岛素抵抗和肝脂肪变性。
在此，我们评估了CD40-TRAF6相互作用的小分子抑制剂（SMI）SMI 6860766对DIO小鼠肥胖及其并发症发生发展的影响。
用SMI 6860766治疗未导致体重增加出现差异，但改善了葡萄糖耐量。此外，用SMI 6860766治疗使附睾脂肪组织中CD45(+)白细胞数量减少了69%。特别是，脂肪组织中CD4(+)和CD8(+) T细胞以及巨噬细胞的数量显著减少。
我们的结果表明，小分子介导的CD40-TRAF6相互作用抑制是一种有前景的治疗策略，可通过改善葡萄糖耐量、减少免疫细胞在脂肪组织中的积累以及使免疫反应偏向更具抗炎性的状态来治疗肥胖的代谢并发症。
