Toll-like receptors 2 and 4 impair insulin-mediated brain activity by interleukin-6 and osteopontin and alter sleep architecture
Toll-like receptors 2 and 4 impair insulin-mediated brain activity by interleukin-6 and osteopontin and alter sleep architecture
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DOI：
10.1096/fj.11-191023
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发表时间：
2012-05-01
期刊：
影响因子：
4.8
通讯作者：
Hennige, Anita M.
中科院分区：
文献类型：
--
作者：
Sartorius, Tina;Lutz, Stefan Z.;Hennige, Anita M.
脑中胰岛素作用受损代表向2型糖尿病进展的早期步骤，并且已知饱和游离脂肪酸水平升高会损害前驱糖尿病受试者的胰岛素作用。Toll样受体（TLR）家族是一种将脂肪酸与炎症和胰岛素抵抗联系起来的潜在介质。因此，给C3 H/HeJ/TLR 2-KO（TLR 2/4缺陷）小鼠喂食高脂饮食（HFD），并通过使用遥测植入物分析脑中的胰岛素作用以及皮质和运动活性。TLR 2/4缺陷小鼠受到保护，免受HFD诱导的葡萄糖耐受不良和脑中的胰岛素抵抗，并显示出在C3 H/HeJ小鼠中未观察到的皮质和运动活性的改善。睡眠记录显示，缺陷小鼠白天的快速眼动睡眠增加了42%，这些小鼠在夜间清醒的时间增加了41%。用中和IL-6抗体治疗对照小鼠，改善了脑中胰岛素的作用以及皮质活性，并将骨桥蛋白降低至TLR 2/4缺陷小鼠的水平。总之，我们的数据表明，缺乏功能性TLR 2/4通过IL-6/骨桥蛋白依赖性机制保护小鼠免受脂肪介导的胰岛素作用，大脑活动，运动和睡眠结构的损害。Sartorius，T.，卢茨，S。Z.，Hoene，M.，Waak，J.，彼得，A.，Weigert，C.，Rammensee，H. G.，Kahle，P. J.，哈林，H.-美国、Hennige，A. M. Toll样受体2和4通过白细胞介素6和骨桥蛋白损害胰岛素介导的脑活动，并改变睡眠结构。FASEB J.26，1799-1809（2012）。www.fasebj.org
Impaired insulin action in the brain represents an early step in the progression toward type 2 diabetes, and elevated levels of saturated free fatty acids are known to impair insulin action in prediabetic subjects. One potential mediator that links fatty acids to inflammation and insulin resistance is the Toll-like receptor (TLR) family. Therefore, C3H/HeJ/TLR2-KO (TLR2/4-deficient) mice were fed a high-fat diet (HFD), and insulin action in the brain as well as cortical and locomotor activity was analyzed by using telemetric implants. TLR2/4-deficient mice were protected from HFD-induced glucose intolerance and insulin resistance in the brain and displayed an improvement in cortical and locomotor activity that was not observed in C3H/HeJ mice. Sleep recordings revealed a 42% increase in rapid eye movement sleep in the deficient mice during daytime, and these mice spent 41% more time awake during the night period. Treatment of control mice with a neutralizing IL-6 antibody improved insulin action in the brain as well as cortical activity and diminished osteopontin protein to levels of the TLR2/4-deficient mice. Together, our data suggest that the lack of functional TLR2/4 protects mice from a fat-mediated impairment in insulin action, brain activity, locomotion, and sleep architecture by an IL-6/osteopontin-dependent mechanism.-Sartorius, T., Lutz, S. Z., Hoene, M., Waak, J., Peter, A., Weigert, C., Rammensee, H.-G., Kahle, P. J., Haring, H.-U., Hennige, A. M. Toll-like receptors 2 and 4 impair insulin-mediated brain activity by interleukin-6 and osteopontin and alter sleep architecture. FASEB J. 26, 1799-1809 (2012). www.fasebj.org