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Development of obesity-induced inflammation and insulin resistance: The role of adipose tissue, fatty acids, and Toll-like receptors.

机译：肥胖引起的炎症和胰岛素抵抗的发展：脂肪组织，脂肪酸和Toll样受体的作用。

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摘要

The innate immune receptors, toll-like receptor-2 (Tlr2) and toll-like receptor-4 (Tlr4), are implicated in the development of inflammation and insulin resistance in various cell populations. However, little is known about the relationship of these receptors in diet-induced obesity (DIO). We have shown that Tlr4 deficient C57BL/10ScN mice were protected against DIO, specifically when mice were fed a high saturated fatty acid (SFA) diet. Moreover, these mice exhibited a specific reduction in adipose tissue (AT) inflammation as evidenced by the reduction in nuclear factor kappa B (NFkappaB) activation, proinflammatory gene expression, and macrophage accumulation. There was also a marked increase in Tlr2 expression in mice fed a high fat diet. 3T3-L1 adipocytes treated with the Tlr2 agonist, zymosan A (ZymA), exhibited increased NFkappaB and activator protein-1 (AP-1) activation, proinflammatory gene expression, reactive oxygen species (ROS) accumulation, and insulin resistance, similarly to palmitate or Tlr4 agonist lipopolysaccharide (LPS). These effects were attenuated in adipocytes treated with a specific c-jun N-terminal kinase (JNK) inhibitor (SP600125) indicating involvement of this intracellular kinase in SFA and Tlr agonistmediated signaling. Finally, we demonstrated that Tlr2 -/- mice were also protected from DIO. However, unlike Tlr4 deficient 10ScN mice there were no significant changes in body weight, energy intake, or lipid profile. Inflammatory and oxidative stress markers in serum (C-reactive protein (CRP), endotoxin, and monocyte chemoattractant protein-1(MCP-1)) and AT (Tumor necrosis factor; (TNF), interleukin-6 (IL-6), MCP-1, F4/80, and nitric oxide synthase-2 (NOS2) transcript abundance) were attenuated in Tlr2 -/- and 10ScN mice, which was more apparent in mice fed high SFA diet. Insulin sensitivity was improved in 10ScN, but not Tlr2-/- mice. However, stromal vascular (SV) cells isolated from AT of Tlr2 -/- mice had a marked increase in insulin sensitivity, demonstrating the potential involvement of Tlr2 in obesity-induced insulin resistance in AT. Based on these studies, Tlr2 and Tlr4 may represent ideal targets for pharmaceutical, as well as dietary, interventions designed to attenuate obesity and related co-morbidities, including Type 2 diabetes mellitus (DM) and cardiovascular disease (CVD).
机译：先天性免疫受体，toll​​样受体2（Tlr2）和toll样受体4（Tlr4），与多种细胞群的炎症和胰岛素抵抗有关。然而，人们对饮食诱导的肥胖症（DIO）中这些受体之间的关系知之甚少。我们已经显示，Tlr4缺陷的C57BL / 10ScN小鼠受到DIO保护，特别是当给小鼠喂食高饱和脂肪酸（SFA）饮食时。此外，这些小鼠表现出脂肪组织（AT）炎症的特异性减少，如核因子κB（NFkappaB）激活，促炎基因表达和巨噬细胞积累的减少所证明。高脂饮食喂养的小鼠中Tlr2表达也显着增加。用Tlr2激动剂酵母聚糖A（ZymA）处理的3T3-L1脂肪细胞表现出增加的NFkappaB和活化蛋白1（AP-1）活化，促炎性基因表达，活性氧（ROS）积累和胰岛素抵抗，类似于棕榈酸酯或Tlr4激动剂脂多糖（LPS）。在用特定的c-jun N末端激酶（JNK）抑制剂（SP600125）处理的脂肪细胞中，这些作用减弱了，表明该细胞内激酶参与了SFA和Tlr激动剂介导的信号传导。最后，我们证明了Tlr2-/-小鼠也受到DIO的保护。但是，与Tlr4缺陷的10ScN小鼠不同，体重，能量摄入或脂质分布没有明显变化。血清（C反应蛋白（CRP），内毒素和单核细胞趋化蛋白1（MCP-1））和AT（肿瘤坏死因子;（TNF），白介素6（IL-6））的炎症和氧化应激标志物， MCP-1，F4 / 80和一氧化氮合酶2（NOS2）转录本的丰度在Tlr2-/-和10ScN小鼠中减弱，在喂食高SFA饮食的小鼠中更明显。在10ScN中，胰岛素敏感性有所改善，但在Tlr2-/-小鼠中却没有。但是，从Tlr2-/-小鼠的AT分离出的基质血管（SV）细胞的胰岛素敏感性显着增加，表明Tlr2可能参与了肥胖引起的AT胰岛素抵抗。基于这些研究，Tlr2和Tlr4可能代表药物和饮食干预措施的理想目标，这些干预措施旨在减轻肥胖症和相关合并症，包括2型糖尿病（DM）和心血管疾病（CVD）。

著录项

  • 作者

    Davis, Jeremy E.;

  • 作者单位

    Iowa State University.;

  • 授予单位 Iowa State University.;
  • 学科 Biology Molecular.;Health Sciences Immunology.;Health Sciences Nutrition.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 170 p.
  • 总页数 170
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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