Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes
Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes
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DOI：
10.1152/ajpendo.00302.2006
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发表时间：
2007-03-01
影响因子：
5.1
通讯作者：
Kumar, S.
中科院分区：
文献类型：
--
作者：
Creely, S. J.;McTernan, P. G.;Kumar, S.
2型糖尿病（T2 DM）与慢性低度炎症有关。脂肪组织（AT）可能是炎症的重要部位。3 T3-L1研究表明，脂多糖（LPS）激活Toll样受体（TLR）引起炎症。对于本研究，我们1）检查了LPS对人腹部皮下（AbdSc）脂肪细胞中TLR和脂肪细胞因子的激活，2）检查了人AbdSc脂肪细胞中NF-κ B的阻断，3）检查了瘦、肥胖和T2 DM受试者的AbdSc AT中的先天免疫途径，以及4）检查了T2 DM受试者中循环LPS的相关性。结果显示，LPS使TLR-2蛋白表达增加2倍（P < 0.05）。用LPS处理AbdSc脂肪细胞引起TNF-α和IL-6分泌的显著增加（IL-6，对照：2.7 +/- 0.5 vs. LPS：4.8 +/- 0.3 ng/ml; P < 0.001; TNF-α，对照：1.0 +/- 0.83 vs. LPS：32.8 +/- 6.23 pg/ml; P < 0.001）。NF-κ B抑制剂减少AbdSc脂肪细胞中的IL-6（对照：2.7 +/- 0.5 vs NF-κ B抑制剂：2.1 +/- 0.4 ng/ml; P < 0.001）。在T2 DM患者中，TLR- 2、MyD 88、TRAF-6和NF-κ B的AbdSc AT蛋白表达增加（P < 0.05），并且在LPS处理的脂肪细胞中TLR-2、TRAF-6和NF-κ B的AbdSc AT蛋白表达增加（P < 0.05）。与匹配的对照组相比，T2 DM受试者的循环LPS高76%。对照组LPS与胰岛素呈正相关（r = 0.678，P < 0.0001）。罗格列酮（RSG）显著降低了既往未经治疗的T2 DM患者亚组的空腹血清胰岛素水平（降低51%，P = 0.0395）和血清LPS水平（降低35%，P = 0.0139）。总之，我们的研究结果表明，T2 DM与内毒素血症增加有关，AT能够启动先天性免疫反应。因此，增加的肥胖可能增加促炎细胞因子，因此有助于T2 DM的致病风险。
Type 2 diabetes (T2DM) is associated with chronic low-grade inflammation. Adipose tissue ( AT) may represent an important site of inflammation. 3T3-L1 studies have demonstrated that lipopolysaccharide (LPS) activates toll-like receptors (TLRs) to cause inflammation. For this study, we 1) examined activation of TLRs and adipocytokines by LPS in human abdominal subcutaneous (AbdSc) adipocytes, 2) examined blockade of NF-kappa B in human AbdSc adipocytes, 3) examined the innate immune pathway in AbdSc AT from lean, obese, and T2DM subjects, and 4) examined the association of circulating LPS in T2DM subjects. The findings showed that LPS increased TLR-2 protein expression twofold (P < 0.05). Treatment of AbdSc adipocytes with LPS caused a significant increase in TNF-alpha and IL-6 secretion (IL-6, Control: 2.7 +/- 0.5 vs. LPS: 4.8 +/- 0.3 ng/ml; P < 0.001; TNF-alpha, Control: 1.0 +/- 0.83 vs. LPS: 32.8 +/- 6.23 pg/ml; P < 0.001). NF-kappa B inhibitor reduced IL-6 in AbdSc adipocytes (Control: 2.7 +/- 0.5 vs. NF-kappa B inhibitor: 2.1 +/- 0.4 ng/ml; P < 0.001). AbdSc AT protein expression for TLR- 2, MyD88, TRAF6, and NF-kappa B was increased in T2DM patients (P < 0.05), and TLR-2, TRAF-6, and NF-kappa B were increased in LPS-treated adipocytes (P < 0.05). Circulating LPS was 76% higher in T2DM subjects compared with matched controls. LPS correlated with insulin in controls (r = 0.678, P < 0.0001). Rosiglitazone (RSG) significantly reduced both fasting serum insulin levels ( reduced by 51%, P = 0.0395) and serum LPS ( reduced by 35%, P = 0.0139) in a subgroup of previously untreated T2DM patients. In summary, our results suggest that T2DM is associated with increased endotoxemia, with AT able to initiate an innate immune response. Thus, increased adiposity may increase proinflammatory cytokines and therefore contribute to the pathogenic risk of T2DM.