Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet
Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet
复制标题
DOI：
10.1007/s00125-010-1747-3
复制
发表时间：
2010-08-01
期刊：
影响因子：
8.2
通讯作者：
Donath, Marc Y.
中科院分区：
文献类型：
--
作者：
Ehses, J. A.;Meier, D. T.;Donath, Marc Y.
炎症是人类2型糖尿病胰岛素抵抗和胰岛β细胞衰竭的原因之一。Toll样受体是一种高度保守的模式识别受体，协调包括NEFA在内的多种物质的先天炎症反应。在此，我们研究了TLR2在高脂饮食(HFD)引起的小鼠代谢紊乱中的潜在作用。分析了雌性和雌性产仔小鼠TLR2(+/+)和TLR2(-/-)小鼠的葡萄糖耐量、胰岛素敏感性、胰岛素分泌以及对食物和高脂饮食的能量代谢。用分子方法检查脂肪、肝脏、肌肉和胰岛的病理和炎症。在体外研究了巨噬细胞和树突状免疫细胞以及胰岛对NEFA诱导的细胞因子的产生。与TLR2(+/+)对照小鼠相比，雄性和雌性TLR2(-/-)小鼠在饮食中的葡萄糖稳态没有显示出任何差异，可以免受HFD的不利影响。雌性TLR2(-/-)小鼠在喂养20周HFD后表现出显著的葡萄糖耐量、胰岛素敏感性和胰岛素分泌的改善。这些效应与TLR2(-/-)小鼠优先燃烧脂肪的能力增加以及组织炎症减少有关。来自TLR2(-/-)小鼠的骨髓来源的树突状细胞和胰岛对NEFA混合物的反应没有增加IL-1β的表达，而TLR2(+/+)对照组织却增加了IL-1β的表达。这些数据表明，TLR2是通过调节能量底物的利用和组织炎症来增加膳食脂肪摄入量和调节葡萄糖动态平衡之间的分子联系。
Inflammation contributes to both insulin resistance and pancreatic beta cell failure in human type 2 diabetes. Toll-like receptors (TLRs) are highly conserved pattern recognition receptors that coordinate the innate inflammatory response to numerous substances, including NEFAs. Here we investigated a potential contribution of TLR2 to the metabolic dysregulation induced by high-fat diet (HFD) feeding in mice.Male and female littermate Tlr2 (+/+) and Tlr2 (-/-) mice were analysed with respect to glucose tolerance, insulin sensitivity, insulin secretion and energy metabolism on chow and HFD. Adipose, liver, muscle and islet pathology and inflammation were examined using molecular approaches. Macrophages and dendritic immune cells, in addition to pancreatic islets were investigated in vitro with respect to NEFA-induced cytokine production.While not showing any differences in glucose homeostasis on chow diet, both male and female Tlr2 (-/-) mice were protected from the adverse effects of HFD compared with Tlr2 (+/+) littermate controls. Female Tlr2 (-/-) mice showed pronounced improvements in glucose tolerance, insulin sensitivity, and insulin secretion following 20 weeks of HFD feeding. These effects were associated with an increased capacity of Tlr2 (-/-) mice to preferentially burn fat, combined with reduced tissue inflammation. Bone-marrow-derived dendritic cells and pancreatic islets from Tlr2 (-/-) mice did not increase IL-1 beta expression in response to a NEFA mixture, whereas Tlr2 (+/+) control tissues did.These data suggest that TLR2 is a molecular link between increased dietary lipid intake and the regulation of glucose homeostasis, via regulation of energy substrate utilisation and tissue inflammation.