Department of Surgery, Faculty of Medicine, University of British Columbia, Child & Family Research Institute, 950 W 28th Ave, Vancouver, BC, Canada V5Z 4H4.
Diabetologia. 2010 Aug;53(8):1795-806. doi: 10.1007/s00125-010-1747-3. Epub 2010 Apr 21.
AIMS/HYPOTHESIS: 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-1beta expression in response to a NEFA mixture, whereas Tlr2(+/+) control tissues did.
CONCLUSION/INTERPRETATION: 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.
目的/假设：炎症导致人类 2 型糖尿病的胰岛素抵抗和胰岛β细胞衰竭。Toll 样受体（TLR）是高度保守的模式识别受体，可协调对包括 NEFA 在内的多种物质的先天炎症反应。在这里，我们研究了 TLR2 在高脂肪饮食（HFD）喂养诱导的小鼠代谢失调中的潜在作用。
分析雄性和雌性同窝 Tlr2(+/+)和 Tlr2(-/-)小鼠在正常饮食和 HFD 下的葡萄糖耐量、胰岛素敏感性、胰岛素分泌和能量代谢情况。使用分子方法检查脂肪、肝脏、肌肉和胰岛的病理和炎症。还研究了体外巨噬细胞和树突状免疫细胞以及胰岛，以研究 NEFA 诱导的细胞因子产生。
虽然在正常饮食下葡萄糖稳态没有差异，但与 Tlr2(+/+)同窝对照相比，雄性和雌性 Tlr2(-/-)小鼠均能免受 HFD 的不利影响。雌性 Tlr2(-/-)小鼠在接受 HFD 喂养 20 周后，葡萄糖耐量、胰岛素敏感性和胰岛素分泌明显改善。这些作用与 Tlr2(-/-)小鼠优先燃烧脂肪的能力增加有关，同时组织炎症减少。TLR2(-/-)小鼠的骨髓来源树突状细胞和胰岛在受到混合 NEFA 刺激时不会增加 IL-1β的表达，而 Tlr2(+/+)对照组织则会。
结论/解释：这些数据表明，TLR2 是增加饮食脂质摄入与调节葡萄糖稳态之间的分子联系，通过调节能量底物利用和组织炎症。
