School of Public Health and Joint China-US Research Center for Environment and Pulmonary Diseases, Zhejiang Chinese Medical University, Hangzhou, China; College of Medicine, Hangzhou Normal University, Hangzhou, China.
School of Public Health and Joint China-US Research Center for Environment and Pulmonary Diseases, Zhejiang Chinese Medical University, Hangzhou, China.
J Nutr Biochem. 2021 Sep;95:108761. doi: 10.1016/j.jnutbio.2021.108761. Epub 2021 Jun 6.
Inflammation in insulin-sensitive tissues (e.g., liver, visceral adipose tissue [VAT]) plays a major role in obesity and insulin resistance. Recruitment of innate immune cells drives the dysregulation of glucose and lipid metabolism. We aimed to seek the role of Toll like receptor 3 (TLR3), a pattern recognition receptor involved in innate immunity, obesity and the metabolic disorder. TLR3 expression in liver and VAT from diet induced obese mice and in VAT from overweight women was examined. Body weight, glucose homeostasis and insulin sensitivity were evaluated in TLR3 wild-type and knockout (KO) mice on a chow diet (CD) or high-fat diet for 15 weeks. At euthanasia, blood was collected, and plasma biochemical parameters and adipokines were determined with commercial kits. Flow cytometry was used to measure macrophage infiltration and activation in VAT. Standard western blot, immunohistochemistry and quantative PCR were used to assess molecules in pathways about lipid and glucose metabolism, insulin and inflammation in tissues of liver and VAT. Utilizing human and animal samples, we found that expression of TLR3 was upregulated in the liver and VAT in obese mice as well as VAT in overweight women. TLR3-deficiency protected against high-fat diet induced obesity, glucose intolerance, insulin resistance and lipid accumulation. Lipolysis was enhanced in VAT and hepatic lipogenesis was inhibited in TLR3 KO animals. Macrophages infiltration into adipose tissue was attenuated in TLR3 KO mice, accompanied with inhibition of NF-κB-dependent AMPK/Akt signaling pathway. These findings demonstrated that TLR3 ablation prevented obesity and metabolic disorders, thereby providing new mechanistic links between inflammation and obesity and associated metabolic abnormalities in lipid/glucose metabolism.
在胰岛素敏感组织（如肝脏、内脏脂肪组织[VAT]）中的炎症在肥胖和胰岛素抵抗中起着主要作用。先天免疫细胞的募集驱动葡萄糖和脂质代谢的失调。我们旨在寻求参与先天免疫、肥胖和代谢紊乱的模式识别受体 Toll 样受体 3（TLR3）的作用。我们检测了饮食诱导肥胖小鼠肝脏和 VAT 以及超重女性 VAT 中的 TLR3 表达。在 chow 饮食（CD）或高脂肪饮食下，15 周后，在 TLR3 野生型和敲除（KO）小鼠中评估了体重、葡萄糖稳态和胰岛素敏感性。安乐死后，采集血液，并使用商业试剂盒测定血浆生化参数和脂肪因子。利用流式细胞术测量 VAT 中的巨噬细胞浸润和激活。利用标准 Western blot、免疫组织化学和定量 PCR 来评估肝脏和 VAT 中与脂质和葡萄糖代谢、胰岛素和炎症相关的途径中的分子。利用人和动物样本，我们发现 TLR3 的表达在肥胖小鼠的肝脏和 VAT 以及超重女性的 VAT 中上调。TLR3 缺失可预防高脂肪饮食诱导的肥胖、葡萄糖不耐受、胰岛素抵抗和脂质堆积。TLR3 KO 动物的 VAT 中的脂肪分解增强，肝脏中的脂肪生成受到抑制。TLR3 KO 小鼠的脂肪组织中巨噬细胞浸润减少，同时抑制 NF-κB 依赖性 AMPK/Akt 信号通路。这些发现表明，TLR3 缺失可预防肥胖和代谢紊乱，从而为炎症与肥胖及其相关的脂质/葡萄糖代谢异常之间的新机制联系提供了证据。
