收稿日期: 2023-04-17
录用日期: 2023-11-09
网络出版日期: 2024-02-01
基金资助
国家自然科学基金(82173791);上海市自然科学基金(23ZR1436600)
Regulation of high-fat diet-induced microglial metabolism by transient receptor potential vanilloid type 1
Received date: 2023-04-17
Accepted date: 2023-11-09
Online published: 2024-02-01
Supported by
National Natural Science Foundation of China(82173791);Shanghai Science and Technology Commission Fund Grant(23ZR1436600)
目的·利用转录组以及脂质组分析技术研究瞬时受体电位香草素1型（transient receptor potential vanilloid type 1，TRPV1）通道的激活对高脂饮食诱导的小胶质细胞代谢的调控作用。方法·以8周龄C57BL/6J小鼠（WT）和Trpv1-/-（KO）小鼠为实验动物，高脂饲料（high-fat diet，HFD）分别喂养3d、7d、8周诱导造模（WT和KO组，n=3；WT-HFD和KO-HFD组，n=4）。通过免疫荧光试验测量WT-HFD和KO-HFD组小鼠大脑中TRPV1通道的表达以及细胞定位。通过RNA测序和液相色谱-质谱法确定WT-HFD和KO-HFD组小鼠的大脑表型。结果·与WT组小鼠相比，WT-HFD组小鼠体内小胶质细胞Trpv1 mRNA的表达水平显著增加。与WT-HFD组小鼠相比，KO-HFD组小鼠的脑脂质代谢、线粒体功能、葡萄糖转移以及糖酵解相关基因的表达水平下调。脂质组分析显示，虽然KO-HFD组小鼠的脑组织中脂质积累，但是Trpv1基因敲除减弱了HFD诱导的小胶质细胞活化，此外，TRPV1激动剂辣椒素在体外减弱棕榈酸诱导的线粒体膜电位去极化。结论·TRPV1通过线粒体驱动的燃料可用性机制调节小胶质细胞的脂质和葡萄糖代谢。
关键词： 瞬时受体电位香草素1型; 小胶质细胞; 代谢; 脂质; 线粒体
沙旭栋 , 王晨飞 , 鲁佳 , 虞志华 . 瞬时受体电位香草素1型对高脂饮食诱导的小胶质细胞代谢的调控[J]. 上海交通大学学报（医学版）, 2023 , 43(12) : 1493 -1506 . DOI: 10.3969/j.issn.1674-8115.2023.12.004
Objective ·Transcriptomic and lipidomic analysis techniques were used to investigate the role of transient receptor potential vanilloid type 1 (TRPV1) channel activation in the regulation of high-fat diet-induced microglial metabolism. Methods ·Eight-week-old C57BL/6J mice (WT) and Trpv1-/- (KO) mice were used as experimental animals, and fed high-fat diet (HFD) for 3 days, 7 days, and 8 weeks to induce modelling (WT and KO groups, n = 3; WT-HFD and KO-HFD groups, n = 4). TRPV1 channel expression and cellular localisation were measured by immunofluorescence in the brains of mice in the WT-HFD and KO-HFD group. RNA sequencing and liquid chromatography-mass spectrometry were performed to determine the brain phenotype of mice in the WT-HFD and KO-HFD groups. Results ·The expression level of Trpv1 mRNA in microglia was significantly increased in mice in the WT-HFD group compared to mice in the WT group. The expression levels of genes related to brain lipid metabolism, mitochondrial function, glucose transfer, and glycolysis were down-regulated in the KO-HFD group of mice compared with the WT-HFD group of mice. Lipidomic analysis showed that although lipids accumulated in the brain tissue of mice in the KO-HFD group, Trpv1 knockdown attenuated HFD-induced microglia activation, and in addition the TRPV1 agonist capsaicin attenuated palmitate-induced depolarisation of mitochondrial membrane potential in vitro. Conclusion ·Together, these findings suggest that TRPV1 regulates lipid and glucose metabolism in microglia via fuel availability driven by a mitochondrial mechanism.
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