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抗阻运动通过TREM2/NF-κB/STAT3信号通路调控海马小胶质细胞极化进而改善2型糖尿病小鼠认知功能障碍

张宝文^1,2, 李颖^1,2, 寇现娟^1,2,*

¹武汉体育学院运动医学院，武汉 430079；²运动训练监控湖北省重点实验室，武汉 430079

摘要

本文旨在探究抗阻运动对2型糖尿病(type 2 diabetes mellitus, T2DM)小鼠认知功能障碍的影响及作用机制。取6只8周龄雄性m/m小鼠作为对照(Con)组，12只同周龄db/db小鼠随机分为模型对照(db/db)组和抗阻运动(db+RE)组，每组6只，给予db+RE组小鼠8周抗阻运动干预，每周检测小鼠空腹血糖及体重。干预结束后，用水迷宫实验检测小鼠空间学习记忆能力，Nissl染色检测小鼠海马组织神经元损伤，Western blot检测小鼠海马组织中PSD93、PSD95、BDNF、CREB、p-CREB、IL-6、IL-1β、TNF-α、Iba-1、iNOS、CD206、Arg1、髓系细胞触发受体2 (triggering receptor expressed on myeloid cells 2, TREM2)、NF-κB、p-STAT3、STAT3蛋白表达水平，qRT-PCR 检测海马组织炎症因子及TREM2的mRNA表达水平，免疫荧光染色检测 Iba-1、CD206、CD86、TREM2蛋白表达和共定位。结果显示，与Con组相比，db/db组小鼠空间学习记忆能力下降，海马神经元受损，PSD93、PSD95、BDNF、CD206、Arg1、TREM2蛋白表达水平及p-CREB/CREB比值显著下调，炎症因子IL-6、IL-1β、TNF-α的mRNA及蛋白表达水平显著上升，iNOS、Iba-1和NF-κB蛋白水平及p-STAT3/STAT3比值显著上升。8周抗阻运动可改善db/db小鼠的空间学习记忆能力，减轻海马神经元损伤，促进海马组织M2型小胶质细胞极化进而缓解神经炎症。上述结果提示，抗阻运动可以改善T2DM小鼠认知功能障碍，其机制可能是通过TREM2/NF-κB/STAT3信号通路调控海马组织小胶质细胞极化而实现。

关键词： 抗阻运动; 糖尿病; 认知功能障碍; 小胶质细胞极化; TREM2

Resistance exercise regulates hippocampal microglia polarization through TREM2/NF-κB/STAT3 signal pathway to improve cognitive dysfunction in T2DM mice

ZHANG Bao-Wen^1,2, LI Ying^1,2, KOU Xian-Juan^1,2,*

¹College of Sports Medicine, Wuhan Sports University, Wuhan 430079, China；²Hubei Key Laboratory of Exercise Training and Monitoring, Wuhan 430079, China

Abstract

The study aimed to explore the effect and mechanism of resistance exercise (RE) on cognitive dysfunction in type 2 diabetes mellitus (T2DM) mice. Six 8-week-old male m/m mice were used as control (Con) group, and db/db mice of the matched age were randomly divided into model control (db/db) group and db+RE group, with 6 mice in each group. The db+RE group was given 8 weeks of resistance climbing ladder exercise intervention. The fasting blood glucose and body weight of the mice were measured weekly. After the intervention, the spatial learning and memory of the mice were detected by Morris water maze, and the neuronal damage in the hippocampus of the mice was detected by Nissl staining. The protein expression levels of PSD93, PSD95, BDNF, CREB, p-CREB, IL-6, IL-1β, TNF-α, Iba-1, iNOS, CD206, Arg1, triggering receptor expressed on myeloid cells 2 (TREM2), NF-κB, p-STAT3, and STAT3 were detected by Western blot. The mRNA expression levels of inflammatory factors and TREM2 in hippocampus were evaluated by qRT-PCR, and the expression and localization of Iba-1, CD206, CD86, and TREM2 were determined by immunofluorescence staining. The results showed that the spatial learning and memory of the db/db group were significantly declined, the neurons in the hippocampus were damaged, the protein levels of PSD93, PSD95, BDNF, CD206, Arg1, TREM2 and the ratio of p-CREB/CREB were significantly down-regulated, the mRNA and protein expression levels of IL-6, IL-1β and TNF-α were significantly up-regulated, and the protein levels of iNOS, Iba-1, NF-κB and the ratio of p-STAT3/STAT3 were significantly increased compared with the Con group. However, the 8-week RE improved the spatial learning and memory of db/db mice, alleviated the damage of hippocampal neurons, promoted the polarization of M2 microglia, and inhibited the neuroinflammation. The above results suggest that RE can improve cognitive dysfunction in T2DM mice, and its mechanism may be related to regulating microglia polarization via TREM2/NF-κB/STAT3 signaling pathway.

Key words: resistance exercise; diabetes mellitus; cognitive dysfunction; microglia polarization; TREM2

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通讯作者：寇现娟　　E-mail:

引用本文：

张宝文, 李颖, 寇现娟. 抗阻运动通过TREM2/NF-κB/STAT3信号通路调控海马小胶质细胞极化进而改善2型糖尿病小鼠认知功能障碍[J]. 生理学报 2024; 76 (5): 717-731.

ZHANG Bao-Wen, LI Ying, KOU Xian-Juan. Resistance exercise regulates hippocampal microglia polarization through TREM2/NF-κB/STAT3 signal pathway to improve cognitive dysfunction in T2DM mice. Acta Physiol Sin 2024; 76 (5): 717-731 (in Chinese with English abstract).