Hu Ying, Xu Jixiong, Wang Jiancheng, Wang Jiao, Li Yuxia, Chen Wen, Zhang Qin
Department of Endocrinology and Metabolism, the 1St Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi Province, People's Republic of China.
Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, 330006, Jiangxi Province, People's Republic of China.
Mol Neurobiol. 2025 May 20. doi: 10.1007/s12035-025-04922-5.
Visceral adipose tissue-derived extracellular vesicles (VAT-EVs) and their cargo miR-9-3p contribute to cognitive dysfunction and insulin resistance. Resveratrol (RES) prevents T2DM-induced cognitive impairment. This study investigates the interactive role of VAT-EVs and RES in diabetes-associated cognitive dysfunction (DACD) and the potential mechanisms. T2DM mice were constructed by high-fat diet (HFD)-feeding and streptozotocin (STZ) injection. Blood glucose and insulin levels evaluated the insulin resistance. Novel object recognition test (ORT) and Morris water maze (MWM) test assessed cognitive impairment. Nissl, H&E, and TUNEL stainings evaluated neuronal death. Immunofluorescence staining, immunostaining, DHE staining, Perls' staining, biochemical assays, and Western blots determined ER, oxidative stress, and ferroptosis. ELISA measured cytokines. VAT-EVs were isolated from adipose tissues of T2DM mice and characterized by transmission electron microscopy (TEM), Western blot, and dynamic light scattering detection. Treatment of resveratrol (RES) without or with miR-9-3p mimics investigated their interactive roles in DACD. Luciferase reporter assay, Western blot, and qRT-PCR validated the binding of miR-9-3p in SLC7A11. The blood glucose and insulin results and behavioral tests showed that T2DM mice exhibited insulin resistance and cognitive impairments. T2DM mice showed impaired structures, increased apoptosis, and enhanced inflammation, ER, oxidative stress, and ferroptosis in the hippocampus. RES diminished HFD-VAT-EVs-induced insulin resistance and cognitive declines through decreasing ER and oxidative stress, inflammation, and iron overload. Mechanistically, RES decreased miR-9-3p to upregulate SLC7A11 and subsequently mitigate ferroptosis. RES protected cognitive dysfunction and insulin resistance in T2DM via diminishing VAT-EVs and their cargo miR-9-3p-induced ER and oxidative stress, inflammation, and ferroptosis in the hippocampus.
内脏脂肪组织衍生的细胞外囊泡（VAT-EVs）及其所载的miR-9-3p会导致认知功能障碍和胰岛素抵抗。白藜芦醇（RES）可预防2型糖尿病（T2DM）诱导的认知障碍。本研究探讨了VAT-EVs和RES在糖尿病相关认知功能障碍（DACD）中的相互作用及其潜在机制。通过高脂饮食（HFD）喂养和链脲佐菌素（STZ）注射构建T2DM小鼠模型。通过检测血糖和胰岛素水平评估胰岛素抵抗情况。采用新物体识别试验（ORT）和莫里斯水迷宫（MWM）试验评估认知障碍。通过尼氏染色、苏木精-伊红（H&E）染色和TUNEL染色评估神经元死亡情况。通过免疫荧光染色、免疫组化、二氢乙啶（DHE）染色、普鲁士蓝染色、生化分析和蛋白质免疫印迹法检测内质网（ER）、氧化应激和铁死亡情况。采用酶联免疫吸附测定（ELISA）法检测细胞因子。从T2DM小鼠的脂肪组织中分离出VAT-EVs，并通过透射电子显微镜（TEM）、蛋白质免疫印迹法和动态光散射检测对其进行表征。用白藜芦醇（RES）单独或与miR-9-3p模拟物联合处理，研究它们在DACD中的相互作用。荧光素酶报告基因检测、蛋白质免疫印迹法和定量逆转录聚合酶链反应（qRT-PCR）验证了miR-9-3p与溶质载体家族7成员11（SLC7A11）的结合。血糖和胰岛素检测结果以及行为学试验表明，T2DM小鼠存在胰岛素抵抗和认知障碍。T2DM小鼠海马区结构受损、细胞凋亡增加、炎症反应增强、内质网应激、氧化应激和铁死亡加剧。RES通过降低内质网应激、氧化应激、炎症反应和铁过载，减轻了高脂饮食诱导的内脏脂肪组织衍生细胞外囊泡（HFD-VAT-EVs）所致的胰岛素抵抗和认知功能下降。机制上，RES通过降低miR-9-3p的表达来上调SLC7A11，进而减轻铁死亡。RES通过减少VAT-EVs及其所载miR-9-3p诱导的海马区内质网应激、氧化应激、炎症反应和铁死亡，保护T2DM小鼠的认知功能障碍和胰岛素抵抗。
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