雷公藤红素通过上调BBB上GLUT1改善肥胖所致认知功能障碍的机制研究

Obesity is a growing problem worldwide, and is closely associated with an increased incidence of cognitive impairment. However, mechanisms for cognitive impairment induced by obesity and the approach to reverse cognitive decline remain to be investigated. Accumulating evidence indicates that increased blood-brain barrier (BBB) permeability contributes to cognitive impairment in multiple disease status. Moreover, recent studies indicate that reduction of glucose transporter 1 (GLUT1) leads to BBB breakdown, and thioredoxin-interacting protein (TXNIP) suppresses GLUT1 expression and function. Our preliminary experiments found that celastrol could significantly reverse TXNIP overexpression, GLUT1 inhibition, BBB breakdown and cognitive impairment induced by obesity. However, in an in vitro BBB model, GLUT1 siRNA transfection abrogated the neuroprotective effects of celastrol against palmitic acid-induced BBB breakdown. Based on these findings, we propose the hypothesis that inhibition of GLUT1 may contribute to BBB breakdown and the cognitive impairment induced by obesity, and celastrol may ameliorate obesity-induced BBB breakdown and cognitive impairment by increasing the activity and expression of GLUT1 through inhibiting TXNIP overexpression. Our project would establish animal and cell model to verify the critical role of GLUT1 in obesity-induced BBB breakdown and cognitive impairment, and to elucidate the mechanism by which celastrol reverses GLUT1 reduction and cognitive impairment induced by obesity. The validation of this hypothesis will suggest a new idea for researching the pathogenesis of cognitive deficits induced by obesity, and provide the therapeutical target of celastrol against obesity-induced cognitive impairment.

肥胖所致认知功能障碍病理机制尚不明确，临床缺少有效治疗药物。文献研究证实血脑屏障（BBB）损伤是认知功能障碍的重要病理基础，GLUT1缺失可诱导BBB损伤，而TXNIP对GLUT1具有负调控作用。我们前期研究发现，肥胖可上调海马上TXNIP，下调GLUT1，损伤BBB导致认知功能障碍，而雷公藤红素可逆转上述现象；细胞水平沉默GLUT1可抵消雷公藤红素对高脂诱导BBB损伤的保护作用。据此我们提出假说：GLUT1下调介导肥胖诱导的BBB损伤及认知功能障碍，雷公藤红素可通过抑制TXNIP上调GLUT1，进而改善肥胖所致认知功能障碍。本课题拟采用BBB细胞模型及肥胖小鼠模型，运用RNA干扰、免疫共沉淀等分子生物学技术，从整体、细胞、分子水平研究GLUT1在肥胖所致认知功能障碍中的作用，阐明雷公藤红素上调GLUT1改善肥胖所致BBB损伤和认知功能障碍的机制，为肥胖所致认知功能障碍的防治提供新思路。

肥胖所致认知功能障碍已成为威胁人类生命健康、生存质量的高危因素。然而，其病理机制尚不清楚，目前临床尚缺少有效治疗药物。我们用高脂饲料长期喂养诱导小鼠肥胖模型，并考察雷公藤红素给药对肥胖及认知功能障碍的治疗作用。Morris水迷宫实验评价小鼠的空间学习记忆能力，新事物认知实验评估小鼠的非空间学习记忆。结果显示，雷公藤红素给药不仅可以显著缓解高脂饮食引起的体重增加、糖耐量不耐受和胰岛素抵抗等生理生化指标改变，还可显著改善肥胖诱导的空间记忆和非空间记忆功能下降。代谢组和转录组结果提示，雷公藤红素可能通过逆转高脂饮食引起的二十二碳六烯酸和二十碳五烯酸浓度下降，下调海马组织中NOD-like receptor信号通路，进而改善肥胖小鼠的认知功能障碍。此外，肥胖患者常常伴随非酒精性脂肪性肝病，可能在代谢紊乱和认知功能障碍的发生发展中起到重要作用。因此，我们进一步利用广泛靶向代谢组学解析了非酒精性脂肪性肝炎(NASH)患者和小鼠的代谢特征，发现NASH患者和小鼠中初级胆汁酸、丙氨酸、天冬氨酸和谷氨酸等代谢通路均发生显著变化。胆汁酸靶向代谢组结果提示，NASH患者和小鼠存在胆汁酸代谢紊乱现象，初级和次级胆汁酸水平均显著增加。以上结果提示，胆汁酸、丙氨酸、天冬氨酸和谷氨酸代谢紊乱是NASH疾病的重要特征，胆汁酸及其他代谢物有望作为生物标志物用于临床NASH无创诊断及肝纤维化程度评估。动物实验结果显示利用考来烯胺改善胆汁酸代谢紊乱可显著降低NASH小鼠的肝细胞脂肪变性和肝纤维化。本项目不仅为雷公藤红素治疗肥胖所致认知功能下降提供理论依据，还将为NASH发病机制和药物靶点研究开辟新方向，具有重要的科学价值和临床应用潜力。

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