Centre for Molecular Biosciences, University of Ulster, Coleraine, UK.
SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, UK.
Diabetes Obes Metab. 2018 May;20(5):1166-1175. doi: 10.1111/dom.13210. Epub 2018 Feb 11.
To demarcate pathological events in the brain as a result of short-term to chronic high-fat-diet (HFD) feeding, which leads to cognitive impairment and neuroinflammation, and to assess the efficacy of Xenin-25[Lys(13)PAL] in chronic HFD-fed mice.
C57BL/6 mice were fed an HFD or a normal diet for 18 days, 34 days, 10 and 21 weeks. Cognition was assessed using novel object recognition and the Morris water maze. Markers of insulin signalling and inflammation were measured in brain and plasma using immunohistochemistry, quantitative PCR and multi-array technology. Xenin-25[Lys(13)PAL] was also administered for 5 weeks in chronic HFD-fed mice to assess therapeutic potential at a pathological stage.
Recognition memory was consistently impaired in HFD-fed mice and spatial learning was impaired in 18-day and 21-week HFD-fed mice. Gliosis, oxidative stress and IRS-1 pSer were increased in the brain on day 18 in HFD-fed mice and were reduced by Xenin-25[Lys(13)PAL] in 21-week HFD-fed mice. In plasma, HFD feeding elevated interleukin (IL)-6 and chemokine (C-X-C motif) ligand 1 at day 34 and IL-5 at week 10. In the brain, HFD feeding reduced extracellular signal-regulated kinase 2 (ERK2), mechanistic target of rapamycin (mTOR), NF-κB1, protein kinase C (PKC)θ and Toll-like receptor 4 (TLR4) mRNA at week 10 and increased expression of glucacon-like peptide-1 receptor, inhibitor of NF-κB kinase β, ERK2, mTOR, NF-κB1, PKCθ and TLR4 at week 21, elevations that were abrogated by Xenin-25[Lys(13)PAL].
HFD feeding modulates cognitive function, synapse density, inflammation and insulin resistance in the brain. Xenin-25[Lys(13)PAL] ameliorated markers of inflammation and insulin signalling dysregulation and may have therapeutic potential in the treatment of diseases associated with neuroinflammation or perturbed insulin signalling in the brain.
描绘短期至慢性高脂肪饮食（HFD）喂养导致认知障碍和神经炎症的大脑病理事件，并评估 Xenin-25[Lys(13)PAL]在慢性 HFD 喂养小鼠中的疗效。
C57BL/6 小鼠接受 HFD 或正常饮食 18 天、34 天、10 周和 21 周。使用新物体识别和 Morris 水迷宫评估认知能力。使用免疫组织化学、定量 PCR 和多阵列技术测量大脑和血浆中的胰岛素信号和炎症标志物。Xenin-25[Lys(13)PAL]也在慢性 HFD 喂养的小鼠中给药 5 周，以评估在病理阶段的治疗潜力。
HFD 喂养的小鼠识别记忆始终受损，18 天和 21 周 HFD 喂养的小鼠空间学习受损。HFD 喂养的小鼠在第 18 天大脑中星形胶质细胞增生、氧化应激和 IRS-1 pSer 增加，Xenin-25[Lys(13)PAL]可降低 21 周 HFD 喂养的小鼠的这些标志物。在血浆中，HFD 喂养在第 34 天升高白细胞介素（IL）-6 和趋化因子（C-X-C 基序）配体 1，在第 10 周升高 IL-5。在大脑中，HFD 喂养在第 10 周降低细胞外信号调节激酶 2（ERK2）、雷帕霉素（mTOR）的机制靶点、核因子-κB1、蛋白激酶 C（PKC）θ 和 Toll 样受体 4（TLR4）mRNA，并在第 21 周增加胰高血糖素样肽-1 受体、NF-κB 激酶β抑制剂、ERK2、mTOR、NF-κB1、PKCθ 和 TLR4 的表达，Xenin-25[Lys(13)PAL]可消除这些变化。
HFD 喂养调节大脑中的认知功能、突触密度、炎症和胰岛素抵抗。Xenin-25[Lys(13)PAL]改善炎症和胰岛素信号失调的标志物，可能具有治疗与大脑神经炎症或胰岛素信号紊乱相关疾病的治疗潜力。
