Department of Animal and Poultry Science, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA.
School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA.
Behav Brain Res. 2020 Sep 1;393:112787. doi: 10.1016/j.bbr.2020.112787. Epub 2020 Jun 27.
Studies have shown that long-term exposure to high fat and other obesogenic diets results in insulin resistance and altered blood brain barrier permeability, dysregulation of intracellular signaling mechanisms, changes in DNA methylation levels and gene expression, and increased oxidative stress and neuroinflammation in the hippocampus, all of which are associated with impaired spatial memory. The ubiquitin-proteasome system controls the majority of protein degradation in cells and is a critical regulator of synaptic plasticity and memory formation. Yet, whether protein degradation in the hippocampus becomes dysregulated following weight gain and is associated with obesity-induced memory impairments is unknown. Here, we used a high fat diet procedure in combination with behavioral and subcellular fractionation protocols and a variety of biochemical assays to determine if ubiquitin-proteasome activity becomes altered in the hippocampus during obesity development and whether this is associated with impaired spatial memory. We found that only 6 weeks of exposure to a high fat diet was sufficient to impair performance on an object location task in rats and resulted in dynamic dysregulation of ubiquitin-proteasome activity in the nucleus and cytoplasm of cells in the hippocampus. Furthermore, these changes in the protein degradation process extended into cortical regions also involved in spatial memory formation. Collectively, these results indicate that weight gain-induced memory impairments may be due to altered ubiquitin-proteasome signaling that occurs during the early stages of obesity development.
研究表明，长期暴露于高脂肪和其他致肥胖饮食会导致胰岛素抵抗和血脑屏障通透性改变、细胞内信号机制失调、DNA 甲基化水平和基因表达改变以及海马体中氧化应激和神经炎症增加，所有这些都与空间记忆受损有关。泛素-蛋白酶体系统控制细胞中大多数蛋白质的降解，是突触可塑性和记忆形成的关键调节剂。然而，体重增加后海马体中的蛋白质降解是否失调以及是否与肥胖引起的记忆障碍有关尚不清楚。在这里，我们使用高脂肪饮食程序结合行为和亚细胞分级分离方案以及各种生化测定来确定在肥胖发展过程中，泛素-蛋白酶体活性是否在海马体中发生改变，以及这是否与空间记忆受损有关。我们发现，仅 6 周的高脂肪饮食暴露就足以损害大鼠在物体位置任务中的表现，并导致海马体细胞核和细胞质中泛素-蛋白酶体活性的动态失调。此外，蛋白质降解过程的这些变化还扩展到皮质区域，这些区域也参与空间记忆的形成。总的来说，这些结果表明，体重增加引起的记忆障碍可能是由于肥胖发展早期发生的泛素-蛋白酶体信号改变所致。
