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，长期接触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发生变化，以及海马区氧化应激和神经炎症增加，所有这些都与受损的空间记忆有关。泛素-蛋白酶体系统控制着细胞中的大部分蛋白质降解，并且是突触可塑性和记忆形成的关键调节器。然而，海马体中的蛋白质降解是否在体重增加后变得失调并与肥胖引起的记忆障碍有关尚不清楚。这里，我们将高脂肪饮食程序与行为和亚细胞分离方案以及各种生化分析相结合，以确定在肥胖发展过程中海马中泛素 - 蛋白酶体的活性是否发生改变，以及这是否与空间记忆受损有关。我们发现仅 6 周暴露于高脂肪饮食就足以损害大鼠在物体定位任务中的表现，并导致海马细胞核和细胞质中泛素蛋白酶体活性的动态失调。此外，蛋白质降解过程中的这些变化扩展到皮层区域，也参与了空间记忆的形成。总的来说，