Metabolic syndrome is a key risk factor and co-morbidity in multiple sclerosis (MS) and other neurological conditions, such that a better understanding of how a high fat diet contributes to oligodendrocyte loss and the capacity for myelin regeneration has the potential to highlight new treatment targets. Results demonstrate that modeling metabolic dysfunction in mice with chronic high fat diet (HFD) consumption promotes loss of oligodendrocyte progenitors across the brain and spinal cord. A number of transcriptomic and metabolomic changes in ER stress, mitochondrial dysfunction, and oxidative stress pathways in HFD-fed mouse spinal cords were also identified. Moreover, deficits in TCA cycle intermediates and mitochondrial respiration were observed in the chronic HFD spinal cord tissue. Oligodendrocytes are known to be particularly vulnerable to oxidative damage, and we observed increased markers of oxidative stress in both the brain and spinal cord of HFD-fed mice. We additionally identified that increased apoptotic cell death signaling is underway in oligodendrocytes from mice chronically fed a HFD. When cultured under high saturated fat conditions, oligodendrocytes decreased both mitochondrial function and differentiation. Overall, our findings show that HFD-related changes in metabolic regulators, decreased mitochondrial function, and oxidative stress contribute to a loss of myelinating cells. These studies identify HFD consumption as a key modifiable lifestyle factor for improved myelin integrity in the adult central nervous system and in addition new tractable metabolic targets for myelin protection and repair strategies.

中文翻译：

---

高脂肪饮食会导致中枢神经系统线粒体功能障碍、氧化应激和少突胶质细胞损失。

代谢综合征是多发性硬化症 (MS) 和其他神经系统疾病的关键危险因素和合并症，因此更好地了解高脂肪饮食如何导致少突胶质细胞损失和髓磷脂再生能力有可能突显新的治疗方法目标。结果表明，对长期摄入高脂肪饮食（HFD）的小鼠进行代谢功能障碍建模会促进大脑和脊髓中少突胶质细胞祖细胞的损失。还发现了 HFD 喂养的小鼠脊髓中 ER 应激、线粒体功能障碍和氧化应激途径的许多转录组和代谢组变化。此外，在慢性 HFD 脊髓组织中观察到 TCA 循环中间体和线粒体呼吸的缺陷。众所周知，少突胶质细胞特别容易受到氧化损伤，我们观察到高脂饮食小鼠的大脑和脊髓中氧化应激标记物增加。我们还发现，长期喂食 HFD 的小鼠少突胶质细胞中的细胞凋亡信号正在增加。当在高饱和脂肪条件下培养时，少突胶质细胞会降低线粒体功能和分化。总体而言，我们的研究结果表明，与 HFD 相关的代谢调节因子的变化、线粒体功能下降和氧化应激会导致髓鞘细胞的丧失。这些研究将 HFD 摄入确定为改善成人中枢神经系统髓磷脂完整性的关键可改变生活方式因素，此外还为髓磷脂保护和修复策略提供了新的易于处理的代谢目标。