Glucose metabolism disturbances may result in diabetes-associated cognitive decline (DACI). Methionine restriction (MR) diet has emerged as a potential dietary strategy for managing glucose homeostasis. However, the effects and underlying mechanisms of MR on DACI have not been fully elucidated. Here, we found that a 13-week MR (0.17 % methionine, w/w) intervention starting at 8 weeks of age improved peripheral insulin sensitivity in male db/db mice, a model for type 2 diabetes. Notably, MR significantly improved working as well as long-term memory in db/db mice, accompanied by increased PSD-95 level and reduced neuroinflammatory factors, malondialdehyde (MDA), and 8-hydroxy-2′-deoxyguanosine (8-OHdG). We speculate that this effect may be mediated by MR activating hepatic fibroblast growth factor 21 (FGF21) and the brain FGFR1/AMPK/GLUT4 signaling pathway to enhance brain glucose metabolism. To further delineate the mechanism, we used intracerebroventricular injection of adeno-associated virus to specifically knock down FGFR1 in the brain to verify the role of FGFR1 in MR-mediated DACI. It was found that the positive effects of MR on DACI were offset, reflected in decreased cognitive function, impaired synaptic plasticity, upregulated neuroinflammation, and balanced enzymes regulating reactive oxygen species (Sod1, Sod2, Nox4). Of note, the FGFR1/AMPK/GLUT4 signaling pathway and brain glucose metabolism were inhibited. In summary, our study demonstrated that MR increased peripheral insulin sensitivity, activated brain FGFR1/AMPK/GLUT4 signaling through FGF21, maintained normal glucose metabolism and redox balance in the brain, and thereby alleviated DACI. These results provide new insights into the effects of MR diet on cognitive dysfunction caused by impaired brain energy metabolism.

中文翻译：

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蛋氨酸限制通过激活 FGF21 缓解糖尿病相关的认知障碍


葡萄糖代谢紊乱可能导致糖尿病相关认知能力下降 （DACI）。蛋氨酸限制 （MR） 饮食已成为管理葡萄糖稳态的潜在饮食策略。然而，MR 对 DACI 的影响和潜在机制尚未完全阐明。在这里，我们发现从 8 周龄开始的 13 周 MR （0.17% 蛋氨酸，w/w） 干预改善了雄性 db/db 小鼠（一种 2 型糖尿病模型）的外周胰岛素敏感性。值得注意的是，MR 显着改善了 db/db 小鼠的工作和长期记忆，同时增加了 PSD-95 水平并减少了神经炎症因子、丙二醛 （MDA） 和 8-羟基-2′-脱氧鸟苷 （8-OHdG）。我们推测这种作用可能是由 MR 激活肝成纤维细胞生长因子 21 （FGF21） 和脑 FGFR1/AMPK/GLUT4 信号通路增强脑葡萄糖代谢介导的。为了进一步阐明其机制，我们使用脑室内注射腺相关病毒特异性敲低大脑中的 FGFR1，以验证 FGFR1 在 MR 介导的 DACI 中的作用。研究发现，MR 对 DACI 的积极影响被抵消，反映在认知功能下降、突触可塑性受损、神经炎症上调以及调节活性氧的平衡酶 （Sod1、Sod2、Nox4）。值得注意的是，FGFR1/AMPK/GLUT4 信号通路和脑葡萄糖代谢受到抑制。综上所述，我们的研究表明，MR 增加了外周胰岛素敏感性，通过 FGF21 激活了大脑 FGFR1/AMPK/GLUT4 信号传导，维持了大脑中正常的葡萄糖代谢和氧化还原平衡，从而缓解了 DACI。 这些结果为 MR 饮食对脑能量代谢受损引起的认知功能障碍的影响提供了新的见解。