Intermittent fasting (IF) is an ecological strategy to control various metabolic disorder symptoms, but its protective effect on type 1 diabetes (T1D)-induced cognitive dysfunction and the underlying mechanisms remain poorly defined. Herein, we examined the efficacy of IF in altering the behaviors and brain metabolome in T1D mice and investigated the potential molecular mechanisms. We demonstrated that IF remarkably improved frontal cortical-dependent memory in T1D mice and reduced the loss of neuronal cells. Metabolomics and targeted mass spectrometry assays showed that IF reprogrammed the composition of the frontal cortical metabolome in T1D mice, including activating the aspartate and glutamate pathway and reversing glycerophospholipid and sphingolipid depositions. Mechanistically, IF attenuated the levels of oxidative stress proteins, like NOX2, NOX4, 8-OHdG, and 4-HNE, and inhibited the levels of pro-apoptotic factors Bax and cleaved Caspase-3, ultimately improving the memory ability of T1D mice. In vitro studies confirmed the protective effect of the supplemented N-acetylaspartate, a pivotal metabolite involved in IF-regulated T1D-induced cognitive dysfunction, in high glucose-stimulated SH-SY5Y cells by eliminating toxic lipids accumulation, oxidative stress, and apoptosis. To conclude, the frontal cortical metabolites mediated the protective effects of IF against T1D-induced cognitive dysfunction by attenuating oxidative stress and apoptotic signaling. Thus, IF can be a potential therapeutic strategy for T1D-induced cognitive dysfunction.
Keywords: Apoptosis; Cognitive dysfunction; Intermittent fasting; Metabolomics; Oxidative stress; Type 1 diabetes.
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