Intermittent Fasting Alleviates Diabetes-Associated Cognitive Impairment Through FGF21-Mediated Lipid Remodeling and Mitochondrial Redox Regulation

Background: Cognitive impairment is a clinically relevant neurological complication of diabetes, yet its metabolic mechanisms remain incompletely understood. This study aimed to determine whether fibroblast growth factor 21 (FGF21), a fasting-responsive metabolic hormone, mediates the neuroprotective effects of intermittent fasting (IF) in diabetes-associated cognitive impairment, and to explore the underlying mechanisms. Methods: Streptozotocin (STZ)-induced type 1 diabetes-associated cognitive impairment (T1DCI) mice were used together with FGF21 genetic deletion and exogenous FGF21 supplementation. Cognitive function, neuronal injury, hippocampal lipid metabolism, mitochondrial function, protein acetylation, and SIRT3-associated deacetylation were evaluated. Results: IF significantly increased FGF21 levels in serum and hippocampus and improved cognitive deficits, whereas these effects were attenuated in FGF21-deficient mice. FGF21 supplementation improved cognitive performance and attenuated neuronal damage, accompanied by MAPK-related signaling changes. Lipidomic analysis revealed decreased phosphatidylcholine and triacylglycerols in the hippocampus of T1DCI mice, which were partially restored by FGF21. Consistently, FGF21 increased the expression of LPIN3, DGAT2, and CHPT1, key enzymes involved in PC and TAG biosynthesis. FGF21 also improved mitochondrial function and was associated with reduced protein acetylation, while SIRT3 inhibition attenuated these effects. Conclusions: These findings suggest that FGF21 contributes to the neuroprotective effects of IF in diabetes-associated cognitive impairment, potentially through coordinated regulation of lipid metabolism and mitochondrial function.