Quercetin Ameliorates Cognitive Impairment in Obese Mice by Activating the PI3K/AKT/GSK3β Signaling Pathway via the Microbiota–Gut–Brain Axis

Abstract Obesity and its associated insulin resistance are important risk factors for cognitive impairment. In this study, a 10-week C57BL/6 mouse model was established to investigate the effects of dietary quercetin supplementation at 0.05% (w/w) on HFFD-induced obesity-related cognitive impairment. The results showed that quercetin significantly reduced HFFD-induced body weight gain (P < 0.05) and improved serum lipid abnormalities and cognitive performance. Integrated multi-omics analysis further revealed that quercetin reshaped the gut microbiota composition, notably increasing Akkermansia muciniphila, restored intestinal barrier function, and regulated serum metabolite profiles. These alterations subsequently suppressed neuroinflammation, activated the hippocampal PI3K/AKT/GSK3β signaling pathway (with increases of 46%, 49%, and 50% in p-PI3K, p-Akt, and p-GSK-3β expression, respectively), and inhibited abnormal tau phosphorylation and neuronal apoptosis. The novelty of this study lies in constructing an integrated regulatory axis linking dietary quercetin, gut microbiota, serum metabolites, and hippocampal insulin signaling, providing novel mechanistic insights into quercetin in neuro-metabolic diseases.