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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 &amp;lt; 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\/GSK3\u03b2 signaling pathway (with increases of 46%, 49%, and 50% in p-PI3K, p-Akt, and p-GSK-3\u03b2 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.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c04686","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:01:47Z","timestamp":1790971307000},"page":"31601-31615","source":"Crossref","is-referenced-by-count":0,"title":["Quercetin Ameliorates\nCognitive Impairment in Obese\nMice by Activating the PI3K\/AKT\/GSK3\u03b2 Signaling Pathway via\nthe Microbiota\u2013Gut\u2013Brain Axis"],"prefix":"10.1021","volume":"74","author":[{"given":"Wenxuan","family":"Li","sequence":"first","affiliation":[{"name":"Shandong Agricultural University , , ,","place":["Taian, China, 271018"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Pei","sequence":"additional","affiliation":[{"name":"The Affiliated Taian City Central Hospital of Qingdao University , , ,","place":["Taian, Shandong, China, 271000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junteng","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Agricultural University , , ,","place":["Taian, China, 271018"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shandong Agricultural University , , ,","place":["Taian, China, 271018"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2054-6823","authenticated-orcid":true,"given":"Wenyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shandong Agricultural University , , ,","place":["Taian, China, 271018"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Shandong Agricultural University , , ,","place":["Taian, China, 271018"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingxu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Shandong Agricultural University , , ,","place":["Taian, China, 271018"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[{"name":"Shandong Agricultural University , , ,","place":["Taian, China, 271018"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Xiao","sequence":"additional","affiliation":[{"name":"University of Massachusetts , , , ,","place":["Amherst, Massachusetts, United States, 01003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1816-3217","authenticated-orcid":true,"given":"Dapeng","family":"Li","sequence":"additional","affiliation":[{"name":"Shandong Agricultural University , , ,","place":["Taian, China, 271018"]},{"name":"University of Massachusetts , , , ,","place":["Amherst, Massachusetts, United States, 01003"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"issue":"5","key":"2026101408091766100_cit1","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1038\/s41574-019-0176-8","article-title":"Obesity: global\nepidemiology and pathogenesis","volume":"15","author":"Blu\u0308her","year":"2019","journal-title":"Nat. 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