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Although estradiol has been shown to enhance memory and synaptic function in preclinical studies, clinical studies of hormone therapy in menopausal women are less clear, and its efficacy may be diminished in the context of metabolic dysfunction. This study investigated whether high\u2010fat diet\u2010induced obesity impairs the beneficial effects of estradiol on hippocampus\u2010dependent memory and synaptic plasticity in middle\u2010aged, ovariectomized female mice. Female C57BL\/6J mice were fed a low\u2010fat or high\u2010fat diet starting at 9\u201310\u2009months of age and underwent ovariectomy at approximately 12\u2009months followed by treatment with 17\u03b2\u2010estradiol or vehicle. Spatial memory was assessed using the novel object location task. Long\u2010term potentiation was measured in acute hippocampus slices via field recordings at the Schaffer collateral\u2010CA1 synapses. Estradiol treatment significantly improved spatial memory, but the effect of estradiol was attenuated by approximately 36% in high\u2010fat diet\u2010fed mice. Estradiol also significantly enhanced long\u2010term potentiation in slices from low\u2010fat diet\u2010fed mice but had no effect in high\u2010fat diet\u2010fed mice. These findings suggest that high\u2010fat diet may interfere with the neuroprotective mechanisms of estrogen within the hippocampus and highlight the importance of metabolic health status in determining the efficacy of hormone therapy during aging.<\/jats:p>","DOI":"10.14814\/phy2.70867","type":"journal-article","created":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T06:13:44Z","timestamp":1775888024000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["High\u2010fat diet attenuates estradiol's efficacy on cognitive function and hippocampal synaptic plasticity in middle\u2010aged ovariectomized mice"],"prefix":"10.14814","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6440-6286","authenticated-orcid":false,"given":"V.","family":"Felintro","sequence":"first","affiliation":[{"name":"Department of Cell and Molecular Biology Tulane University  New Orleans Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. 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