{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T04:40:09Z","timestamp":1792730409571,"version":"4.5.0"},"reference-count":55,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Center for Complementary and Integrative Health"},{"name":"the Office of Dietary Supplements","award":["P50AT006273"],"award-info":[{"award-number":["P50AT006273"]}]},{"award":["P50AT006273"],"award-info":[{"award-number":["P50AT006273"]}],"id":[{"id":"https:\/\/ror.org\/01wtjyf13","id-type":"ROR","asserted-by":"publisher"}]},{"name":"MU-CBIS pilot grant and the MU Research Council"},{"name":"NIH","award":["K01 HL-125503"],"award-info":[{"award-number":["K01 HL-125503"]}]},{"name":"NIH","award":["DK059637"],"award-info":[{"award-number":["DK059637"]}]},{"name":"NIH","award":["DK020593"],"award-info":[{"award-number":["DK020593"]}]},{"award":["K01 HL-125503"],"award-info":[{"award-number":["K01 HL-125503"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DK059637"],"award-info":[{"award-number":["DK059637"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DK020593"],"award-info":[{"award-number":["DK020593"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Loss of ovarian hormones leads to obesity and insulin resistance (IR), increasing the risk of cardiovascular and metabolic diseases. We previously showed that aged female ERa knockout (\u03b1KO) and ERb knockout (\u03b2KO) mice differentially respond to ovariectomy, with a greater adverse metabolic response in \u03b2KO mice. We later showed that young ovariectomized (OVX) \u03b2KO mice were somewhat resistant to exercise-mediated metabolic benefits including adipose tissue browning. Background\/Objectives: We tested the hypothesis that feeding a high phytoestrogen soy-based diet (SOY) would improve metabolic health in older OVX female mice and that \u03b1KO and \u03b2KO mice would differentially respond to the diet. Since phytoestrogens weakly bind ERs, and it is known that activation of ERa mediates insulin sensitizing and weight loss benefits, and ERb is known to improve adipocyte mitochondrial responses, we hypothesized that \u03b1KO mice would be less responsive to the systemic metabolic benefits of SOY, whereas \u03b2KO mice would be less responsive to adipocyte-specific benefits. Methods: We examined OVX and ovary-intact aged (~1 yr) wildtype (WT), \u03b1KO, and \u03b2KO female mice (n = 7\u201312\/group). One week following OVX, mice were randomized to receive either SOY (585 mg phytoestrogens\/kg) or a phytoestrogen-free diet (&lt;15 mg\/kg, CON) and were followed for 11 weeks. Mice were assessed for body composition (EchoMRI), energy expenditure (EE via Promethion metabolic cage system), glucose tolerance (i.p. glucose tolerance test), insulin sensitivity (HOMA-IR, Adipo-IR), adipose tissue gene and protein expression for insulin signaling markers, and fasting blood lipids. To provide additional mechanistic insight, primary adipocytes were treated with phytoestrogens and assessed for insulin-mediated phosphorylation of Akt. Results: Era mediated important metabolic benefits of SOY in aged OVX mice. OVX \u03b1KO mice were unresponsive to SOY-mediated improvements in body composition and glucose tolerance, whereas SOY improved those metrics, as well as increased spontaneous physical activity in OVX WT and \u03b2KO mice (all p &lt; 0.05). Primary adipocyte cell culture experiments revealed that insulin-mediated phosphorylation of Akt occurred even with ER\u03b1-antagonization, with no effects of estrogen or phytoestrogen treatment, at least in the small set of experiments performed. Conclusions: SOY improved body composition and glucose tolerance in old OVX mice, effects that were absent in ER\u03b1-null mice. Soy-based diets may improve metabolic health in settings of ovarian hormone suppression via mechanisms requiring estrogen signaling pathway activation.<\/jats:p>","DOI":"10.3390\/nu18203451","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T10:20:38Z","timestamp":1792578038000},"page":"3451","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Estrogen Receptor-Mediated Effects of a Phytoestrogen-Rich Soy-Based Diet on Metabolic Health Following Ovariectomy in Aged Mice"],"prefix":"10.3390","volume":"18","author":[{"given":"Terese M.","family":"Zidon","sequence":"first","affiliation":[{"name":"Division of Food, Nutrition and Exercise Sciences, College of Agriculture, Food, and Natural Resources, University of Missouri, Columbia, MO 65211, USA"},{"name":"Biology Department, Central Methodist University, Fayette, MO 65248, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8297-7995","authenticated-orcid":false,"given":"Young-Min","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Health and Kinesiology, Sport Science Institute & Sports Functional Disability Institute, Incheon National University, Incheon 22012, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Dennis B.","family":"Lubahn","sequence":"additional","affiliation":[{"name":"Division of Food, Nutrition and Exercise Sciences, College of Agriculture, Food, and Natural Resources, University of Missouri, Columbia, MO 65211, USA"},{"name":"Department of Biochemistry, College of Agriculture, Food, and Natural Resources, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7563-0806","authenticated-orcid":false,"given":"Victoria J.","family":"Vieira-Potter","sequence":"additional","affiliation":[{"name":"Division of Food, Nutrition and Exercise Sciences, College of Agriculture, Food, and Natural Resources, University of Missouri, Columbia, MO 65211, 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