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Life sciences · Journal article
Nutrients · October 21, 2026
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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 (αKO) and ERb knockout (βKO) mice differentially respond to ovariectomy, with a greater adverse metabolic response in βKO mice. We later showed that young ovariectomized (OVX) βKO 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 αKO and βKO 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 αKO mice would be less responsive to the systemic metabolic benefits of SOY, whereas βKO mice would be less responsive to adipocyte-specific benefits. Methods: We examined OVX and ovary-intact aged (~1 yr) wildtype (WT), αKO, and βKO female mice (n = 7–12/group). One week following OVX, mice were randomized to receive either SOY (585 mg phytoestrogens/kg) or a phytoestrogen-free diet (<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 αKO 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 βKO mice (all p < 0.05). Primary adipocyte cell culture experiments revealed that insulin-mediated phosphorylation of Akt occurred even with ERα-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 ERα-null mice. Soy-based diets may improve metabolic health in settings of ovarian hormone suppression via mechanisms requiring estrogen signaling pathway activation.