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Mechanistic dissection of the changes in RMR control across the menopause transition is difficult because rodent models do not naturally undergo menopause. Although rodents lack a natural menopause, chemical treatment with 4-vinylcyclohexene diepoxide (VCD) induces progressive ovarian failure, paralleling the complex hormonal alterations across perimenopause and menopause that occur in humans. To explore the impact of diet upon cardiometabolic phenotype development in this experimental model of menopause, young adult (10-12wk old) female C57BL\/6J mice were fed either PicoLab 5L0D (corn\/soy-based, phytoestrogen-containing) or Inotiv 2920x (wheat\/corn-based, phytoestrogen-free) diets and treated with VCD (160mg\/kg\/d for 20d) or sesame oil vehicle. In mice fed 5L0D, VCD caused a reduction in RMR and thereby total energy expenditure which was followed by exaggerated adipose gains, despite no changes in food intake. In contrast, in mice fed 2920x, VCD modestly suppressed activity-dependent expenditure but had no effects on RMR, food intake, or adiposity. VCD had no significant modulatory effects upon sodium intake behaviors, digestive efficiency, or endothelial-dependent vascular relaxation in mice fed either diet, though diet alone did influence these endpoints. Together, these findings demonstrate that diet composition significantly modifies the development of cardiometabolic phenotypes in the VCD rodent model of menopause. Future studies utilizing VCD-induced ovarian failure in rodents to model menopause must carefully consider the modulatory effect of diet formulation upon phenotype development, and thereby the translational relevance of results.<\/jats:p>","DOI":"10.1152\/ajpregu.00321.2025","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:10:34Z","timestamp":1790874634000},"update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Diet Composition Modifies Cardiometabolic Phenotype Development in the 4-Vinylcyclohexene Dioxide (VCD) Ovarian Failure Model of Menopause"],"prefix":"10.1152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4414-8798","authenticated-orcid":false,"given":"Natalia M.","family":"Mathieu","sequence":"first","affiliation":[{"name":"Medical College of Wisconsin"},{"name":"Medical College of 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