Menopause in humans is associated with reduced resting metabolic rate (RMR), accelerated adipose gains, and increased risk of various cardiometabolic diseases. Modeling menopause in rodents is difficult, as rodents do not naturally undergo menopause. Chemical treatment with 4-vinylcyclohexene diepoxide (VCD) induces progressive ovarian failure in rodents, paralleling the hormonal changes that occur in the transition from perimenopause to menopause in humans. To date only a small number of studies have used VCD treatment in rodents to study metabolic consequences, but these studies are inconsistent with regard to environmental factors such as ambinet temperature and diet. The objective of this project was to optimize the translational relevance of VCD-induced ovarian failure in rodents as a model of the metabolic effects of menopause. We hypothesized that VCD treatment would suppress RMR and increase adipose gains, mimicking what occurs in women transitioning through menopause, and that diet formulation would modify the development of metabolic phenotypes in this model. Female C57BL/6J mice were housed with nesting materials at 22-23°C and randomized to one of four treatment groups (n=10 each) based upon the combination of VCD or sesame oil (SO) vehicle, and the supply of either corn/soy-based PicoLab 5L0D (contains phytoestrogens) vs wheat/corn-based Inotiv 2920x (minimal phytoestrogens) diets. Starting at 12 weeks of age, mice were injected daily for 20 days with SO or VCD (160 mg/kg/d, ip). At 12, 17, 22, & 27 weeks of age (=0, +35, +70, & +105d after VCD start) mice underwent metabolic phenotyping, including analyses of body composition (nuclear magnetic resonance, NMR, Bruker) and multiplexed home-cage (Promethion, Sable Systems Int’l) and metabolic caging (Tecniplast) measures of energy expenditure, intake behaviors, and physical activity. Estrous cycling, by cytology, stopped after 58±3 (2920x) vs 52±3 (5L0D) days after VCD start (p< 0.05). Body mass and composition were similar across all groups until cycling stopped. Thereafter, VCD caused accelerated weight gain in mice fed 5L0D (+42±3 vs +23±2 mg/d, p< 0.05) due to excess fat gain, while VCD had no significant modulatory effect upon total or fat masses in mice fed 2920x. VCD had no effects on food intake or digestive efficiency, regardless of diet. In contrast, VCD caused a sustained (through +35, +70, and +105d) suppression of resting (-11%, p< 0.05), and thus total (0.41±0.01 vs 0.45±0.01 kcal/h, p< 0.05) energy expenditure (EE) in mice fed 5L0D, versus only a transient suppression of activity-dependent EE in mice fed 2920x. These findings confirm the utility of VCD in rodents to model metabolic changes that are observed with menopause in humans, but simultaneously highlight the significant modulatory impact of diet formulation upon phenotype development. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Dorrington et al. (Fri,) studied this question.