Decreased levels of estrogen associated with menopause have been linked to significant weight gain in women, increasing their risk of developing metabolic disorders including obesity, insulin resistance and diabetes. Recent studies suggest that hormone replacement therapy could help prevent weight gain and improve insulin sensitivity, as estrogen plays a critical role in the regulation of glucose homeostasis and lipid metabolism. However, data from clinical trials including women with a range of health conditions show conflicting results. In this study, we aimed to determine whether consumption of a high-fat diet that negatively affects the metabolic status prior to menopause could reduce the beneficial effects of hormone therapy on the metabolic outcomes after loss of estrogen. Nine-month-old female C57BL/6J mice and Long-Evans rats were used in this study. The animals were fed with either a high-fat diet (HFD, BioServ #F3282) or a control diet (LFD, BioServ #F4031) for 12 weeks, then ovariectomized (OVX). In a randomized manner, the animals received a silastic tube implant containing either 17β-estradiol (E2) or vehicle (VEH, cholesterol) and stayed on their respective diets for 8 additional weeks. Dual-energy X-ray Absorptiometry and glucose tolerance test were performed before (LFD, HFD) and in the four groups after OVX (HFD+VEH, HFD+E2, LFD+VEH, LFD+E2) to assess body composition and metabolic status. Twelve weeks of HFD resulted in increased body weight and fat mass, and induced glucose intolerance in mice and rats compared to LFD-fed animals. After ovariectomy, LFD-VEH mice and rats showed a significant weight gain and increase in fat mass compared to LFD-fed intact subjects. In addition, LFD-VEH mice showed elevated blood glucose and insulin levels and developed insulin resistance compared to LFD-fed intact mice; these changes were not observed in rats. Interestingly, no change in body weight, fat mass or blood glucose and insulin levels were observed in HFD-VEH animals after ovariectomy compared to HFD-fed intact subjects. Estradiol treatment was effective in preventing weight gain and significantly decreased fat mass in LFD-fed animals compared to intact subjects while leading to a significant reduction in body weight and a large decrease in fat mass in HFD-fed animals. A subset of mice was subjected to indirect calorimetry measurements. Our data showed that the respiratory exchange ratio (RER) was overall lower in HFD fed mice compared to LFD fed mice, which is consistent with the higher fat content of their diet. Interestingly, the RER was raised significantly in HFD fed mice after OVX, indicating an increased use of carbohydrates (or a decreased use of fatty acids) for producing energy; no change was observed in RER of LFD fed mice and E2 did not have a significant effect on RER regardless of the diet. Next, heat production was determined by analysis of covariance (ANCOVA) to correct for the difference in body weight between the groups. Heat production was not different between LFD fed and HFD fed intact mice; however, it was increased after OVX in HFD-VEH mice but not in LFD-VEH mice. Interestingly, E2 treatment after OVX increased heat production compared to intact mice, regardless of their diet. Finally, locomotor activity was decreased after OVX regardless of the diet, which was prevented in HFD fed mice but not in LFD fed mice. These results demonstrate that E2 treatment prevented the development of metabolic impairments following OVX in LFD-fed animals and improved the metabolic status of HFD-fed animals by promoting energy expenditure and resulting in decreased fat mass, blood glucose levels and increased insulin sensitivity. Funding: NIH P01AG071746 P1, P4 and PPG Cores. 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.
Desmoulins et al. (Fri,) studied this question.