Pre-Existing Metabolic Conditions Impair the Beneficial Effects of Estrogen on Memory and Cognition in Ovariectomized Mice

Loss of estrogen, as a result of menopause, has been associated with cognitive decline and memory loss. Intriguingly, studies conducted with postmenopausal healthy women suggest that hormone replacement therapy improves cognitive functions. In contrast, clinical data involving subjects with a wide range of health conditions indicate that the effect of estrogen treatment varies. In addition to the cognitive decline, postmenopausal women have an increased risk of developing metabolic disorders including obesity, insulin resistance, and diabetes. In this study, we tested the hypothesis that pre-existing metabolic conditions reduce the beneficial effects of estradiol treatment and are responsible for the conflicting findings in cognitive functions after menopause. Female, seven-month-old C57BL/6J mice were fed with either a high-fat diet (HFD, BioServ #F3282) or a control diet (LFD, BioServ #F4031) for 10 to 14 weeks, then ovariectomized (OVX). In a randomized manner, mice received a silastic tube implant containing either 17β-estradiol (E2) or vehicle (VEH, cholesterol) and stayed on their respective diets. Body composition and metabolic parameters were measured in the four groups (HFD+VEH, HFD+E2, LFD+VEH, LFD+E2) to assess metabolic status, and novel object recognition test was performed to assess memory and cognition. Before OVX, HFD fed mice had significantly increased body weight, fat mass, basal blood glucose and insulin levels compared to mice fed with LFD. After OVX, LFD-VEH mice developed obesity and had elevated blood glucose and insulin levels, whereas E2 treatment prevented the metabolic changes. Interestingly, HFD-VEH mice had a reduction in fat mass after OVX, which was further decreased with E2 treatment. Overall, mice treated with E2 had lower body weight, fat mass, blood glucose and insulin levels compared to VEH treated mice regardless of their diet, and HFD fed mice had a higher body weight than mice fed the LFD, irrespective of their treatment. The novel object recognition test revealed that LFD-E2 mice spent significantly more time exploring the novel object than LFD-VEH mice. In contrast, there was no difference in exploration time between HFD-VEH and HFD-E2 treated mice. These preliminary results suggest that 1) E2 treatment may be beneficial to prevent the development of metabolic changes and improve cognitive function in LFD fed mice; 2) OVX alone did not worsen the metabolic status of diet-induced obese mice; 3) E2 treatment partially improved the metabolic status of HFD fed mice by decreasing fat mass, blood glucose and insulin levels; and 4) E2 treatment did not improve memory and cognition of HFD fed mice. Source of funding: P01AG071746 8456. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.