High‐fat diet attenuates estradiol's efficacy on cognitive function and hippocampal synaptic plasticity in middle‐aged ovariectomized mice

Loss of circulating ovarian hormones during menopause is associated with increased risk for cognitive decline in women. Although estradiol has been shown to enhance memory and synaptic function in preclinical studies, clinical studies of hormone therapy in menopausal women are less clear, and its efficacy may be diminished in the context of metabolic dysfunction. This study investigated whether high-fat diet-induced obesity impairs the beneficial effects of estradiol on hippocampus-dependent memory and synaptic plasticity in middle-aged, ovariectomized female mice. Female C57BL/6J mice were fed a low-fat or high-fat diet starting at 9-10 months of age and underwent ovariectomy at approximately 12 months followed by treatment with 17β-estradiol or vehicle. Spatial memory was assessed using the novel object location task. Long-term potentiation was measured in acute hippocampus slices via field recordings at the Schaffer collateral-CA1 synapses. Estradiol treatment significantly improved spatial memory, but the effect of estradiol was attenuated by approximately 36% in high-fat diet-fed mice. Estradiol also significantly enhanced long-term potentiation in slices from low-fat diet-fed mice but had no effect in high-fat diet-fed mice. These findings suggest that high-fat diet may interfere with the neuroprotective mechanisms of estrogen within the hippocampus and highlight the importance of metabolic health status in determining the efficacy of hormone therapy during aging.