Estrogen: A master regulator of bioenergetic systems in the brain and body

• Estrogen regulates and integrates the metabolic system of the female brain and body.
• Estrogen decline coincides with compromised metabolic phenotype of the brain.
• Bioenergetic adaptations to estrogen loss could determine Alzheimer’s risk.
• Metabolic biomarker profiles could identify at-risk populations.
• Biomarker profiles can serve as indicators of therapeutic efficacy.

Estrogen is a fundamental regulator of the metabolic system of the female brain and body. Within the brain, estrogen regulates glucose transport, aerobic glycolysis, and mitochondrial function to generate ATP. In the body, estrogen protects against adiposity, insulin resistance, and type II diabetes, and regulates energy intake and expenditure. During menopause, decline in circulating estrogen is coincident with decline in brain bioenergetics and shift towards a metabolically compromised phenotype. Compensatory bioenergetic adaptations, or lack thereof, to estrogen loss could determine risk of late-onset Alzheimer’s disease. Estrogen coordinates brain and body metabolism, such that peripheral metabolic state can indicate bioenergetic status of the brain. By generating biomarker profiles that encompass peripheral metabolic changes occurring with menopause, individual risk profiles for decreased brain bioenergetics and cognitive decline can be created. Biomarker profiles could identify women at risk while also serving as indicators of efficacy of hormone therapy or other preventative interventions.