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.
Keywords: 17b-estradiol unless otherwise specified; 3xTgAD; AD; Adipokine; Adipose tissue; Aging; Alzheimer’s disease; ArKO; Aβ; BMI; Biomarker; CEE; CMRglu; COX; CSF; DPN; E(1); E(2); E(3); ER; ERE; ERα; ERα knockout; ERβ; Estrogen; FDG; HOMA-IR; HT; IDE; IGF-1; IGF-1R; IR; Insulin; MCI; MMSE; MPA; Menopause; Metabolism; Mitochondria; OVX; OXPHOS; PDH; PET; PPT; ROS; SHBG; T2DM; TCA; Type 2 diabetes; Type II diabetes mellitus; VaD; amyloid beta(1–42), beta-amyloid; aromatase knockout; body-mass index; cerebral metabolic rate of glucose uptake; cerebrospinal fluid; complex IV; conjugated equine estrogen; diarylpropionitrile (an ERβ-selective agonist); estradiol, 17β-estradiol; estriol; estrogen receptor; estrogen receptor alpha, also referred to as ESR1; estrogen receptor beta, also referred to as ESR2; estrogen response element; estrone; fluorodeoxyglucose; homeostatic assessment of insulin resistance; hormone therapy; insulin degrading enzyme; insulin growth factor-1; insulin growth factor-1 receptor; insulin receptor; mER; medroxyprogesterone acetate; membrane associated estrogen receptor; mild cognitive impairment; mini-mental state exam; mitochondrial DNA; mtDNA; ovariectomized, ovariectomy; oxidative phosphorylation; positron emission tomography; propylpyrazoletriol (an ERα-selective agonist); pyruvate dehydrogenase; rCBF; reactive oxygen species; regional cerebral blood flow; sex hormone-binding globulin; tricarboxylic citric acid; triple-transgenic mouse model of Alzheimer’s disease; vascular dementia; α-ketoglutarate dehydrogenase; αERKO; αKGDH.
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