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

Abstract

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.

Figure 1. Estrogen regulation of intracellular brain metabolism pathways

Estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance glucose uptake and metabolism, aerobic glycolysis, tricarboxylic acid cycle (TCA)-coupled oxidative phosphorylation and ATP generation. In parallel, E₂ increases antioxidant defense and antiapoptotic mechanisms. Estrogen receptors at the membrane, in mitochondria and within the nucleus are well positioned to regulate coordinated mitochondrial and nuclear gene expression required for optimal bioenergetics.

Figure 2. Estrogen regulation of bioenergetic system

Estrogen regulates many of the key enzymes involved in mitochondrial bioenergetics, including glucose transporters, hexokinase (HK), pyruvate dehydrogenase (PDH), aconitase (Aco2), alpha ketoglutarate dehydrogenase (aKGDH), succinate dehydrogenase (SDH), and Complexes I, III, and IV of the electron transport chain.

Figure 3. Estrogen regulation of whole-body metabolism

Estrogen receptors are expressed throughout peripheral systems involved in metabolism. Estrogen affects adipose tissue distribution and risk of obesity, insulin resistance and risk of diabetes, and concentration of the adipokines leptin, ghrelin, and adiponectin. Loss of estrogen at menopause leads to significant changes in many of these systems, which can be stabilized with the use of hormone therapy. Adverse metabolic profiles, e.g. type 2 diabetes and metabolic syndrome, can increase risk of developing Alzheimer’s disease.