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Aging is associated with visceral adiposity, metabolic disorders, and chronic low-grade inflammation. 17α-estradiol (17α-E2), a naturally occurring enantiomer of 17β-estradiol (17β-E2), extends life span in male mice through unresolved mechanisms. We tested whether 17α-E2 could alleviate age-related metabolic dysfunction and inflammation. 17α-E2 reduced body mass, visceral adiposity, and ectopic lipid deposition without decreasing lean mass. These declines were associated with reductions in energy intake due to the activation of hypothalamic anorexigenic pathways and direct effects of 17α-E2 on nutrient-sensing pathways in visceral adipose tissue. 17α-E2 did not alter energy expenditure or excretion. Fasting glucose, insulin, and glycosylated hemoglobin were also reduced by 17α-E2, and hyperinsulinemic-euglycemic clamps revealed improvements in peripheral glucose disposal and hepatic glucose production. Inflammatory mediators in visceral adipose tissue and the circulation were reduced by 17α-E2. 17α-E2 increased AMPKα and reduced mTOR complex 1 activity in visceral adipose tissue but not in liver or quadriceps muscle, which is in contrast to the generalized systemic effects of caloric restriction. These beneficial phenotypic changes occurred in the absence of feminization or cardiac dysfunction, two commonly observed deleterious effects of exogenous estrogen administration. Thus, 17α-E2 holds potential as a novel therapeutic for alleviating age-related metabolic dysfunction through tissue-specific effects., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Menopause-related withdrawal of ovarian estrogens is associated with reduced energy metabolism and overall impairment of substrate oxidation. Estradiol's withdrawal after menopause is associated with a reduction in energy metabolism and impaired substrate oxidation, which contributes to weight gain and visceral fat accumulation. Here we aimed to investigate the association between plasma estradiol concentrations and energy expenditure (EE)/substrate oxidation in a group of overweight postmenopausal women before and after a fatty meal challenge. Women were divided into three groups according to their plasma estradiol concentrations (E2): group 1 - E 2  ≤ 39, group 2 - 40 ≤ E 2  ≤ 59, and group 3 - E 2  ≥ 60 pg/mL. VO 2 and VCO 2 volumes were collected following indirect calorimetry 5 h following a single lipid overload meal (1100 kcal, 72% of fat). For comparisons between groups and within the same group, a linear regression model with mixed effects was applied (P < 0.05). Forty-four women aged 55 ± 0.7 years-old, 8 ± 1.1 years following menopause, with a BMI of 30.5 ± 0.5 kg/m 2 , and 41.9 ± 0.7% of body fat were enrolled the study. Plasma E2 concentrations were: group 1 - 30.4 ± 1.9, group 2 - 46.9 ± 1.5, and group 3 - 91.3 ± 12.0 pg/mL (P < 0.0001). EE at baseline and in the resting state was 1320 ± 24.3 kcal/d, and increased to 1440 ± 27.0 kcal/d 30 min following ingestion of the fatty meal (P < 0.0001), and rose again to an average of 1475 ± 30.3 kcal/d at the completion of experiment (P < 0.0001). Carbohydrate oxidation (Chox) was 0.155 ± 0.01 g/min at resting, maintained as 0.133 ± 0.00 g/min 30 min after ingestion of the fatty meal, and was 0.123 ± 0.01 g/min at the end of the testing period. Lipid oxidation (Lipox) was 0.041 ± 0.003 g/min at resting, increasing to 0.054 ± 0.003 g/min at 30 min (P = 0.01), and reaching 0.063 ± 0.003 g/min at the end of the experiment (P < 0.0001). There was no difference between groups for EE, Chox or Lipox. Our data suggest that EE and substrate oxidation were modulated following a lipid-meal challenge equally in all groups and this did not differ with plasma E2 concentrations., (Copyright © 2016 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)