期刊
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
卷 72, 期 1, 页码 3-15出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/gerona/glv309
关键词
17 alpha-Estradiol; Adipose tissue; Hypothalamus; Inflammation; Metabolism
资金
- National Institutes of Health [P01 AG041122]
- Robert and Arlene Kogod Career Development Award in Aging Research
- Minnesota Obesity Center [P30 DK050456]
- FAPESP [2015/05801-7]
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR001863] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL111121] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [K01DK099402] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [K99AG051661, R37AG013925, P01AG041122, F30AG046061] Funding Source: NIH RePORTER
- Biotechnology and Biological Sciences Research Council [BB/I020748/1] Funding Source: researchfish
- BBSRC [BB/I020748/1] Funding Source: UKRI
Aging is associated with visceral adiposity, metabolic disorders, and chronic low-grade inflammation. 17 alpha-estradiol (17 alpha-E2), a naturally occurring enantiomer of 17 beta-estradiol (17 beta-E2), extends life span in male mice through unresolved mechanisms. We tested whether 17 alpha-E2 could alleviate age-related metabolic dysfunction and inflammation. 17 alpha-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 17 alpha-E2 on nutrient-sensing pathways in visceral adipose tissue. 17 alpha-E2 did not alter energy expenditure or excretion. Fasting glucose, insulin, and glycosylated hemoglobin were also reduced by 17 alpha-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 17 alpha-E2. 17 alpha-E2 increased AMPK alpha 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, 17a-E2 holds potential as a novel therapeutic for alleviating age-related metabolic dysfunction through tissue-specific effects.
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