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J Gerontol A Biol Sci Med Sci. 2017 Jan;72(1):3-15. Epub 2016 Jan 24.

17α-Estradiol Alleviates Age-related Metabolic and Inflammatory Dysfunction in Male Mice Without Inducing Feminization.

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Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.
Center for Clinical Research and School of Biomedical Sciences, University of Queensland, Herston, Australia.
Division of Endocrinology and Metabolism, University of Pittsburgh, Pennsylvania.
Department of Internal Medicine, Yale University, New Haven, Connecticut.
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
Institutes for Cell & Molecular Biosciences and Ageing, Newcastle University.
Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Beverly Hills, California.
Department of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota.
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut.
Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.


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.


17α-Estradiol; Adipose tissue; Hypothalamus; Inflammation; Metabolism

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