title: 17α-Estradiol Alleviates Age-related Metabolic and Inflammatory Dysfunction in Male Mice Without Inducing Feminization.
abstract: 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.
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Stout
authors.affiliation: Center for Clinical Research and School of Biomedical Sciences, University of Queensland, Herston, Australia.
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Steyn
authors.affiliation: Division of Endocrinology and Metabolism, University of Pittsburgh, Pennsylvania.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.affiliation: Department of Internal Medicine, Yale University, New Haven, Connecticut.
authors.forename: Joao-Paulo G
authors.initials: JG
authors.lastname: Camporez
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
authors.forename: John R
authors.initials: JR
authors.lastname: Hawse
authors.affiliation: Institutes for Cell & Molecular Biosciences and Ageing, Newcastle University.
authors.forename: Diana
authors.initials: D
authors.lastname: Jurk
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.
authors.forename: Allyson K
authors.initials: AK
authors.lastname: Palmer
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.
authors.forename: Tamar
authors.initials: T
authors.lastname: Pirtskhalava
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.
authors.forename: Glenda L
authors.initials: GL
authors.lastname: Evans
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Beverly Hills, California.
authors.forename: Roberta
authors.initials: R
authors.lastname: de Souza Santos
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Beverly Hills, California.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Frank
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: White
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.
authors.forename: David G
authors.initials: DG
authors.lastname: Monroe
authors.affiliation: Department of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ravinder J
authors.initials: RJ
authors.lastname: Singh
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.
authors.forename: Grace
authors.initials: G
authors.lastname: Casaclang-Verzosa
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Miller
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Beverly Hills, California.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Clegg
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.
authors.forename: Nathan K
authors.initials: NK
authors.lastname: LeBrasseur
authors.affiliation: Institutes for Cell & Molecular Biosciences and Ageing, Newcastle University.
authors.forename: Thomas
authors.initials: T
authors.lastname: von Zglinicki
authors.affiliation: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.
authors.forename: Tamara
authors.initials: T
authors.lastname: Tchkonia
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota. kirkland.james@mayo.edu.
authors.forename: James L
authors.initials: JL
authors.lastname: Kirkland
mesh_terms: D050154:Adiposity / Q000187:drug effects*; D000375:Aging / Q000502:physiology*; D000818:Animals; D015992:Body Mass Index; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005262:Feminization; D050152:Intra-Abdominal Fat / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D004967:Estrogens; D004958:Estradiol
keywords: 17α-Estradiol; Adipose tissue; Hypothalamus; Inflammation; Metabolism
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