17α-estradiol alleviates age-related metabolic and inflammatory dysfunction in male mice without inducing feminization

Michael B. Stout, Frederik J. Steyn, Michael J. Jurczak, Joao Paulo G Camporez, Yi Zhu, John R Hawse, Diana Jurk, Allyson K. Palmer, Ming Xu, Tamar Pirtskhalava, Glenda L. Evans, Roberta De Souza Santos, Aaron P. Frank, Thomas A. White, David G Monroe, Ravinder Jit Singh, Grace Casaclang-Verzosa, Jordan D Miller, Deborah J. Clegg, Nathan K LeBrasseurThomas Von Zglinicki, Gerald I. Shulman, Tamara Tchkonia, James L Kirkland

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Aging is associated with visceral adiposity, metabolic disorders, and chronic low-grade inflammation. 17α-estradiol (17α-E2), a naturally occurring enantiomer of 17α-estradiol (17α-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 AMPK? 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.

Original languageEnglish (US)
Pages (from-to)3-15
Number of pages13
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume72
Issue number1
DOIs
StatePublished - 2017

    Fingerprint

Keywords

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

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

Cite this

Stout, M. B., Steyn, F. J., Jurczak, M. J., Camporez, J. P. G., Zhu, Y., Hawse, J. R., Jurk, D., Palmer, A. K., Xu, M., Pirtskhalava, T., Evans, G. L., De Souza Santos, R., Frank, A. P., White, T. A., Monroe, D. G., Singh, R. J., Casaclang-Verzosa, G., Miller, J. D., Clegg, D. J., ... Kirkland, J. L. (2017). 17α-estradiol alleviates age-related metabolic and inflammatory dysfunction in male mice without inducing feminization. Journals of Gerontology - Series A Biological Sciences and Medical Sciences, 72(1), 3-15. https://doi.org/10.1093/gerona/glv309