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

Author(s):Show less -

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

• Document type: Journal article
• Source: JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES; v. 72, n. 1, p. 3-15, JAN 2017.
• Web of Science Citations: 20

Abstract

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. (AU)

• FAPESP's process: 15/05801-7 - Investigation of 17 alfa-estradiol´s role in increasing inflammation in the central nervous system
• Grantee: Roberta de Souza Santos
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor