Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice. Academic Article uri icon

Overview

abstract

  • In addition to its role in reproduction, estradiol-17β is critical to the regulation of energy balance and body weight. Estrogen receptor α-null (Erα-/-) mutant mice develop an obese state characterized by decreased energy expenditure, decreased locomotion, increased adiposity, altered glucose homeostasis, and hyperleptinemia. Such features are reminiscent of the propensity of postmenopausal women to develop obesity and type 2 diabetes. The mechanisms by which ERα signaling maintains normal energy balance, however, have remained unclear. Here we used knockin mice that express mutant ERα that can only signal through the noncanonical pathway to assess the role of nonclassical ERα signaling in energy homeostasis. In these mice, we found that nonclassical ERα signaling restored metabolic parameters dysregulated in Erα-/- mutant mice to normal or near-normal values. The rescue of body weight and metabolic function by nonclassical ERα signaling was mediated by normalization of energy expenditure, including voluntary locomotor activity. These findings indicate that nonclassical ERα signaling mediates major effects of estradiol-17β on energy balance, raising the possibility that selective ERα agonists may be developed to reduce the risks of obesity and metabolic disturbances in postmenopausal women.

authors

  • Park, Cheryl J
  • Zhao, Zhen
  • Glidewell-Kenney, Christine
  • Lazic, Milos
  • Chambon, Pierre
  • Krust, Andrée
  • Weiss, Jeffrey
  • Clegg, Deborah J
  • Dunaif, Andrea
  • Jameson, J Larry
  • Levine, Jon E

publication date

  • January 18, 2011

Research

keywords

  • Energy Metabolism
  • Estrogen Receptor alpha
  • Signal Transduction

Identity

PubMed Central ID

  • PMC3026715

Scopus Document Identifier

  • 79551532122

Digital Object Identifier (DOI)

  • 10.1172/JCI36714

PubMed ID

  • 21245576

Additional Document Info

volume

  • 121

issue

  • 2