Genetic rescue of nonclassical ERalpha signaling normalizes energy balance in obese Eralpha-null mutant mice.
Fiche publication
Date publication
février 2011
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHAMBON Pierre
Tous les auteurs :
Park CJ, Zhao Z, Glidewell-Kenney C, Lazic M, Chambon P, Krust A, Weiss J, Clegg DJ, Dunaif A, Jameson JL, Levine JE
Lien Pubmed
Résumé
In addition to its role in reproduction, estradiol-17beta is critical to the regulation of energy balance and body weight. Estrogen receptor alpha-null (Eralpha-/-) 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 ERalpha signaling maintains normal energy balance, however, have remained unclear. Here we used knockin mice that express mutant ERalpha that can only signal through the noncanonical pathway to assess the role of nonclassical ERalpha signaling in energy homeostasis. In these mice, we found that nonclassical ERalpha signaling restored metabolic parameters dysregulated in Eralpha-/- mutant mice to normal or near-normal values. The rescue of body weight and metabolic function by nonclassical ERalpha signaling was mediated by normalization of energy expenditure, including voluntary locomotor activity. These findings indicate that nonclassical ERalpha signaling mediates major effects of estradiol-17beta on energy balance, raising the possibility that selective ERalpha agonists may be developed to reduce the risks of obesity and metabolic disturbances in postmenopausal women.
Référence
J Clin Invest. 2011 Feb 1;121(2):604-12