Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice

In addition to its role in reproduction, estradiol-17 beta is critical to the regulation of energy balance and body weight. Estrogen receptor alpha-null (Er alpha(-/-)) 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 ER alpha signaling maintains normal energy balance, however, have remained unclear. Here we used knockin mice that express mutant ER alpha that can only signal through the noncanonical pathway to assess the role of nonclassical ER alpha signaling in energy homeostasis. In these mice, we found that nonclassical ER alpha signaling restored metabolic parameters dysregulated in Er alpha(-/-) mutant mice to normal or near-normal values. The rescue of body weight and metabolic function by nonclassical ER alpha signaling was mediated by normalization of energy expenditure, including voluntary locomotor activity. These findings indicate that nonclassical ER alpha signaling mediates major effects of estradiol-17 beta on energy balance, raising the possibility that selective ER alpha agonists may be developed to reduce the risks of obesity and metabolic disturbances in postmenopausal women.