Behavioral and metabolic phenotyping of GPR30 and neuronal estrogen receptor- α knockout mice.

Abstract

We have been testing the hypothesis that estrogen signaling through specific estrogen receptors contributes to the regulation of energy homeostasis and behavior. Mice lacking estrogen receptor alpha (ERα) have previously been reported to have an obese phenotype and attenuated locomotor activity. We have extended these findings to show that estrogen signaling through hypothalamic ERα contributes to the regulation of food intake, body weight, and energy expenditure. To better understand the hypothalamic contribution of estrogen signaling, we first characterized some behavioral aspects of the whole-body ERα knockout mouse, and found that they had decreased homecage locomotor activity and voluntary wheel running activity, increased body weight, and changes in fat distribution to favor development of the metabolic syndrome. They were also resistant to the effects of leptin to regulate food intake and body weight. Recently, we have obtained ERα floxed mice and have bred them with nestin-CRE mice to develop mice lacking estrogen receptors in neurons. We have begun characterization of these mice through multiple metabolic and behavioral tests to test the hypothesis that estrogen signaling through neuronal ERα significantly contributes to the phenotype seen in total body ERα knockout mice. Finally, in addition to nuclear receptors, the actions of estrogen may be mediated through GPR30, a membrane/intracellular receptor. Here, we report on metabolic and behavioral phenotyping assays of GPR30 knockout mice, designed to delineate whether the observed phenotype is mediated through genomic effects or by rapid signaling through membrane receptors.