Estrogen-related receptor ß deletion modulates whole-body energy balance via estrogen-related receptor γ and attenuates neuropeptide Y gene expression.

Estrogen-related receptors (ERRs) α, ß and γ are orphan nuclear hormone receptors with no known ligands. Little is known concerning the role of ERRß in energy homeostasis, as complete ERRß-null mice die mid-gestation. We generated two viable conditional ERRß-null mouse models to address its metabolic function. Whole-body deletion of ERRß in Sox2-Cre:ERRß(lox/lox) mice resulted in major alterations in body composition, metabolic rate, meal patterns and voluntary physical activity levels. Nestin-Cre:ERRß(lox/lox) mice exhibited decreased expression of ERRß in hindbrain neurons, the predominant site of expression, decreased neuropeptide Y (NPY) gene expression in the hindbrain, increased lean body mass, insulin sensitivity, increased energy expenditure, decreased satiety and decreased time between meals. In the absence of ERRß, increased ERRγ signaling decreased satiety and the duration of time between meals, similar to meal patterns observed for both the Sox2-Cre:ERRß(lox/lox) and Nestin-Cre:ERRß(lox/lox) strains of mice. Central and/or peripheral ERRγ signaling may modulate these phenotypes by decreasing NPY gene expression. Overall, the relative expression ratio between ERRß and ERRγ may be important in modulating ingestive behavior, specifically satiety, gene expression, as well as whole-body energy balance.