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

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