Estrogen-related receptors (ERRs) α, β and γ are orphan nuclear hormone receptors with no known ligands. Little is known concerning the role of ERRβ in energy homeostasis, as complete ERRβ-null mice die mid-gestation. We generated two viable conditional ERRβ-null mouse models to address its metabolic function. Whole-body deletion of ERRβ in Sox2-Cre:ERRβlox/lox mice resulted in major alterations in body composition, metabolic rate, meal patterns and voluntary physical activity levels. Nestin-Cre:ERRβlox/lox mice exhibited decreased expression of ERRβ 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 ERRβ, increased ERRγ signaling decreased satiety and the duration of time between meals, similar to meal patterns observed for both the Sox2-Cre:ERRβlox/lox and Nestin-Cre:ERRβlox/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 ERRβ and ERRγ may be important in modulating ingestive behavior, specifically satiety, gene expression, as well as whole-body energy balance.
Selective reduction of Estrogen-related receptor β (ERRβ) expression in the CNS resulted in an increased ratio of ERRγ gene expression relative to ERRβ, decreased NPY gene expression in the hindbrain, significantly decreased intermeal interval and satiety, and enhanced body weight, lean mass, insulin sensitivity, and whole-body energy metabolism. These data support the hypothesis that an extra-hypothalamic site, such as the hindbrain, can modulate peripheral tissue metabolism and food intake.