The study investigates the regulatory roles of REV-ERBα and REV-ERBβ in circadian behavior and metabolism. Using comparative cistromes, the researchers found extensive overlap between the binding sites of these receptors and the master circadian regulator BMAL1, suggesting a direct connection between Bmal1 and REV-ERBα/β regulatory circuits. Genes within the intersection of BMAL1, REV-ERBα, and REV-ERBβ cistromes are enriched for both clock and metabolic functions. Depletion of both REV-ERBα and REV-ERBβ in double-knockout mice (DKOs) led to profound disruptions in circadian expression of core clock and lipid homeostatic gene networks, resulting in altered wheel-running behavior and deregulated lipid metabolism. These findings highlight the integral role of REV-ERBα/β in coordinating circadian rhythm and metabolism, suggesting a more complex and central role for these receptors in the core clock mechanism.The study investigates the regulatory roles of REV-ERBα and REV-ERBβ in circadian behavior and metabolism. Using comparative cistromes, the researchers found extensive overlap between the binding sites of these receptors and the master circadian regulator BMAL1, suggesting a direct connection between Bmal1 and REV-ERBα/β regulatory circuits. Genes within the intersection of BMAL1, REV-ERBα, and REV-ERBβ cistromes are enriched for both clock and metabolic functions. Depletion of both REV-ERBα and REV-ERBβ in double-knockout mice (DKOs) led to profound disruptions in circadian expression of core clock and lipid homeostatic gene networks, resulting in altered wheel-running behavior and deregulated lipid metabolism. These findings highlight the integral role of REV-ERBα/β in coordinating circadian rhythm and metabolism, suggesting a more complex and central role for these receptors in the core clock mechanism.