Proposed model for rhythmic regulation of IRP/IRE activity. Left side — during the light phase (ZT5, coinciding with fasting phase in ad libitum fed mice): IRP2 levels are relatively lower, but still able to exert some translational inhibition on their targets. This is why in Ireb2/Irp2 -deficient animals, depression is seen. IRP1 is less active, likely due to FeS cluster assembly that precludes its IRE binding and this may be brought about by increased Fe(II) levels or other cues such as oxygen fluctuations. Right side — at beginning of dark phase (ZT12, feeding phase): IRP2 is abundant and actively repressing, but IRP1 is also active and can compensate for the loss of IRP2 in the corresponding Ireb2/Irp2 -deficient animals
