Rhythmic Oxygen Levels Reset Circadian Clocks through HIF1α

The mammalian circadian system consists of a master clock in the brain that synchronizes subsidiary oscillators in peripheral tissues. The master clock maintains phase coherence in peripheral cells through systemic cues such as feeding-fasting and temperature cycles. Here, we examined the role of oxygen as a resetting cue for circadian clocks. We continuously measured oxygen levels in living animals and detected daily rhythms in tissue oxygenation. Oxygen cycles, within the physiological range, were sufficient to synchronize cellular clocks in a HIF1 alpha-dependent manner. Furthermore, several clock genes responded to changes in oxygen levels through HIF1 alpha. Finally, we found that a moderate reduction in oxygen levels for a short period accelerates the adaptation of wild-type but not of HIF1 alpha-deficient mice to the new time in a jet lag protocol. We conclude that oxygen, via HIF1 alpha activation, is a resetting cue for circadian clocks and propose oxygen modulation as therapy for jet lag.