Title: Synchronization between peripheral circadian clock and feeding-fasting cycles in microfluidic device sustains oscillatory pattern of transcriptome
Many processes of mammalian behavior and physiology, such as sleeping and feeding, are cyclically regulated during the 24h solar day by the circadian clock system. Desynchronization between physiological and behavioural rhythms increases the risk of developing some, including metabolic, disorders1. Although there is a lot of scientific evidence about the link between circadian clock and metabolism, the design of an experimental strategy for investigating and dissecting the contribution of specific oscillatory metabolic pattern on circadian clock is a challenge.
In this work, we start to rationally investigate how the dynamic oscillatory nature of metabolic signals, resembling daily feeding-fasting cycle, alter or, even profoundly reset, the cell-autonomous circadian clock in peripheral tissues. We hypothesize that frequency-encoded metabolic stimulations affect the cell-autonomous circadian clock and alter the rhythmicity of the cellular transcriptome. We also explore whether mismatch of cell-autonomous circadian clock and phases of 24h metabolic cycles could affect circadian rhythms.
Here, we specifically develop a microfluidic approach to perform periodic cyclic stimulations under controlled
microenvironmental conditions2,3,4, while continuously monitoring circadian oscillations. Long-term circadian study of mammalian microfluidic cell culture shows the unexpected importance of frequency-encoded metabolic perturbations for resetting the circadian clock. Furthermore, through cyclic temporal stimulations, we dissect the contributions of the feeding and fasting phases on clock resetting with oscillatory stimulation synchronous and asynchronous with cellautonomous circadian clock.
We show that the circadian Per2 expression is better sustained via a 24h period and 12h:12h frequency-encoded
metabolic stimulation applied for 3 daily cycles, aligned to the cell-autonomous clock, entraining the expression of
hundreds of genes mostly belonging to circadian rhythms and cell cycle pathways. On the contrary misaligned feedingfasting cycles synchronize and amplify the expression of extracellular matrix-associated genes, aligned during the light-phase.
This study underlines the role of the synchronicity between life-style-associated metabolic signals and peripheral clocks
on the circadian entrainment.