Abstract
The circadian system cyclically regulates many physiological and behavioral processes within the day. Desynchronization between physiological and behavioral rhythms increases the risk of developing some, including metabolic, disorders. Here we investigate how the oscillatory nature of metabolic signals, resembling feeding-fasting cycles, sustains the cell-autonomous clock in peripheral tissues. By controlling the timing, period and frequency of glucose and insulin signals via microfluidics, we find a strong effect on Per2::Luc fibroblasts entrainment. We show that the circadian Per2 expression is better sustained via a 24 h period and 12 h:12 h 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 feeding-fasting 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.
Highlights
The circadian system cyclically regulates many physiological and behavioral processes within the day
It was shown that rhythmic feeding and caloric content are involved in various nutrient-sensing pathways, such as insulin/IGF-1, SIRT1, NAMPT, AMPK, PGC-1a, mTOR, GSK3b, and FGF21, that are both necessary and sufficient to synchronize the circadian expression of peripheral clocks[20,21,22,23,24,25,26]
These results showed the feasibility of circadian studies using microfluidic technology
Summary
The circadian system cyclically regulates many physiological and behavioral processes within the day. In vivo studies provide information about the entire organism, with limited capability of dissecting the contributions of the different circadian inputs (such as light, feeding/fasting regimes, activity, temperature) or other major factors (such as the endocrine system, metabolite fluctuations) in the circadian system of peripheral tissues[27,28,29]. In vitro circadian experiments[30,31,32], based on a single pulse of metabolic stimulation mimicking the onset of the feeding phase, showed evidence of peripheral circadian alteration[4,33,34,35,36] These in vitro experiments show limited capability in reproducing the rhythms of metabolic signals associated with dietary regimens and timing
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