Shifting eating to the circadian rest phase misaligns the peripheral clocks with the master SCN clock and leads to a metabolic syndrome

Dec 3, 2015Proceedings of the National Academy of Sciences of the United States of America

Eating during the body’s rest time disrupts internal clocks and may cause metabolic problems

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Abstract

Restricted feeding creates a 12-hour shift in peripheral circadian clocks in mice without altering the master circadian clock.

The master circadian clock in the suprachiasmatic nucleus remains unaffected during restricted feeding.
Molecular signals through which restricted feeding induces peripheral clock shifts were identified in mice.
The lack of expression of PPARα and glucagon receptors in the master circadian clock prevents its shift during restricted feeding.
This misalignment between the peripheral and master circadian clocks leads to abnormal gene expression related to homeostasis.
Long-term effects of this misalignment may include metabolic disorders such as diabetes, obesity, and metabolic syndrome.

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The light-entrained master central circadian clock (CC) located in the suprachiasmatic nucleus (SCN) not only controls the diurnal alternance of the active phase (the light period of the human light-dark cycle, but the mouse dark period) and the rest phase (the human dark period, but the mouse light period), but also synchronizes the ubiquitous peripheral CCs (PCCs) with these phases to maintain homeostasis. We recently elucidated in mice the molecular signals through which metabolic alterations induced on an unusual feeding schedule, taking place during the rest phase [i.e., restricted feeding (RF)], creates a 12-h PCC shift. Importantly, a previous study showed that the SCN CC is unaltered during RF, which creates a misalignment between the RF-shifted PCCs and the SCN CC-controlled phases of activity and rest. However, the molecular basis of SCN CC insensitivity to RF and its possible pathological consequences are mostly unknown. Here we deciphered, at the molecular level, how RF creates this misalignment. We demonstrate that the PPARα and glucagon receptors, the two instrumental transducers in the RF-induced shift of PCCs, are not expressed in the SCN, thereby preventing on RF a shift of the master SCN CC and creating the misalignment. Most importantly, this RF-induced misalignment leads to a misexpression (with respect to their normal physiological phase of expression) of numerous CC-controlled homeostatic genes, which in the long term generates in RF mice a number of metabolic pathologies including diabetes, obesity, and metabolic syndrome, which have been reported in humans engaged in shift work schedules.

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Shifting eating to the circadian rest phase misaligns the peripheral clocks with the master SCN clock and leads to a metabolic syndrome

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