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

Abstract

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 lightdark 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.circadian clocks misalignment | shift work | diabetes | metabolic syndrome | mouse U nder physiological conditions, the light-entrained central master circadian clock (CC), which is located in the suprachiasmatic nucleus (SCN), synchronizes the ubiquitous peripheral CCs (PCCs) and generates a diurnal alternance of phases of activity and rest, both of which are at the origin of rhythmic variations of gene expression, which are essential to maintain metabolic and behavioral homeostasis (1-3). It is well established that shifting the feeding time in the mouse from the "active" to the "rest" phase [so-called restricted feeding (RF)] leads to a 12-h shift in the expression of PCC components (4). As the SCN CC is not affected during RF (4), this situation leads to a misalignment between the diurnal active and rest phases and the expression of PCC components. We recently unveiled in mice the origin and the identity of the molecular signals through which RF leads to this 12-h shift in the expression of PCC components (5). However, the molecular mechanisms that confer to the SCN CC an insensitivity to RF, as well as the consequences of the misalignment between the PCCs and the master SCN CC on homeostasis, are still largely unexplored (3, 6). In the present study, we elucidated, at the molecular level, how the SCN CC is protected against the RF-induced shift of PCCs, which is induced by metabolic alterations (5), a...

Insulin post-transcriptionally modulates Bmal1 protein to affect the hepatic circadian clock

“…Actually, a recent paper has shown that a long term of RF induces diabetes, fatty liver and obesity in mice42. Thus, our results provide a new clue to understand the link between perturbation of the circadian rhythm system and the development of metabolic syndrome.…”

Inhibition of expression of the circadian clock gene Period causes metabolic abnormalities including repression of glycometabolism in Bombyx mori cells

“…The results of the current study confirmed the existence of a peripheral clock in silkworm BmN cells44. Recent studies have shown that changes in feeding patterns may disrupt the peripheral clock in mice, leading to metabolic syndrome4546, while a fat-metabolism disorder in Drosophila caused by food restriction was also regulated by the peripheral clock47. However, although individual animal cells have spontaneous rhythms, they are also regulated by the core cranial nerve core.…”

Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours

“…As RF early metabolic alterations did affect the expression of Per1, Per2, and RevErbα, we analyzed the transcript of CC components after RF for 4, 8, 15, 30, and 90 d. In liver and IECs, all of them were shifted after RF4, but it took 8 d to achieve the same shifts in muscle and heart (see below). Importantly, once established these shifts were stable as long as RF was not interrupted, whereas the "original circadian active and rest phases" remained unchanged throughout the RF period (13).…”