ornate clock
© Vera Kratochvil/public domain
Shift work sleep disorder comprises a group of symptoms including insomnia, proneness to accidents and inattentiveness that typically afflict people whose work schedules shift between day and night, disrupting their normal circadian cycles. The disorder heightens such health risks as obesity, diabetes, heart disease and may be implicated in increased incidence of cancer.

Normally, the light-entrained circadian clock, which is located in the brain's suprachiasmatic nucleus, controls the alternating diurnal active phase and the rest phase. In humans, the active phase is during the light period and the rest phase is the dark period; in mice, it is the opposite. While a night worker on a reliable and unchanging schedule can adapt to some extent, most health experts maintain that night work is not ideal for the vast majority of workers.

It is known that many of the metabolic factors associated with the disorder arise from shifting the eating schedule from the active phase to the rest phase, but the actual mechanisms have not been studied. Now, a group of researchers from the University of Strasbourg and the Centre National de la Recherche Scientifique have published two related studies in the Proceedings of the National Academy of Sciences that reveal, for the first time, the origin and identity of the metabolic signals generated when feeding is shifted to the rest cycle.

The researchers studied a group of eight- to 12-week-old male mice. Control mice received open feeding during both active and rest cycles; the test group received restricted feeding (RF) only during the rest cycle, and fasting during the active cycle. As the metabolism expressed by the two groups diverged, the researchers were able to determine how the RF mice developed metabolic syndrome in response to restricted feeding.

In the first paper, the researchers documented how shifting the master central circadian clock via RF leads to metabolic syndrome by misaligning the body's peripheral circadian clocks. They determined that this is caused by the non-expression of receptors in the suprachiasmatic nucleus for glucagon and proliferator-activated receptor alpha. This prevents the master circadian clock from shifting to the new feeding schedule and creates a misalignment that breaks the peripheral circadian clocks.

In the second paper, the researchers demonstrated that the shift of the master circadian cycle induced alterations of two important metabolic pathways that shift the body's peripheral circadian clocks by 12 hours.

The authors write, "Assuming that specific metabolic perturbations generated by switching the feeding time could selectively affect the time of expression of some of the core circadian cycle components, we looked for both metabolic and peripheral circadian clock alterations at early RF times." These alterations occurred in two phases: First, the shifted eating schedule broke the existing peripheral circadian clocks; this caused reduced insulin secretion, triggering untimely increases in glucagon. Then the new eating cycle generated shifting peripheral circadian clocks. Additionally, RF caused overproduction of corticosterone, causing problems in muscles and heart by inhibiting the shift to the new circadian cycle in those tissues.

More information: Shifting eating to the circadian rest phase misaligns the peripheral clocks with the master SCN clock and leads to a metabolic syndrome. PNAS 2015 112 (48) E6691-E6698; published ahead of print November 16, 2015, DOI: 10.1073/pnas.1519807112