The suprachiasmatic nucleus (SCN) is generally considered the master clock, independently driving all circadian rhythms. We recently demonstrated the SCN receives metabolic and cardiovascular feedback adeptly altering its neuronal activity. In the present study, we show that microcuts effectively removing SCN-arcuate nucleus (ARC) interconnectivity in Wistar rats result in a loss of rhythmicity in locomotor activity, corticosterone levels, and body temperature in constant dark (DD) conditions. Elimination of these reciprocal connections did not affect SCN clock gene rhythmicity but did cause the ARC to desynchronize. Moreover, unilateral SCN lesions with contralateral retrochiasmatic microcuts resulted in identical arrhythmicity, proving that for the expression of physiological rhythms this reciprocal SCN-ARC interaction is essential. The unaltered SCN c-Fos expression following glucose administration in disconnected animals as compared to a significant decrease in controls demonstrates the importance of the ARC as metabolic modulator of SCN neuronal activity. Together, these results indicate that the SCN is more than an autonomous clock, and forms an essential component of a larger network controlling homeostasis. The present novel findings illustrate how an imbalance between SCN and ARC communication through circadian disruption could be involved in the etiology of metabolic disorders.

The circadian disruption in shift-workers is suggested to be a risk factor to develop overweight and metabolic dysfunction. The conflicting time signals given by shifted activity, shifted food intake and exposure to light at night occurring in the shift-worker are proposed to be the cause for the loss of internal synchrony and the consequent adverse effects on body weight and metabolism. Because food elicited signals have proven to be potent entraining signals for peripheral oscillations, here we review the findings from experimental models of shift-work and verify whether they provide evidence about the causal association between shifted feeding schedules, circadian disruption and altered metabolism. We found mainly four experimental models that mimic the conditions of shift-work: protocols of forced sleep deprivation, of forced activity during the normal rest phase, exposure to light at night and shifted food timing. A big variability in the intensity and duration of the protocols was observed, which led to a diversity of effects. A common result was the disruption of temporal patterns of activity; however, not all studies explored the temporal patterns of food intake. According to studies that evaluate time of food intake as an experimental model of shift-work and studies that evaluate shifted food consumption, time of food intake may be a determining factor for the loss of balance at the circadian and metabolic level.

Restricted feeding schedules (RFS) entrain digestive, hormonal, and metabolic functions as well as oscillations of clock genes, such as Per1 and Per2, in peripheral organs. In the brain, in particular the hypothalamus, RFS induce and shift daily rhythms of Per1 and Per2 expression. To determine whether RFS affect clock genes in extra-SCN oscillators in a uniform manner, the present study investigated daily rhythms of Per1, Per2, and Bmal1 expression in various hypothalamic regions. Wistar rats were entrained to daily RFS (2 h food access starting at ZT6, RFS) or fed ad libitum (C) for three weeks. Brains were sampled every 3 h starting at ZT0, and were processed with in situ hybridization. In response to RFS, Per1 expression showed a 3 h phase advance in the suprachiasmatic nucleus (SCN), while Per2 and Bmal1 remained unaffected. Per1 was triggered at ZT6, anticipating food access in both arcuate (ARC) and dorsomedial nuclei (DMH), and was unaffected in the ventromedial (VMH) and paraventricular (PVN) nuclei. In contrast, Per2 expression during RFS showed a marked postprandial peak in the PVN, was unchanged in the ARC, and was down-regulated in the DMH and VMH. The temporal patterns of Bmal1 expression were not significantly modified in RFS rats. RFS differentially affected clock-gene expression (phase change, up- or downregulation) depending on the combination of hypothalamic nuclei and targeted genes. Present data highlight that metabolic or temporal cues elicited by feeding modify the temporal organization in the hypothalamus and are not exclusive for a food-entrained oscillator.

Internal synchrony among external cycles and internal oscillators allows adaptation of physiology to cyclic demands for homeostasis. Night work and shift work lead to a disrupted phase relationship between external time cues and internal rhythms, also losing internal coherence among oscillations. This process results in internal desynchrony (ID) in which behavioral, hormonal, and metabolic variables cycle out of phase. It is still not clear whether ID originates at a peripheral or at a central level. In order to determine the possible role of hypothalamic oscillators in ID, we explored with a rat model of “night work” daily rhythms of activity and clock gene expression in the hypothalamus. This study provides evidence that wakefulness and activity during the normal resting phase lead to a shift in the diurnal rhythms of c-Fos and induce a rhythm of PER1 in the arcuate and dorsomedial nucleus of the hypothalamus, both associated with metabolism and regulation of the sleep/wake cycle. Moreover, the number of orexin (ORX)—positive neurons and c-Fos in the perifornical area increased during the working period, suggesting a relevant switch of activity in this brain region induced by the scheduled activity; however, the colocalization of c-Fos in ORX-positive cells was not increased. In contrast, the suprachiasmatic nucleus and the paraventricular nucleus remained locked to the light/dark cycle, resulting in ID in the hypothalamus. Present data suggest that ID occurs already at the level of the first output projections from the SCN, relaying nuclei that transmit temporal signals to other brain areas and to the periphery.