The noradrenergic Locus Cœruleus is one of the major arousal structures involved in inducing wakefulness. While brain noradrenaline (NA) amounts display 24-h variations, the origin of NA rhythm is... Show moreThe noradrenergic Locus Cœruleus is one of the major arousal structures involved in inducing wakefulness. While brain noradrenaline (NA) amounts display 24-h variations, the origin of NA rhythm is currently unknown. In this study, we tested the hypothesis that NA rhythm could result from its rhythmic synthesis. Therefore, we investigated the 24-h expression profile of NA rate-limiting enzyme, tyrosine hydroxylase (th), in the Locus Cœruleus (LC) of the nocturnal rat and the diurnal rodent Arvicanthis, under 12 h:12 h light/dark (LD) and constant darkness (DD) conditions. In both species, th mRNA levels vary significantly over 24-h. In nocturnal rats, th mRNA profiles show a unimodal rhythm, with peak values in late day in LD, and in the middle of the subjective day in DD. In contrast, th mRNA rhythm in Arvicanthis is characterized by a bimodal profile, with higher levels at the beginning of the day and of the night in LD, and in the middle of the subjective day and night in DD. The rhythmic pattern of th expression may be dependent on a LC clock machinery. Therefore, we investigated the expression of three clock genes, namely bmal1, per1, and per2, and found that their mRNAs display significant variations between day and nighttime points in both species, but in opposite directions. These data show that NA rhythm may be related to circadian expression of th gene in both species, but differs between nocturnal and diurnal rodents. Furthermore, the phase opposition of clock gene expression in the rat compared to Arvicanthis suggests that the clock machinery might be one of the mechanisms involved in th rhythmic expression. Show less
In mammals, behavioral activity is regulated both by the circadian system, orchestrated by the suprachiasmatic nucleus (SCN), and by arousal structures, including the serotonergic system. While the... Show moreIn mammals, behavioral activity is regulated both by the circadian system, orchestrated by the suprachiasmatic nucleus (SCN), and by arousal structures, including the serotonergic system. While the SCN is active at the same astronomical time in diurnal and nocturnal species, little data are available concerning the serotonergic (5HT) system in diurnal mammals. In this study, we investigated the functioning of the 5HT system, which is involved both in regulating the sleep/wake cycle and in synchronizing the SCN, in a diurnal rodent, Arvicanthis ansorgei. Using in situ hybridization, we characterized the anatomical extension of the raphe nuclei and we investigated 24 h mRNA levels of the serotonin rate-limiting enzyme, tryptophan hydroxylase 2 (tph2). Under both 12 h:12 h light/dark (LD) and constant darkness (DD) conditions, tph2 mRNA expression varies significantly over 24 h, displaying a bimodal profile with higher values around the (projected) light transitions. Furthermore, we considered several SCN outputs, namely melatonin, corticosterone, and locomotor activity. In both LD and DD, melatonin profiles display peak levels during the biological night. Corticosterone plasma levels show a bimodal rhythmic profile in both conditions, with higher levels preceding the two peaks of Arvicanthis locomotor activity, occurring at dawn and dusk. These data demonstrate that serotonin synthesis in Arvicanthis is rhythmic and reflects its bimodal behavioral phenotype, but differs from what has been previously described in nocturnal species. Show less
In mammals, behavioral activity is regulated both by the circadian system, orchestrated by the suprachiasmatic nucleus (SCN), and by arousal structures, including the serotonergic system. While... Show moreIn mammals, behavioral activity is regulated both by the circadian system, orchestrated by the suprachiasmatic nucleus (SCN), and by arousal structures, including the serotonergic system. While the SCN is active at the same astronomical time in diurnal and nocturnal species, little data are available concerning the serotonergic (5HT) system in diurnal mammals. In this study, we investigated the functioning of the 5HT system, which is involved both in regulating the sleep/wake cycle and in synchronizing the SCN, in a diurnal rodent, Arvicanthis ansorgei. Using in situ hybridization, we characterized the anatomical extension of the raphe nuclei and we investigated 24 h mRNA levels of the serotonin rate-limiting enzyme, tryptophan hydroxylase 2 (tph2). Under both 12 h:12 h light/dark (LD) and constant darkness (DD) conditions, tph2 mRNA expression varies significantly over 24 h, displaying a bimodal profile with higher values around the (projected) light transitions. Furthermore, we considered several SCN outputs, namely melatonin, corticosterone, and locomotor activity. In both LD and DD, melatonin profiles display peak levels during the biological night. Corticosterone plasma levels show a bimodal rhythmic profile in both conditions, with higher levels preceding the two peaks of Arvicanthis locomotor activity, occurring at dawn and dusk. These data demonstrate that serotonin synthesis in Arvicanthis is rhythmic and reflects its bimodal behavioral phenotype, but differs from what has been previously described in nocturnal species. Show less
Shift work causes circadian misalignment and is a risk factor for obesity. While some characteristics of the human circadian system and energy metabolism differ between males and females, little is... Show moreShift work causes circadian misalignment and is a risk factor for obesity. While some characteristics of the human circadian system and energy metabolism differ between males and females, little is known about whether sex modulates circadian misalignment effects on energy homeostasis. Here we show-using a randomized crossover design with two 8-d laboratory protocols in 14 young healthy adults (6 females)-that circadian misalignment has sex-specific influences on energy homeostasis independent of behavioral/environmental factors. First, circadian misalignment affected 24-h average levels of the satiety hormone leptin sex-dependently (P < 0.0001), with a similar to 7% decrease in females (P < 0.05) and an similar to 11% increase in males (P < 0.0001). Consistently, circadian misalignment also increased the hunger hormone ghrelin by similar to 8% during wake periods in females (P < 0.05) without significant effect in males. Females reported reduced fullness, consistent with their appetite hormone changes. However, males reported a rise in cravings for energy-dense and savory foods not consistent with their homeostatic hormonal changes, suggesting involvement of hedonic appetite pathways in males. Moreover, there were significant sex-dependent effects of circadian misalignment on respiratory quotient (P < 0.01), with significantly reduced values (P < 0.01) in females when misaligned, and again no significant effects in males, without sex-dependent effects on energy expenditure. Changes in sleep, thermoregulation, behavioral activity, lipids, and catecholamine levels were also assessed. These findings demonstrate that sex modulates the effects of circadian misalignment on energy metabolism, indicating possible sex-specific mechanisms and countermeasures for obesity in male and female shift workers. Show less
The human circadian system regulates hunger independently of behavioral factors, resulting in a trough in the biological morning and a peak in the biological evening. However, the role of the only... Show moreThe human circadian system regulates hunger independently of behavioral factors, resulting in a trough in the biological morning and a peak in the biological evening. However, the role of the only known orexigenic hormone, ghrelin, in this circadian rhythm is unknown. Furthermore, although shift work is an obesity risk factor, the separate effects of the endogenous circadian system, the behavioral cycle, and circadian misalignment on ghrelin has not been systematically studied. Here we show-by using two 8-day laboratory protocols-that circulating active (acylated) ghrelin levels are significantly impacted by endogenous circadian phase in healthy adults. Active ghrelin levels were higher in the biological evening than the biological morning (fasting +15.1%, P = 0.0001; postprandial +10.4%, P = 0.0002), consistent with the circadian variation in hunger (P = 0 .028). Moreover, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial active ghrelin levels (+5.4%; P = 0 .04). While not significantly influencing hunger (P > 0.08), circadian misalignment increased appetite for energy-dense foods (all P < 0.05). Our results provide possible mechanisms for the endogenous circadian rhythm in hunger, as well as for the increased risk of obesity among shift workers. Show less
Many favorable metabolic effects have been attributed to thermogenic activity of brown adipose tissue (BAT). Yet, time of day has rarely been considered in this field of research. Here, we show... Show moreMany favorable metabolic effects have been attributed to thermogenic activity of brown adipose tissue (BAT). Yet, time of day has rarely been considered in this field of research. Here, we show that a diurnal rhythm in BAT activity regulates plasma lipid metabolism. We observed a high-amplitude rhythm in fatty acid uptake by BAT that synchronized with the light/dark cycle. Highest uptake was found at the onset of the active period, which coincided with high lipoprotein lipase expression and low angiopoietin-like 4 expression by BAT. Diurnal rhythmicity in BAT activity determined the rate at which lipids were cleared from the circulation, thereby imposing the daily rhythm in plasma lipid concentrations. In mice as well as humans, postprandial lipid excursions were nearly absent at waking. We anticipate that diurnal BAT activity is an important factor to consider when studying the therapeutic potential of promoting BAT activity. Show less
