Several common postdischarge symptoms, such as sleep disorders, headache, drowsiness or general malaise, evoke disturbances of circadian rhythms due to jet lag (ie crossing time zones) or shift work rotation. Considering that general anesthesia is associated with numerous effects on the central nervous system, we hypothesized that it may also act on the circadian timing system. We first determined the effects of the circadian timing on general anesthesia. We observed that identical doses of propofol showed marked circadian fluctuations in duration of effects, with a peak at the middle of the resting period (ie 7 h after lights on). Then, we examined the effects of general anesthesia on circadian timing, by analysing stable free-running circadian rhythms (ie in constant environmental conditions), an experimental approach used widely in circadian biology. Free-running rats were housed in constant darkness and temperature to assess possible phase-shifting effects of propofol anesthesia according to the time of the day. When administered around (72 h) the daily rest/activity transition point, a 30-min propofol anesthesia induced a 1-h phase advance in the free-running rest-activity rhythm, while anesthesia had no significant resetting effect at other times of the day. Anesthesia-induced hypothermia was not correlated with the phase-shifting effects of propofol anesthesia. From our results, anesthesia itself can reset circadian timing, and acts as a synchronizing cue for the circadian clock. Neuropsychopharmacology (2007) 32, 728-735.

Circadian rhythms in nocturnal and diurnal mammals are primarily synchronized to local time by the light/dark cycle. However, nonphotic factors, such as behavioral arousal and metabolic cues, can also phase shift the master clock in the suprachiasmatic nuclei (SCNs) and/or reduce the synchronizing effects of light in nocturnal rodents. In diurnal rodents, the role of arousal or insufficient sleep in these functions is still poorly understood. In the present study, diurnal Sudanian grass rats, Arvicanthis ansorgei, were aroused at night by sleep deprivation (gentle handling) or caffeine treatment that both prevented sleep. Phase shifts of locomotor activity were analyzed in grass rats transferred from a light/dark cycle to constant darkness and aroused in early night or late night.

Metabolic disorders induced by high-fat feeding in rodents evoke some, if not all, of the features of human metabolic syndrome. The occurrence and severity of metabolic disorders, however, varies according to rodent species, and even strain, as well as the diet. Therefore, in the present study, we investigated the long-term obesogenic and diabetogenic effects of three high-fat diets differing by their fat/carbohydrate ratios. Sprague-Dawley rats were fed a control high-carbohydrate and low-fat diet [HCD; 3:16:6 ratio of fat/carbohydrate/protein; 15.48 kJ/g (3.7 kcal/g)], a high-fat and medium-carbohydrate diet [HFD1; 53:30:17 ratio of fat/carbohydrate/protein; 19.66 kJ/g (4.7 kcal/g)], a very-high-fat and low-carbohydrate diet [HFD2; 67:9:24 ratio of fat/carbohydrate/protein; 21.76 kJ/g (5.2 kcal/g)] or a very-high-fat and carbohydrate-free diet [HFD3; 75:0:25 ratio of fat/carbohydrate/protein; 24.69 kJ/g (5.9 kcal/g)] for 10 weeks. Compared with the control diet (HCD), rats fed with high-fat combined with more (HFD1) or less (HFD2) carbohydrate exhibited higher BMI (body mass index; +13 and +10% respectively; P<0.05) and abdominal fat (+70% in both HFD1 and HFD2; P<0.05), higher plasma leptin (+130 and +135% respectively; P<0.05), lower plasma adiponectin levels (-23 and -30% respectively; P<0.05) and impaired glucose tolerance. Only the HFD1 group had insulin resistance. By contrast, a very-high-fat diet devoid of carbohydrate (HFD3) led to impaired glucose tolerance, insulin resistance and hypoadiponectinaemia (-50%; P<0.05), whereas BMI, adiposity and plasma leptin did not differ from respective values in animals fed the control diet. We conclude that increasing the fat-to-carbohydrate ratio to the uppermost (i.e. carbohydrate-free) in a high-fat diet prevents the development of obesity, but not the prediabetic state (i.e. altered glucose tolerance and insulin sensitivity).

Objective: To assess whether circadian desynchronization leads to metabolic alterations capable of promoting dietary obesity and/or impairing glucose tolerance. Design: Rats fed either with chow pellets (i.e., low-fat diet with 4% mass of fat) or high-fat diet (34% mass of fat). Half of each diet group was exposed to a fixed light-dark cycle or to a 10-h weekly shift in the light-dark cycle from Thursday to Sunday (20 shifts). To enforce the shifted animals to be active at unusual times of the day, food was available only during the daily dark period for all groups. Results: Shifting the light-dark cycle on a weekly basis was efficient to induce circadian desynchronization, as evidenced by strong disturbances in the daily expression of locomotor activity. Shifted rats fed with a nocturnal low-fat diet had lower plasma insulin and similar blood glucose compared to rats fed with the same diet under a fixed light-dark cycle. Nocturnal high-fat feeding led to an abdominal fat overload associated with increased plasma leptin and basal glucose. These metabolic changes were not significantly modified by circadian desynchronization. Conclusion: Chronic desynchronization with low-fat diet impaired insulin regulation. Metabolic changes induced by the highfat diet were not aggravated by chronic desynchronization.

Mounting evidence indicates a strong link between metabolic diseases and circadian dysfunctions. The metabolic hormone leptin, substantially increased in dietary obesity, displays chronobiotic properties. Here we investigated whether leptin is involved in the alteration of timing associated with obesity, via direct or indirect effects on the suprachiasmatic nucleus (SCN), the site of the master clock. Photic synchronization was studied in obese ob/ob mice (deficient in leptin), either injected or not with high doses of recombinant murine leptin (5 mg/kg). This was performed first at a behavioral level, by shifting the light-dark cycle and inducing phase shifts by 30-minute light pulses and then at molecular levels (c-FOS and P-ERK1/2). Moreover, to characterize the targets mediating the chronomodulatory effects of leptin, we studied the induction of phosphorylated signal transducer and activator of transcription 3 (P-STAT3) in the SCN and in different structures projecting to the SCN, including the medial hypothalamus. Ob/ob mice showed altered photic synchronization, including augmented light-induced phase delays. Acute leptin treatment normalized the photic responses of the SCN at both the behavioral and molecular levels (decrease of light-induced c-FOS). Leptin-induced P-STAT3 was modulated by light in the arcuate nucleus and both the ventromedial and dorsomedial hypothalamic nuclei, whereas its expression was independent of the presence of leptin in the SCN. These results suggest an indirect action of leptin on the SCN, possibly mediated by the medial hypothalamus. Taken together, these results highlight a central role of leptin in the relationship between metabolic disturbances and circadian disruptions.

Temporal organization of the molecular clockwork and behavioral output were investigated in nocturnal rats housed in constant darkness and synchronized to nonphotic cues (daily normocaloric or hypocaloric feeding and melatonin infusion) or light (light-dark cycle and daily 1-h light exposure). Clock gene (Per1, Per2 and Bmal1) and clock-controlled gene (Vasopressin) expression in the suprachiasmatic nuclei was assessed over 24 h. Light and exogenous melatonin synchronized the molecular clock, signaling, respectively, 'daytime' and 'nighttime', without affecting temporal organization of behavioral output (rest/activity rhythm). By contrast, synchronization to hypocaloric feeding led to a striking temporal change between gene expression in the suprachiasmatic clock and waveform of locomotor activity rhythm, rats then becoming active during the subjective day (diurnal-like temporal organization). When the time of feeding coincided with activity offset, normocaloric feeding also synchronized the locomotor activity rhythm with no apparent switch in temporal organization. Peak of Per2 expression in the piriform cortex occurred between the beginning and the middle of the activity/feeding period, depending on the synchronizer. These data demonstrate that even though the suprachiasmatic clockwork can be synchronized to nonphotic cues, hypocaloric feeding likely acts downstream from clock gene oscillations in the suprachiasmatic nuclei to yield a stable yet opposite organization of the rest/activity cycle.

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Chronic jet lag or shift work is deleterious to human metabolic health, in that such circadian desynchronization is associated with being overweight and the prevalence of altered glucose metabolism. Similar metabolic changes are observed with age, suggesting that chronic jet lag and accelerated cell aging are intimately related, but the association remains to be determined. We addressed whether jet lag induces metabolic and cell aging impairments in young grass rats (2-3 mo old), using control old grass rats (12-18 mo old) as an aging reference. Desynchronized young and control old subjects had impaired glucose tolerance (+60 and +280%) when compared with control young animals. Despite no significant variation in liver DNA damage, shorter telomeres were characterized, not only in old animal liver cells (218%), but also at an intermediate level in desynchronized young rats (29%). The same pattern was found for deacetylase sirtuin (SIRT)-1 (257 and 229%), confirming that jet-lagged young rats have an intermediate aging profile. Our data indicate that an experimental circadian desynchronization in young animals is associated with a precocious aging profile based on 3 well-known markers, as well as a prediabetic phenotype. Such chronic jet lag-induced alterations observed in a diurnal species constitute proof of principle of the need to develop preventive treatments in jet-lagged persons and shift workers.-Grosbellet, E., Zahn, S., Arrivé, M., Dumont, S., Gourmelen, S., Pévet, P., Challet, E., Criscuolo, F. Circadian desynchronization triggers premature cellular aging in a diurnal rodent. FASEB J. 29, 4794-4803 (2015). www.fasebj.org