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Original Studies |
Laboratoire des Régulations Physiologiques et des Rythmes Biologiques chez l’Homme 67085 Strasbourg Cedex; and Service de Médecine Interne, CHU Hautepierre, 67098 Strasbourg Cedex, France
Address all correspondence and requests for reprints to: C. Simon, Laboratoire des Régulations Physiologiques et Rythmes Biologiques chez l’Homme Faculté de Médecine, 4 rue Kirschleger, 67085 Strasbourg Cedex, France. E-mail: Chantal.Simon{at}medecine.u-strasbg.fr
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Abstract |
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During nighttime sleep, leptin levels increased to a maximum (109.9 ± 2.5% of the 24-h mean) and then decreased to reach a nadir in the late afternoon. The mean diurnal variation was 18.0 ± 3.8% of the 24-h mean. In the daytime sleep condition, leptin levels rose during the night of deprivation to a maximum of 104.7 ± 2.3% of the 24-h mean, decreased to a minimum around 0700 h, and then rose again during diurnal sleep (108.4 ± 3.1% of the 24-h mean); the mean diurnal variation was 13.4 ± 3.6% of the 24-h mean. ANOVA revealed a significant interaction between time of day and sleep effects (P < 0.05).
The diurnal and the sleep-related variations of plasma leptin mirrored those of body temperature and roughly paralleled those of plasma glucose and insulin; the amplitudes of the diurnal leptin variations were significantly correlated with the amplitudes of the diurnal body temperature variations (P < 0.05). Plasma leptin levels also displayed irregular pulses of low amplitude (mean duration, 70 min) that were not affected by sleep, but were associated with a significant decrease in glucose and insulin levels (P < 0.01).
These results demonstrate that under continuous enteral nutrition, plasma leptin levels are modulated by both a slight circadian component and sleep, which interact under normal conditions, and suggest that leptin is implicated in circadian thermoregulatory adjustments.
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Introduction |
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To determine the influences of circadian rhythmicity and sleep on the 24-h plasma leptin variations independently of meal ingestion, we used an experimental strategy of acute sleep shift in normal subjects submitted to 24-h periods of constant routine conditions, involving continuous nutrition and bed rest in controlled sound-proof, air-conditioned, and dim light chambers. The 24-h profiles obtained in the same subjects, once under basal conditions with normal nocturnal sleep and once with a night of total sleep deprivation followed by an 8-h daytime sleep, were compared. Caloric and fluid intake were given in the form of a continuous normocaloric enteral nutrition to avoid possible effects of repeated meal ingestion and fasting. The temporal profiles of body temperature, plasma glucose and plasma insulin levels were determined simultaneously.
Plasma leptin levels have also been shown to be pulsatile, with transient pulses superimposed on the diurnal profiles (16, 17). The frequency of the leptin pulses observed is very close to that of the slow oscillations described for plasma glucose and insulin secretion (18, 19), which are best identified during continuous enteral nutrition and are known to be affected by sleep (20). A rapid sampling procedure (10-min intervals) was therefore used to assess the influence of sleep on the leptin ultradian pulses and to determine their temporal relationships with the glucose and insulin ultradian rhythms.
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Subjects and Methods |
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Seven healthy day-active male subjects, aged 21–25 yr, participated in this experiment. All subjects were of normal weight, with an average body mass index of 22.2 ± 0.6 kg/m2, and had normal routines of work, meals, and sleep. They were selected after medical examination, screening tests, and questionnaires on their usual sleep-wake cycles, work, and light exposure schedules. Subjects with any personal history of obesity or sleep disorders, those who had experienced time shift or sleep deprivation during the previous weeks, as well as smokers, subjects with underlying signs of disease, or subjects taking medication were excluded from the study. They all gave their written informed consent, and the study was approved by the local ethics committee.
Procedure
The experiments were performed in soundproof, air-conditioned sleep chambers communicating with an adjoining room where blood samples and sleep data were collected.
The subjects were studied twice in random order, with a 1-month interval between the experiments; they were admitted to the laboratory for a continuous period of about 48 h, with admission at 2200 h to undergo a night of habituation from 2300–0700 h. They ate standard meals at 0700 and 1200 h; they were then studied once during a normal 24-h sleep-wake cycle, with a nocturnal sleep from 2300–0700 h, and once during a 24-h cycle with an acute 8-h shift in the sleep period obtained by a total sleep deprivation during the night and a daytime recovery sleep from 0700–1500 h. The subjects remained supine for the 4 h preceding blood sampling and throughout the experiment to avoid postural influence. When awake, they were maintained in dim light (<100 lux) and were allowed to read or watch television. During the night of sleep deprivation, they were kept under continuous watch and conversed with the laboratory staff.
To avoid the influence of repeated meal ingestion and fasting, the subjects received continuous enteral nutrition (Sondalis ISO, Sopharga Puteaux, France; 50% carbohydrate, 35% fat, and 15% protein; 378 kilojoules/h), which began at 1600 h. A catheter was then inserted under local anesthesia in an antecubital vein and was kept patent with heparinized solutions. Electrodes were attached for uninterrupted electrophysiological recordings. Rectal temperature was recorded once per min by a probe (YSI 400, Yellow Springs Instrument Co., Yellow Springs, OH), and values were averaged for each 10-min period.
Blood sampling and hormone assays
Blood samples were taken continuously throughout the 24-h experiments from 2300 h on day 1 to 2300 h on day 2 at 10-min intervals, using a peristaltic pump. Ethylenediamine tetraacetate-K2-treated tubes (1 mg/mL) were used. Blood samples were immediately centrifuged at 4 C, and plasma was stored at -25 C until assay. Plasma glucose levels were measured using a glucose oxidase method (Boehringer Mannheim, Mannheim, Germany), with an intraassay coefficient of variation (CV) below 1.3%. Plasma leptin levels were determined by RIA using a commercial kit (Linco Research, St. Charles, MO), with a lower sensitivity of 0.5 ng/mL; the intraassay CV was 4.4% for values below 15 ng/mL and 3.4% for values above 15 ng/mL. Plasma insulin levels were determined by a double antibody RIA (Sorin Biomedica Diagnostics, Milan, Italy) with a lower level of sensitivity of 4 µU/mL. The mean intraassay CV was 6.6% for values below 50 µU/mL and 10.6% for values above 50 µU/mL. All samples from one individual were analyzed in a single assay.
Sleep recording and analysis
Polygraphic sleep recordings included two electroencephalographic derivations, two electrooculograms, one electromyogram, and one electrocardiogram. Sleep stages were scored at 30-s intervals according to the Rechtshaffen and Kales criteria (21). On this basis, total sleep time, the total durations of slow wave sleep (SWS) and rapid eye movement (REM) sleep, sleep onset, SWS and REM sleep latencies, and the number and duration of intrasleep awakenings were quantified. The sleep efficiency index was defined as the ratio of total sleep time to time allocated to sleep.
Data analysis
Circadian rhythmicity analysis. To quantify the long term diurnal wave changes in leptin, body temperature (Tre), glucose, and insulin independently of the more rapid ultradian variations, a smooth best-fit curve using a robust, locally weighted regression procedure, as proposed by Cleveland (22), was calculated for each individual profile. A window of 2 h was used. The acrophases and nadirs were respectively defined as the times of occurrence of maxima and minima in the best-fit curve. The diurnal mean amplitude of each individual profile was defined as the difference between the nocturnal acrophase (nadir) and the diurnal nadir (acrophase).
Two approaches were used to quantify the long term temporal
relationships between the 24-h changes in plasma leptin and those in
Tre, plasma glucose, and insulin. Firstly, a
cross-correlation analysis (Box-Jenkins Time Series Analysis, BMDP
Statistical Software, Los Angeles, CA) was realized on the best-fit
curves. Cross-correlation coefficients between paired plasma leptin
levels and Tre (and then plasma glucose and insulin levels,
respectively) were calculated at different time lags. For each
individual pair of profiles, the highest coefficient of
cross-correlation was identified. The individual correlation
coefficients were then averaged using Fischer’s z transformation to
yield an average estimate of the correlation between plasma leptin
levels and Tre (and then plasma glucose and insulin levels,
respectively). This average coefficient was computed after a
2 homogeneity test on the individual transformed
coefficients (23). Secondly, the different parameters derived from the
best-fit curves (mean levels, time and level of acrophases and nadirs,
relative and absolute increments associated with sleep, and mean
amplitude) were used to quantify the temporal changes in plasma leptin
levels and their association with changes in Tre, plasma
glucose, and plasma insulin levels.
Pulse analysis. The individual 24-h profiles of plasma leptin, glucose, and insulin levels were analyzed for pulse identification using the computer program ULTRA (24). This algorithm eliminates all peaks when either the increment or the decrement does not reach a certain threshold. The threshold for pulse detection was set at twice the CV; moreover, only the pulses that lasted more then 20 min were considered significant. For each significant pulse, the time of occurrence, the increment, the decrement, and the total duration were determined.
The association between individual pulses of leptin and those of glucose or insulin was tested by means of a lagged coincidence analysis, based on a model of conditional probability deriving from two binomial distributions and leading to an hypergeometric probability density function, as proposed by Veldhuis (25). Coincidence was tested at different lags (i.e. peak maxima in leptin series were stipulated to precede or to follow maxima in paired series by a designed number of time units). Coincidence was defined within a window of ± one sample.
Statistical analysis. The results were expressed as the mean ± SEM. The sleep and circadian parameters from normal rhythms and from shifted day-sleep rhythms were compared using bilateral paired t tests.
An ANOVA for repeated measures with Greenhouse-Geiser correction and a bilateral paired t test with Bonferroni procedure for multiple comparisons were used to assess the statistical differences among the mean levels, the mean number of pulses, and their relative or absolute amplitudes. Three periods were considered: 2300–0700 h, 0700–1500 h, and 1500–2300 h.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Total sleep time and sleep efficiency were similar in both
experimental conditions (Table 1
). The
latency of sleep onset significantly decreased during daytime sleep
compared with that during nighttime sleep, whereas the duration and the
latency of REM sleep and SWS were not affected by sleep shift.
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Figure 1 illustrates the mean 24-h
profiles of plasma leptin, Tre, plasma insulin, and plasma
glucose obtained in the two experimental conditions, i.e.
with a normal nocturnal sleep from 2300–0700 h (left) and
with a nocturnal sleep deprivation followed by a diurnal recovery sleep
from 0700–1500 h (right). To eliminate the effects of
interindividual variations in mean plasma leptin levels (ranging from
2.4–8.9 ng/mL), individual values of leptin were expressed as
percentages of the 24-h mean value.
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In the daytime sleep condition, marked differences were observed (Table 2). During the night of sleep deprivation, plasma leptin levels rose
slightly in all subjects, suggesting the existence of an intrinsic
circadian rhythm. The maximum level was slightly lower than that
observed in the condition of normal nocturnal sleep (104.7 ±
2.3% of the 24-h mean levels vs. 109.9 ± 2.5%), but
this difference was not significant. This maximum level occurred later
in the night (P < 0.05) and was followed by an abrupt
decrease during the second part of the night, with a minimum level
between 0700–0915 h depending on the subject. A second rise was then
clearly apparent during the first hours of shifted diurnal sleep with a
maximum at midday, 5 h after sleep onset (108.4 ± 3.1% of
the 24-h mean levels), followed by a progressive decline with a minimum
in the late afternoon. The sleep-associated diurnal maximum was
significantly higher than the inconsistent and slight increase observed
during the daytime in the absence of sleep (P < 0.05).
There was no significant difference in mean plasma leptin levels during
the three 8-h periods considered; the amplitude of the mean diurnal
leptin variations was lower than that during normal nocturnal sleep
(13.4 ± 3.6% of the mean 24-h levels), although the difference
was not significant.
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Relationship with body temperature, glucose, and insulin 24-h profiles in nighttime and daytime sleep conditions
In the conditions of normal nocturnal sleep, the mean rectal Tre profile mirrored the mean plasma leptin profile with a nocturnal minimum and a significant rise in the late afternoon. In contrast, the profiles of mean plasma glucose and insulin paralleled the mean plasma leptin profile with a significant rise in the second part of the night and a progressive decline throughout the day. The peak of leptin at night preceded the nadir in Tre by about 1 h; the cross-correlation analysis showed that the smoothed profiles of plasma leptin and those of Tre were significantly and inversely correlated for six of the seven subjects, with an average cross-correlation coefficient at lag -60 min of -0.68 (P < 0.001). The variations in plasma leptin levels were roughly associated with those of glucose. However, the paired cross-correlation analysis between the smoothed profiles of plasma leptin and the smoothed profiles of plasma glucose and plasma insulin failed to reveal any systematic significant relationship among the subjects.
The daytime sleep conditions made it possible to dissociate some of the temporal relationships observed in the normal conditions of nocturnal sleep. In these conditions, a temporal relationship clearly remained between plasma leptin and Tre, with a mean temperature profile characterized by two nadirs, one during nocturnal sleep deprivation and the other during daytime sleep. The maximum nocturnal plasma leptin level was concomitant with a minimum in Tre, whereas during diurnal sleep, the leptin acrophase followed the Tre nadir; the cross-correlation analysis between the paired profiles of plasma leptin and Tre revealed significant cross-correlation coefficients for several subjects but not for the others, so that the test of Snedecor indicated the nonhomogeneity of the coefficients within the group. In the sleep-shift condition, the Tre minima reached during the night and during diurnal sleep were of similar levels, but both were higher than the minimum noticed during normal nocturnal sleep; this resulted, as observed for plasma leptin, in a diminished, although not significantly, amplitude of the diurnal body temperature variations (1.6 ± 0.2% vs. 2.6 ± 0.3% of the mean 24-h levels).
When both conditions, i.e. normal nocturnal sleep and daytime shifted sleep, were considered together, the amplitudes of the diurnal plasma leptin and Tre variations were significantly correlated (r = 0.57; P < 0.05). This correlation remained significant after adjustment for body mass index. Thus, the larger the decrease in leptin levels from nocturnal maximum to evening minimum, the higher the Tre rise from nocturnal nadir to evening maximum.
As previously described (20), mean plasma glucose and insulin profiles were characterized by a nocturnal decrease followed by a daytime sleep-induced increase, reflecting both circadian and sleep influences. Mean plasma insulin levels were markedly influenced by sleep with only a slight circadian effect, whereas mean nocturnal glucose levels were similar whatever the sleep conditions, suggesting a more potent circadian influence with only a slight sleep effect. Despite this dual circadian and sleep-associated influence on glucose regulation, no systematic quantitative relationship between smoothed plasma leptin and plasma insulin or glucose profiles was observed.
Leptin ultradian pulsatility
Figure 2 gives the individual leptin
profiles in two representative subjects in both conditions,
i.e. with a normal nocturnal sleep from 2300–0700 h
(left) and with a nocturnal sleep deprivation followed by a
diurnal recovery sleep from 0700–1500 h (right).
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). Their
mean amplitude was 0.71 ± 0.12 ng/mL (17.4 ± 0.9% when
expressed as a percentage of the precedent trough level), and their
mean duration was 70.0 ± 4.3 min. The number of pulses was not
influenced by either sleep or time of day, but the high variability in
the interpeak time indicated the irregular periodicity of the leptin
pulses, which contrasted with the relative regularity of the glucose
and insulin oscillations.
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illustrates the mean
relative variations in plasma leptin levels, aligned by the maximum of
the significant pulses (average of 186 individual significant leptin
pulses) together with the concomitant plasma insulin levels. The leptin
pulses were associated with significant variations in plasma insulin
levels (P < 0.01) with a minimum at time zero and the
highest levels 30–40 min before the leptin peak. Similar results were
observed for plasma glucose levels (P < 0.01).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The 24-h profiles observed in normal nocturnal sleep conditions confirm and extend the findings of previous studies indicating a nocturnal increase in plasma leptin levels in normal and obese subjects (6, 7, 8, 10), with an amplitude of about 40–50% of the 24-h mean. In our experimental conditions, confusing or masking effects of food ingestion or prolonged fasting were avoided by replacing the normal caloric intake by constant enteral nutrition. Moreover, the potential influences of posture and physical activity were eliminated because the subjects remained supine before and throughout the experiment. A 24-h habituation session minimized stress effects due to laboratory procedures. In these conditions, the diurnal variations in plasma leptin levels remained clearly apparent, although their amplitude (18% of the 24-h mean) was reduced, thus confirming that in free living conditions the variations are amplified by food intake, daily energy expenditure, and posture.
Individual subjects, who were asked to comply with a regular schedule of sleep during the week preceding the experiment to optimize interindividual synchronization, were studied twice during 24-h experiments, once with an 8-h normal nocturnal sleep and once with an acute 8-h shift in the sleep period. This methodology allowed us to study the effects of the time of day independently of those of sleep as well as the effects of sleep at an unusual time. The profiles observed in these conditions clearly indicate that circadian rhythmicity and sleep both influence plasma leptin levels. Indeed, during the night, plasma leptin levels increased, whatever the sleep conditions (normal nocturnal sleep or sleep deprivation) and then decreased. The persistence of a slight nocturnal increase despite the 8-h sleep shift and in the absence of variation of any environmental condition such as external temperature, light, physical activity, or diurnal food intake indicates that the diurnal variations are at least partly controlled by a robust endogenous circadian pacemaker, which explains variations with an amplitude of about 13.8% of the 24-h mean. On the other hand, after a night of sleep deprivation, a significant increase in plasma leptin levels was observed after morning sleep onset, which gave evidence of sleep influence whatever the time when it occurs. Such a dual influence is a common finding for numerous biological processes (14), and most of the 24-h endocrine rhythms have been shown to be under multifactorial control, combining a circadian oscillator, located in the suprachiasmatic nuclei of the hypothalamus, and environmental or sleep-related influences. Even hormonal systems, which are markedly modulated by a circadian rhythm such as cortisol or TSH, are influenced by sleep (14, 26, 27). Similarly, the existence of a weak endogenous circadian rhythmicity has been revealed in clearly defined sleep-related rhythms, such as that of PRL or GH, which are known to display a major pulse concomitant to sleep onset (28).
In humans, core body temperature is also characterized by a circadian rhythmicity, which is partly explained by the hypothermic properties of melatonin. However only about 40% of the amplitude of the body temperature rhythm can be accounted for by the endogenous peak of melatonin (29). In the present study, body temperature variations mirrored those of leptin in both experimental conditions. Furthermore, the amplitude of the diurnal variations in plasma leptin levels were significantly correlated with the amplitude of the diurnal body temperature variations, suggesting that leptin could be involved in the acute circadian metabolic adjustments independently of its action on food intake. Indeed, it has been shown that in ob/ob mice, an acute injection of leptin has a profound stimulatory effect on energy expenditure, which is particularly obvious during the period of minimal metabolic rate (30); similarly, administration of leptin twice a day leads to the disappearance of normal body temperature and metabolic rate circadian cycles (31). Such metabolic effects, which have been related to a sympathetic activation of thermogenesis, remain to be demonstrated in man. They would fit in, however, with recent studies indicating that under controlled constant routine, heat production exhibits a significant circadian rhythmicity that parallels heart rate variations and precedes body temperature variations (32). The exact temporal relationships linking plasma leptin and body temperature circadian variations in man have yet to be determined. The inverse relationship between plasma leptin and body temperature could reflect a phase relationship of 8–12 h, with leptin variations leading those in body temperature, so that the diurnal leptin decrease would be related to the subsequent nocturnal body temperature decrease. Alternatively, plasma leptin variations may be due to a counterregulatory negative feedback loop among thermogenesis, body temperature, and leptin secretion.
The significant increase in plasma leptin levels associated with sleep onset, even if it occurred at an abnormal time of the day, was concomitant with the well documented sleep-associated plasma insulin and glucose increases and the body temperature decrease. Changes in plasma insulin and glucose levels associated with sleep reflect changes in glucose utilization during sleep due to diminished brain glucose metabolism and diminished muscle tone (33). Similarly, decreased body temperature is the consequence of a diminished metabolism rate, partially induced by a diminution of sympathetic tone (34). As a consequence, one can expect an adaptive increase in leptin levels due to a stimulatory effect of an increase in plasma insulin or to the diminution of the sympathetic, inhibitory control. Other sleep-related hormonal releases, such as that of GH, may also be implicated.
Concerning leptin pulsatility, we found an average of 13.5 pulses during the 24-h experiments. This number, obtained in man under continuous enteral nutrition, is lower than that observed by Licinio (17), who reported a mean pulse frequency of 32 pulses/24 h. The relative conservative threshold used in our study and the higher blood-sampling frequency used in their study (every 7 min) may partly explain this difference. In addition, the different experimental conditions, such as daytime repeated meal intake or diurnal posture variations, may have influenced in their experiment not only the circadian but also the ultradian rhythmicity. The frequency of the pulses may have been affected or their amplitude, thus making them more difficult to detect. Similarly, the use of a constant glucose infusion associated with a less frequent blood-sampling procedure (every 15 min) probably explains the lower pulse frequency reported by Sinha (16).
In our experimental conditions, the number and the amplitude of the pulses were not affected by either sleep or time of day. However, leptin pulses were associated with a significant decrease in plasma glucose and insulin levels, and a slight, but significant concordance of about 50% was observed between leptin pulses and those of glucose or insulin, with the glucose and insulin pulses leading the leptin pulses. These results suggest that the glucose and insulin ultradian oscillations may affect the subsequent leptin levels, but they also indicate that the concordance is not systematic and that other mechanisms are probably implicated.
In conclusion, our study demonstrates that circadian and ultradian rhythmicities are two components of the plasma leptin pattern in normal man; this may be of physiological significance and should be taken into account when studying leptin in pathological states. Conversely, we also demonstrate that sleep is a physiological regulator of plasma leptin levels; it can, therefore, be suggested that chronic sleep disturbances such as those occurring in night workers or in sleep apnea, situations known to be frequently associated with overweight, may disturb the normal leptin 24-h pattern. Further studies are necessary to elucidate the exact relationship with body temperature regulation and insulin secretion.
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Acknowledgments |
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Received December 31, 1997.
Revised February 19, 1998.
Accepted February 26, 1998.
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