Role of Sleep and Sleep Loss in Hormonal Release and Metabolism

Abstract

Compared to a few decades ago, adults, as well as children, sleep less. Sleeping as little as possible is often seen as an admirable behavior in contemporary society. However, sleep plays a major role in neuroendocrine function and glucose metabolism. Evidence that the curtailment of sleep duration may have adverse health effects has emerged in the past 10 years. Accumulating evidence from both epidemiologic studies and well-controlled laboratory studies indicates that chronic partial sleep loss may increase the risk of obesity and weight gain. The present chapter reviews epidemiologic studies in adults and children and laboratory studies in young adults indicating that sleep restriction results in metabolic and endocrine alterations, including decreased glucose tolerance, decreased insulin sensitivity, increased evening concentrations of cortisol, increased levels of ghrelin, decreased levels of leptin and increased hunger and appetite. Altogether, the evidence points to a possible role of decreased sleep duration in the current epidemic of obesity. Bedtime extension in short sleepers should be explored as a novel behavioral intervention that may prevent weight gain or facilitate weight loss. Avoiding sleep deprivation may help to prevent the development of obesity, particularly in children.

Full text

Role of Sleep and Sleep Loss in Hormonal Release and
Metabolism
Rachel Leproult and Eve Van Cauter
Department of Medicine, University of Chicago, Chicago, Ill., USA
Abstract
Compared to a few decades ago, adults, as well as children, sleep less. Sleeping as little as
possible is often seen as an admirable behavior in contemporary society. However, sleep plays a
major role in neuroendocrine function and glucose metabolism. Evidence that the curtailment of
sleep duration may have adverse health effects has emerged in the past 10 years. Accumulating
evidence from both epidemiologic studies and well-controlled laboratory studies indicates that
chronic partial sleep loss may increase the risk of obesity and weight gain. The present chapter
reviews epidemiologic studies in adults and children and laboratory studies in young adults
indicating that sleep restriction results in metabolic and endocrine alterations, including decreased
glucose tolerance, decreased insulin sensitivity, increased evening concentrations of cortisol,
increased levels of ghrelin, decreased levels of leptin and increased hunger and appetite.
Altogether, the evidence points to a possible role of decreased sleep duration in the current
epidemic of obesity. Bedtime extension in short sleepers should be explored as a novel behavioral
intervention that may prevent weight gain or facilitate weight loss. Avoiding sleep deprivation
may help to prevent the development of obesity, particularly in children.
Hormones that Influence Glucose Regulation and Appetite Control Are
Influenced by Sleep
The temporal organization of the release of the counterregulatory hormones growth hormone
(GH) and cortisol as well as the release of hormones that play a major role in appetite
regulation, such as leptin and ghrelin, is partly dependent on sleep timing, duration and
quality. Glucose tolerance and insulin secretion are also markedly modulated by the sleep-
wake cycle [1]. Sleep propensity and sleep architecture are in turn controlled by the
interaction of two time-keeping mechanisms in the central nervous system, circadian
rhythmicity (i.e. intrinsic effects of biological time, irrespective of the sleep or wake state)
and sleep-wake homeostasis (i.e. a measure of the duration of prior wakefulness, irrespective
of time of day).
Circadian rhythmicity is an endogenous oscillation with a near 24-hour period generated in
the suprachiasmatic nuclei of the hypothalamus. The ability of the SCN nuclei to generate a
circadian signal is not dependent on cell-to-cell interaction and synchronization. Instead,
single SCN cells in culture can generate circadian neural signals [2]. The generation and
maintenance of circadian oscillations in SCN neurons involve a series of clock genes
(including at least per1, per 2, per3, cry1, cry2, tim, clock, B-mal1, CKIε/δ), often referred
to as ‘canonical’, which interact in a complex feedback loop of transcription/translation
Copyright © 2010 S. Karger AG, Basel
Eve Van Cauter, PhD Department of Medicine, MC1027 5841 S. Maryland Avenue Chicago, IL 60637 (USA) Tel. +1 773 702 0169,
Fax +1 773 702 7686, evcauter@medicine.bsd.uchicago.edu.
NIH Public Access
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Published in final edited form as:
Endocr Dev
. 2010 ; 17: 11–21. doi:10.1159/000262524.
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[3,4]. Circadian timing is transmitted to other areas of the brain and to the periphery via
direct neuronal connections with other parts of the hypothalamus, via the control of
sympathetic nervous activity and via hormonal signals, including melatonin. The molecular
and neuronal mechanisms that measure the duration of prior wakefulness and are thus
responsible for the homeo-static control of sleep have not been fully elucidated. Human
sleep is comprised of rapid-eye-movement (REM) sleep and non-REM sleep. Deep non-
REM sleep is characterized by ‘slow waves’ in the electroencephalogram (EEG), which
reflect a mode of synchronous firing of thalamo-cortical neurons. The intensity of non-REM
sleep may be quantified by slow wave activity (SWA; EEG spectral power in the 0.5–4 Hz
frequency range). Slow waves of larger amplitude and greater regularity are reflected in
higher SWA and in deeper sleep. Because SWA decreases in the course of the sleep period,
is higher after sleep deprivation (i.e. extended wakefulness) and lower when the waking
period has been interrupted by a long nap (i.e. shorter wakefulness), SWA is considered as
the major marker of homeostatic sleep pressure. Converging evidence implicates adenosine,
an inhibitory neurotransmitter, in sleep homeostasis in mammals [5]. Prolonged wakefulness
results in increased levels of extracellular adenosine, which partly derive from ATP
degradation, and adenosine levels decrease during sleep [6]. The adenosine receptor
antagonist, caffeine, inhibits SWA [7]. It has been proposed that the restoration of brain
energy during SWS involves the replenishment of glycogen stores [8]. The results of
experiments testing this hypothesis have been mixed. A recent and well-supported
hypothesis regarding sleep homeostasis is that the level of SWA in early sleep is a function
of the strength of cortical synapses developed during wakefulness and that the decline in
SWA across the sleep period reflects the downscaling of these synapses [9].
The major mechanisms by which the modulatory effects of circadian rhythmicity and sleep-
wake homeostasis are exerted on peripheral physiological systems include the modulation of
hypothalamic activating and inhibiting factors controlling the release of pituitary hormones
and the modulation of sympathetic and parasympathetic nervous activity.
The relative contributions of the circadian signal versus homeostatic sleep pressure vary
from endocrine axis to endocrine axis. It has been well-documented that GH is a hormone
essentially controlled by sleep-wake homeostasis. Indeed, in men, the most reproducible
pulse of GH occurs shortly after sleep onset, during slow wave sleep (SWS, stages 3 and 4)
when SWA is high. In both young and older men, there is a ‘dose-response’ relationship
between SWS and nocturnal GH release. When the sleep period is displaced, the major GH
pulse is also shifted and nocturnal GH release during sleep deprivation is minimal or frankly
absent. This impact of sleep pressure on GH is particularly clear in men but can also be
detected in women.
The 24-hour profile of cortisol is characterized by an early morning maximum, declining
levels throughout the daytime, a period of minimal levels in the evening and first part of the
night, also called the quiescent period, and an abrupt circadian rise during the later part of
the night. Manipulations of the sleep-wake cycle only minimally affect the wave shape of
the cortisol profile. Sleep onset is associated with a short-term inhibition of cortisol
secretion that may not be detectable when sleep is initiated in the morning, i.e. at the peak of
corticotropic activity. Awakenings (final as well as during the sleep period) consistently
induce a pulse in cortisol secretion. The cortisol rhythm is therefore primarily controlled by
circadian rhythmicity. Modest effects of sleep deprivation are clearly present as will be
shown below.
The 24-hour profiles of two hormones that play a major role in appetite regulation, leptin, a
satiety hormone secreted by the adipocytes, and ghrelin, a hunger hormone released
primarily from stomach cells, are also influenced by sleep. The human leptin profile is
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mainly dependent on meal intake and therefore shows a morning minimum and increasing
levels throughout the daytime culminating in a nocturnal maximum. Under continuous
enteral nutrition, a condition of constant caloric intake, a sleep-related elevation of leptin is
observed, irrespective of the timing of sleep. Ghrelin levels decrease rapidly after meal
ingestion and then increase in anticipation of the following meal. Both leptin and ghrelin
concentrations are higher during nocturnal sleep than during wakefulness. Despite the
absence of food intake, ghrelin levels decrease during the second part of the night suggesting
an inhibitory effect of sleep per se. At the same time, leptin is elevated, maybe to inhibit
hunger during the overnight fast.
The brain is almost entirely dependent on glucose for energy and is the major site of glucose
disposal. Thus, it is not surprising that major changes in brain activity, such as those
associated with sleep-wake and wake-sleep transitions, impact glucose tolerance. Cerebral
glucose utilization represents 50% of total body glucose disposal during fasting conditions
and 20–30% postprandially. During sleep, despite prolonged fasting, glucose levels remain
stable or fall only minimally, contrasting with a clear decrease during fasting in the waking
state. Thus, mechanisms operative during sleep must intervene to prevent glucose levels
from falling during the overnight fast. Experimental protocols involving intravenous glucose
infusion at a constant rate or continuous enteral nutrition during sleep have shown that
glucose tolerance deteriorates as the evening progresses, reaches a minimum around mid
sleep and then improves to return to morning levels [10,11]. During the first part of the
night, decreased glucose tolerance is due to decreased glucose utilization both by peripheral
tissues (resulting from muscle relaxation and rapid hyperglycemic effects of sleep-onset GH
secretion) and by the brain, as demonstrated by PET imaging studies that showed a 30–40%
reduction in glucose uptake during SWS relative to waking or REM sleep. During the
second part of the night, these effects subside as light non-REM sleep and REM sleep are
dominant, awakenings are more likely to occur, GH is no longer secreted and insulin
sensitivity increases, a delayed effect of low cortisol levels during the evening and early part
of the night.
These important modulatory effects of sleep on hormonal levels and glucose regulation
suggest that sleep loss may have adverse effects on endocrine function and metabolism. It is
only during the past decade that a substantial body of evidence has emerged to support this
hypothesis. Indeed, earlier work had only involved conditions of total sleep deprivation
which are necessarily short term and therefore of dubious long-term clinical implication.
The more recent focus on the highly prevalent condition of chronic partial sleep deprivation
resulted in a major re-evaluation of the importance of sleep for health, and particularly for
the risks of obesity and diabetes. In the two sections below, we first summarize the evidence
from epidemiologic studies and then the evidence from laboratory studies.
Obesity and Sleep Loss: Epidemiologic Evidence
The increasing prevalence of obesity in both children and adults is affecting all
industrialized countries. Figure 1 shows the change in the prevalence of overweight among
American children per age category (2–5, 6–11 and 12–19 years) from 1971 to 2004 [12].
The prevalence of overweight went from about 5% in 1971 to about 15% in 2004 in each
age category.
Increases in food intake and decreases in physical activity are the two most obvious reasons
for the alarming increase in prevalence of obesity but experts agree that other factors must
also be involved. Among those, reductions in sleep duration has been proposed to be one of
the most likely contributing factors [13]. Over the past few decades, nightly sleep duration
(by self-report) has decreased in a mirror image with the increase in the prevalence of
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obesity. In 2008, the poll conducted by the National Sleep Foundation [14] revealed that
American adults sleep on average 6 h 40 min during weekdays and 7 h 25 min during the
weekend. In contrast, in 1960, the average sleep duration was 8.5 h [15]. Thus, over less
than 50 years, a reduction of sleep duration by 1.5–2 h seems to have occurred. Short sleep
durations seems to be also typical in American adolescents. Well-documented laboratory
studies have shown that, when given a 10-hour opportunity to sleep for several days,
children between 10 and 17 years of age sleep for about 9 h, indicating that sleep need is not
less than 9 h [16]. In stark contrast with this physiologic sleep need are the sleep durations
self-reported by American children between 11 and 18 years old in 2006 [17]. Even in the
youngest children, the amount of sleep is less than 9 hours and drops to 7 h or less in 16- to
18-year-olds (fig. 2).
Is there an association between the prevalence of obesity and the prevalence of short sleep
duration? Cross-sectional studies have examined associations between sleep duration and
BMI in both children and adults and prospective studies have tested the hypothesis that short
sleep duration at baseline predicted weight gain or the incidence of obesity over the follow-
up period. All studies controlled for a variety of potential confounders. In adults, as of May
2009, a total of 29 cross-sectional studies and 6 prospective studies originating from a wide
variety of industrialized countries have been published. Thirty of these 35 studies had
positive findings. Obesity risk generally increased for sleep durations under 6 h. There have
been 20 cross-sectional studies in children and all had positive findings. Prospective studies
are particularly important because they provide an indication regarding the direction of
causality. Also, an overweight child is at higher risk of becoming an overweight or obese
adult. Table 1 summarizes the 7 prospective epidemiologic studies so far that have examined
sleep duration and obesity risk in boys and girls. All 7 studies showed a significant
association between short sleep duration at baseline and weight gain or incidence of
overweight or obesity over the follow-up period.
In conclusion, the epidemiologic data consistently support a link between short sleep and
obesity risk. Negative studies were mostly focusing on older adult populations. Of note, two
cross-sectional studies used objectively recorded sleep, rather than self-report, and also
found a significant association between short sleep and higher BMI. A major limitation of
nearly all these studies is that there was no assessment of sleep quality or sleep disorders and
therefore it is generally not known if short sleep was the result of bedtime restriction in a
healthy sleeper or of the inability to achieve more sleep in an individual suffering from a
sleep disorder.
Epidemiologic studies in adults have also shown associations between short sleep and
diabetes risk [25]. Studies are needed to determine if the increased prevalence of type 2
diabetes in children and young adults is also partly predicted by short sleep.
Obesity, Diabetes and Sleep Loss: Evidence from Laboratory Studies
There has been no laboratory study so far that has examined the impact of experimental
recurrent sleep restriction on hormones and metabolism in children. The existing laboratory
studies were all conducted in young to middle-aged adults.
The first well-controlled laboratory study that tested the hypothesis that partial sleep
deprivation could affect the metabolic and endocrine function was published 10 years ago
[26]. Young lean subjects were studied (1) after building a state of sleep debt by restricting
bedtime to 4 h for 6 nights, (2) after full recovery, obtained by extending the bedtime period
to 12 h for 7 nights, and (3) under normal condition of 8 h in bed. This latter 8-hour bedtime
condition was performed 1 year after the two other sleep conditions. Figure 3 shows the 24-
hour profiles of leptin, cortisol, GH and HOMA (homeostatic model assessment, an
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integrated measure of glucose and insulin, that is the product of glucose concentration
(mmol/l) by insulin concentration (mIU/l) divided by 22.5) under the 3 bedtime conditions
[26]. Caloric intake was the same in the 3 conditions, i.e. 3 identical carbohydrate-rich
meals. Posture and physical activity were also controlled as continuous bed rest was
enforced during blood sampling. Clearly, overall leptin levels, evening cortisol levels, and
the HOMA response to breakfast varied in a dose-response relationship with sleep duration.
Shorter sleep duration was associated with greater disturbances in these hormonal and
metabolic variables. Leptin levels were lowest when the subjects were in a state of sleep
debt, signaling the brain an unnecessary need for extra caloric intake. Evening cortisol levels
were highest when the subjects were in a state of sleep debt. A state of sleep debt therefore
appears to delay the normal return to low levels of corticotropic activity. HOMA levels post-
breakfast were the highest in a state of sleep debt indicating a decrease in glucose tolerance
and/or a decrease in insulin sensitivity. The 24-hour GH profiles in the 8- and 12-hour
bedtime conditions were qualitatively similar, with a trend for lower post-sleep peak values
in the extended bedtime that is consistent with a reduced homeostatic drive for sleep with
the decreased duration of the wake period. In the state of sleep debt, a GH pulse prior to
sleep onset was observed, in addition to the normal post-sleep onset GH pulse. The elevation
of GH concentrations during waking could have an adverse impact on glucose metabolism.
A subsequent study [27] examined appetite regulation after 2 nights of 4 h in bed and after 2
nights of 10 h in bed, in a randomized cross-over design. This study confirmed the decrease
in leptin levels seen in the previous study, with a 18% decrease of leptin levels after the
short nights relative to the long nights. Furthermore, ghrelin was assayed and showed a 28%
increase after the 2 nights of 4 h in bed. Questionnaires on hunger and appetite were
completed and indicated a 24% increase in hunger and a 23% increase in global appetite
after the 4-hour nights versus the 10-hour nights. Appetite for high carbohydrate nutrients
was the most affected with a 32% increase. Importantly, the subjective report of increased
hunger was correlated with the increase in ghrelin to leptin ratio (i.e. hunger factor/satiety
factor). These observations suggest that in real life, when food is available everywhere and
all the time, sleep deprived people may consume excessive amounts of calories, particularly
from carbohydrates. A recent study tested this hypothesis using a randomized cross-over
design with either extension or restriction of the usual bedtime period by 1.5 h for 2 weeks
in the laboratory [28]. The subjects were middle-aged overweighed individuals who were
exposed to unlimited amounts of palatable food presented in 3 meals per day and snacks
were continuously available. The volunteers consumed excessive amounts of calories from
meals under both sleep conditions but consumed more calories from snacks when sleep was
restricted rather than extended.
Several studies have also shown that recurrent partial sleep restriction or experimentally
reduced sleep quality results in decreased insulin resistance, another risk factor for weight
gain and obesity. Remarkably, the decrease in insulin sensitivity was not associated with a
compensatory increase in insulin release, and therefore diabetes risk was elevated.
The upper part of table 2 presents a re-analysis of the data from intravenous glucose
tolerance testing (ivGTT) performed in the initial ‘sleep debt study’ [26] after 5 days of
bedtime restriction to 4 h per night and when the subjects were fully rested at the end of the
recovery period. Glucose tolerance was decreased by more than 40% when the subjects were
in the state of sleep debt. This may be partly due to a decrease in brain glucose utilization as
Sg (glucose effectiveness) which quantifies non-insulin-dependent glucose disposal, was
significantly reduced. Insulin-dependent glucose disposal was also decreased since the
glucose disposition index was markedly lower. Consistent findings have been observed in
several follow-up studies [29,30].
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Recently, a study showed that reduced sleep quality, without change in sleep duration, can
also have adverse effects on glucose metabolism [31]. Slow-wave sleep was suppressed by
delivering acoustic stimuli that replaced deep sleep SWS by shallow NREM sleep (stage 2)
for 3 consecutive nights, mimicking the impact of four to five decades of aging. The lower
part of table 2 shows the results of an ivGTT performed at baseline and after 3 nights of
SWS suppression. The findings are qualitatively similar to those seen after 5 nights of
bedtime curtailment but of lesser magnitude as would be expected since the intervention was
of shorter duration.
Conclusions
Rapidly accumulating evidence suggests that sleep disturbances, including insufficient sleep
due to bedtime curtailment and poor sleep quality, may represent novel risk factors for
obesity and type 2 diabetes. While laboratory studies have been conducted in adults only, a
large number of epidemiologic studies in pediatric populations have demonstrated
associations between short sleep and adiposity that are often stronger than those seen in
adult populations. Sleep curtailment appears to be an increasingly prevalent behavior in
children and, in the United States, adolescents may well be the most sleep-deprived age
group with a difference between self-reported sleep and estimated sleep need of more than 2
h daily. There is a paucity of knowledge regarding how insufficient sleep and sleep disorders
may affect pubertal development and growth, despite the fact that it has been known for
several decades that the release of sex steroids and GH is markedly dependent on sleep
during the pubertal transition. An increasing number of children are obese and may suffer
from obstructive sleep apnea. The impact of this sleep disorder, which is known to promote
insulin resistance and reduced testosterone in adults, on neuroendocrine release and
metabolic function in children is in urgent need of rigorous study.
Acknowledgments
Part of the work described in this article was supported by US National Institute of Health grants P01 AG-11412,
R01 HL-075079, P60 DK-20595, R01 DK-0716960, R01 HL-075025 and M01 RR000055 and by US Department
of Defense award W81XWH-07–2-0071.
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Fig. 1.
Prevalence of overweight (>95th percentile) among American children and adolescents ages
2 to 19 years old from 1971 to 2004.
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Fig. 2.
Self-reported sleep duration in American adolescents in 2004.
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Fig. 3.
Relationship between sleep duration and leptin, cortisol, GH and HOMA.
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Table 1
Prospective studies of sleep (reported by the parents) and obesity risk in boys and girls.
Reference Number of subjects and years of follow-up Results Country of origin
Lumeng et al. [18],
2007 n = 785
aged 9–10 years (3rd grade) and 11–12 years
(6th grade)
short sleep duration in 3rd grade is
associated with overweight in 6th grade USA
Agras et al. [19], 2004 n = 150
sleep reported at 3-5 years weight measured at
9.5 years
less sleep time in childhood is a risk factor
for childhood overweight USA
Reilly et al. [20], 2005 n = 7,758
sleep reported at 38 months obesity measured
at 7 years
short sleep duration (<10.5 h) at age 3 years
is associated with a risk of obesity UK
Taveras et al. [21],
2008 n = 915
sleep reported at 6 months, 1 year and 2 years
BMI z score measured at 3 years
short sleep duration (<12 h/day) during
infancy is associated with a higher BMI z
score at 3 years
USA
Touchette et al. [22],
2008 n = 1,138
sleep duration reported yearly from 2.5 to 6
years BMI measured at 2.5 and 6 years
persistent short sleepers (<10 h) increases
risk of overweight and obesity in later
childhood
Canada
Sugimori et al. [23],
2004 n = 8,170
sleep and BMI measured at ages 3 and 6 years short sleep duration (≤9 h) is associated with
a risk of obesity in boys, not in girls Japan
Snell et al. [24], 2007 n = 2,281
aged 3–12 years at baseline and 5 years later less sleep is associated with higher BMI, 5
years later USA
Endocr Dev. Author manuscript; available in PMC 2011 March 28.

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Table 2
Alterations in glucose metabolism after sleep loss: 2 laboratory studies
p % change from well-rested condition
5 nights of 4-hour bedtimes (n = 11)
Glucose tolerance (% · min-1)≤0.003 –43 ± 12
Acute insulin response to glucose (μU · ml-1 · min) ≤0.03 –27 ±10
Glucose effectiveness ≤0.05 –25 ± 19
Insulin sensitivity, 104 min-1 (μU/ml)-1 ≤0.04 –24 ± 9
Disposition index 0.004 –50 ± 6
3 nights of slow-wave sleep suppression (n = 9)
Glucose tolerance, % · min-1 ≤0.03 –23 ± 9
Acute insulin response to glucose, μU · ml-1 · min ≤0.73 +11 ± 11
Glucose effectiveness ≤0.19 –15 ± 10
Insulin sensitivity, 104 min-1 (μU/ml)-1 ≤0.009 –25 ± 8
Disposition index ≤0.02 –20 ± 7
Endocr Dev. Author manuscript; available in PMC 2011 March 28.