Review

Circadian dysfunction in disease

David A. Bechtold, Julie E. Gibbs and Andrew S.I. Loudon
Faculty of Life Sciences, AV Hill Building, University of Manchester, Manchester, M13 9PT

The classic view of circadian timing in mammals emphasizes a light-responsive master clock within the hypothalamus which imparts temporal information to the
organism. Recent work indicates that such a unicentric
model of the clock is inadequate. Autonomous circadian
timers have now been demonstrated in numerous brain
regions and peripheral tissues in which molecular-clock
machinery drives rhythmic transcriptional cascades in a
tissue-specific manner. Clock genes also participate in
reciprocal regulatory feedback with key signalling pathways (including many nuclear hormone receptors),
thereby rendering the clock responsive to the internal
environment of the body. This implies that circadianclock genes can directly affect previously unforeseen
physiological processes, and that amid such a network
of body clocks, internal desynchronisation may be a key
aspect to circadian dysfunction in humans. Here we
consider the implications of decentralised and internally
responsive clockwork to disease, with a focus on energy
metabolism and the immune response.
Introduction
Virtually all aspects of human physiology are mapped onto
24-hour rhythms. These include sleepwake cycles, body
temperature, hormone secretion, blood pressure, and
metabolism. These biological rhythms are orchestrated by
an endogenous circadian timing system that can generate
robust and temporally relevant (i.e. 24-hour) rhythms even
in the absence of external inputs, which nevertheless
remains sensitive to environmental cues such as light.
Internal timers enable us to anticipate fluctuations in our
environment and adapt our physiology appropriately. Critically, the circadian clock also synchronizes and dictates the
relative phasing of diverse internal physiological processes
and molecular pathways [1]. Such internal coordination
is essential to optimise our metabolic responses and
strengthen inherent homeostatic regulatory mechanisms.
The impact of circadian timing on human health has
garnered increasing attention over recent years, and circadian dysfunction is now considered to be a contributory
factor to the incidence and severity of a wide range of clinical
and pathological conditions, including sleep disorders, cancer, depression, metabolic syndrome, and inflammation
(Figure 1). Much of the initial evidence has come from
studies demonstrating an increased association of disease
with lifestyles that inherently disrupt our natural circadian
behavioural patterns such as chronic shift-work, frequent
air travel, and chronic restriction of sleep. For example,
careers involving long-term shift-work are associated with
Corresponding authors: Bechtold, D.A. (david.bechtold@manchester.ac.uk);
Gibbs, J.E. (Julie.gibbs@manchester.ac.uk); Loudon, A.S.I.
(andrew.loudon@manchester.ac.uk)

an increased incidence of cancer of the breast and colon

[24]. A direct impact of circadian timing on tumourigenesis
may be envisioned because numerous genes regulating the
cell cycle such as Wee1, cyclin D1, and c-Myc are modulated
by the rhythmic activity of core clock genes [5,6]. The clock
gene period has also been implicated directly in tumour
suppression and DNA repair in rodents [7,8], seemingly
independent of its function within the clock. Discerning
the relative impact of disrupted circadian rhythms per se
from the possible pleiotropic actions of individual core clock
genes in human disease will therefore be a challenge. Nevertheless, specific clinical indications related to altered clock
function have been recognised in certain circumstances, and
are already driving therapeutic advancements. For
example, several sleep disorders have been linked directly
to altered circadian function [9] (Box 1).
In the current review, we briefly discuss how the circadian clock engages with diverse physiological systems
through neuronal and molecular outputs. We then focus
on two fundamental aspects of human physiology (energy
metabolism and the immune system) to consider how
disruptions of the circadian clock may contribute to disease.
Anatomy of the circadian clock
In mammals, the hypothalamic suprachiasmatic nucleus
(SCN) serves as the predominant circadian timer in the
body, and is exquisitely responsive to light via the retinal
hypothalamic tract. The dominance of the SCN in dictating
rhythmic behaviours is demonstrated by studies of SCN
transplantation. Here, transplant of donor SCN tissue to
animals bearing SCN lesions (behaviourally arrhythmic)
results in the restoration of behavioural rhythmicity which
matches the circadian phenotype of the donor [1014].
SCN-derived signals involved in entraining locomotor
rhythms are not yet fully characterised, but must include
diffusible signals because encapsulated transplants can
restore rhythms to SCN-lesioned hosts. Yet, in contrast
to locomotor activity, rhythms of secretion of melatonin
and glucocorticoid are not restored after SCN transplants
[1115]. Furthermore, studies of clock gene rhythms in
peripheral organs show that SCN transplantation can reestablish rhythmic expression of clock genes in some peripheral tissues (liver, kidney), but not others (heart,
spleen) [14]. Together, these findings demonstrate that a
combination of humoral factors and direct neuronal contact
are required for the full dissemination of SCN temporal
information to the CNS and peripheral organs.
The neuronal projection pathways of the SCN are relatively well characterised, and provide the SCN access
to numerous brain regions and peripheral tissues [16].
The SCN projects heavily to other hypothalamic centres

0165-6147/$ see front matter 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2010.01.002 Available online 18 February 2010

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Figure 1. Clocks and disease

Inappropriate or dampened circadian rhythms in behaviour and physiology can result from clock gene polymorphisms, de-synchronisation of our environment and
behaviour from our natural endogenous clocks, as well as during aging. Recent evidence suggests that disruption of the circadian system is a contributory factor to clinical
and pathological conditions including sleep disorders, cancer, depression, the metabolic syndrome, and inflammation.

[1720]. Through such connections, the SCN is thought to

impose temporal gating to homeostatic responses of the
hypothalamus, as well as drive the rhythmic release of
hormonal signals such as secretion of melatonin from
the pineal gland. For example, circadian components
of sleepwake cycles are driven principally through
SCN projections to the dorsomedial hypothalamus
(DMN) and posterior hypothalamic area [21]. Importantly,
the SCN can also access peripheral organ systems via
Box 1. PERIOD phosphorylation: genetic disorder to drug
development
A range of human sleep disorders have been linked to circadian
alterations in the timing of sleepwake cycles. These disorders
include advanced sleep phase syndrome (ASPS), delayed sleep
phase syndrome (DSPS), non-24-hour sleepwake syndrome, and
irregular sleepwake patterning [122]. A familial (inherited) form of
advanced sleep-phase syndrome (FASPS) is characterised by a
persistent and substantial (4 hours) advance in sleep onset and
awakening times [123,124], and was the first disorder to link a
known core clock gene directly to a human sleep disorder.
FASPS has been linked to alteration in PERIOD protein phosphorylation by the enzymes casein kinase 1e and d (CK1e and d).
Mutations in the PER2 (S662G), and CK1d (T44A) genes have been
identified in FASPS lineages [125,126], and both are now known to
alter CK1-mediated PER phosphorylation. PER phosphorylation by
CK1 influences transcriptional feedback within the clock by altering
the degradation rate and/or subcellular (nuclear) localisation of the
PER proteins [125,127,128]. Thus, the molecular basis of this form of
FASPS seems to be caused by an increased turnover of nuclear
PER2. Similarly, the tau mutation in hamsters [129] and mice [121],
which lies within the substrate-binding domain of CK1e, accelerates
behavioural rhythms by 4 hours. This mutation leads to hyperphosphorylation-mediated destabilisation of the PER protein
through an increase in targeted degradation [120,121,130]. Impressively, the 4-hour acceleration in circadian period can be observed
from gene rhythms in single cells, to SCN and peripheral tissue
oscillations, as well as in gross behavioural outputs such as
locomotor activity, metabolic rate and feeding cycles [121,130].
These observations have driven the development of novel
pharmaceutical agents that specifically target the enzymatic activity
of CK1e and d. Importantly, these agents can alter the inherent
properties of the clock (phase and period), in vitro and in vivo in a
dose-dependent manner [131,132]. It is tempting to speculate that
these agents may eventually provide a therapeutic route to
modulate or strengthen endogenous rhythms, and have far-reaching implications for human health.

192

paraventricular nucleus (PVN) connections to the sympathetic and parasympathetic neural pathways [22,23].
It has been demonstrated that the liver, the pancreas,
and the visceral adipose tissue all share a common and
specific neuronal connection with the PVN, DMN, and SCN
[18]. The importance of autonomic pathways in the
entrainment and synchronisation of peripheral tissues
by the SCN is highlighted in studies which show that
altered outputs to peripheral organs may underlie the
damping of circadian rhythms observed in metabolic syndrome (obesity and type-2 diabetes) [24,25].
Work over the past decade has shown that the capacity
for circadian timing is not limited to the SCN, and many
other brain regions, as well as virtually all peripheral
tissues can self-sustained circadian oscillation [2634].
Under normal circumstances, it is likely that these
extra-SCN clocks are subordinate to, and synchronised
by the SCN. Nevertheless, local timing systems are clearly
important for individual tissue and organ function. For
example, disruption of the clock specifically within the liver
causes fasting hypoglycaemia, exaggerated clearance of
glucose, and loss of rhythmic expression of hepatic glucose
regulatory genes [35]. We must therefore concede that
circadian rhythms in behaviour and physiology are
directed by a network of oscillators distributed across
the body. In the context of multiple body clocks, it is
important to note that, aside from light-entrainment (of
the SCN), the circadian system is highly responsive to nonphotic entraining stimuli such as meal timing, exercise,
and strong social interaction.
The molecular clock
The molecular basis of circadian timing involves interlocking transcriptional/translational feedback loops which culminate in the rhythmic expression and activity of a set of
core clock genes (Figure 2 and below). Rhythmic clock
genes then dictate the expression of many other genes
(clock-controlled genes, CCGs), which in turn drive cascades of rhythmic gene expression. The impact of these
transcriptional outputs is pronounced; gene microarray
studies show that at least 10% of total cellular transcripts
oscillate in a circadian manner [32,3640]. Interestingly, if

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Figure 2. Molecular clock machinery

The molecular machinery that provides circadian timekeeping consists of a complex circuitry of transcriptional/translational regulatory feedback loops (clock components
shown in grey). In mammals, the current model involves a primary loop with CLOCK (or homologue NPAS2) and BMAL1 as transcriptional activators, and PERIOD (PER1,
PER2 and PER3) and CRYPTOCHROME proteins (CRY1 and CRY2) as transcriptional repressors [1,119]. As levels of cytosolic PER and CRY proteins rise, they associate,
translocate to the nucleus, and repress their own gene transcription through direct interaction with the CLOCK/BMAL1 complex. This feedback cycle provides near 24-hour
timing, and drives the rhythmic expression of several clock-controlled and clock-modulated genes, which in turn mediate circadian rhythms in behaviour and physiology.
Acting on the primary feedback loop are auxiliary loops, which appear to increase the stability and robustness of the oscillations. The most notable interlocking loop is that
involving the nuclear hormone receptors (NRs), REV-ERB and ROR [41,42]. In addition to REV-ERB and ROR, several other NRs (shown in green) interact closely with the
circadian feedback loops, and are responsive to the clock (exhibit rhythmic expression) and able to feedback onto the clock genes themselves. NR regulation of clock genes
also renders the clock responsive to numerous circulating hormones (e.g. cortosol, estrogen), nutrient signals (e.g. derivatives of fatty acids and retinoids) and cellular
redox status (NADH/NAD+ ratio).
Clock proteins are also subject to extensive post-translational modulation that serves to reinforce and fine-tune its 24-hour cycle length. For example, phosphorylation of
PER proteins by casein kinase 1 (CK1) e and d isoforms has significant influence over the duration of the circadian cycle duration (period) [120,121]. Moreover, rhythms in
protein acetylation (mediated by CLOCK acetylase and SIRT1 deacetylase activities) are important in modulating the amplitude and phase of clock gene rhythms, as well as
conferring circadian transcriptional regulation to clock-controlled genes [45,5153]. BMAL1 and PER are subject to acetylation (red stars), which serves to stabilise the
proteins and enhance activity. Cellular energy supply (reflected in ATP/ADP and NAD+/NADH cycles) directly influences clock activity through SIRT1 and AMPK activities.
These auxiliary feedback loops and post-translational controls can modify the internal characteristics of the clock (e.g. the phase, amplitude and period of rhythmic gene
expression), making them intriguing targets for pharmacological intervention.

different tissues are compared, there is relatively little

overlap observed in the genes that cycle. This demonstrates that the circadian system can influence diverse
physiological processes in a tissue-specific manner.
Initially, the circadian clock was defined as a relatively
simple feedback loop based on the reciprocal interaction of
activators CLOCK and BMAL1 and repressors PERIOD
and CRYPTOCHROME (Figure 2). Within this loop,
CLOCK and BMAL1 heterodimers bind to E-box enhancer
elements within the promoter region of the Per and Cry
genes to activate their transcription with subsequent inhibition of CLOCK/BMAL1 activity by PER/CRY heterodimers. It is now clear that the clock incorporates many
auxiliary feedback loops, the most prominent of which
involves the nuclear hormone receptors (NRs) REV-ERB
and ROR [41,42]. REV-ERB and ROR repress and activate
BMAL1 expression, respectively, through shared RORbinding elements (ROREs) within the BMAL1 promoter

[41,42]. Just as the clock feedback loops produce rhythmic

oscillations in CLOCK/BMAL1, REV-ERB and ROR,
similar rhythmic expression cycles are imposed onto any
genes which are responsive to these transcription factors
through E-box, RORE and D-box (recognised by the CCG,
DBP) enhancer elements.
Chromatin remodelling also appears to be an important
component in facilitating clock-regulated gene expression.
CLOCK has recently been shown to function as a histone
acetyltransferase (HAT) [43,44], and transcriptional
rhythms in gene expression can be accompanied by
rhythms in histone acetylation, including within the promoter regions of the PER1, PER2 and CRY1 genes [45].
HAT activity (acetylation) attaches an acetyl group to
the histone, which serves to loosen chromatin structure
and facilitate gene transcription. SIRT1, a protein extensively linked to energy metabolism and aging [46], has
been identified as a histone deacetylase (HDAC) that
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counteracts CLOCK-mediated acetylation [47,48]. Targets
of CLOCK acetylation and/or SIRT1 deacetylation cycles
include not only histones [44], but also clock components
(e.g. BMAL1, PER2) and metabolic and inflammatory
regulators (e.g. PGC-1a, PPARa, NF-kB) [4750]. Rhythmic acetylation is likely to be important in modifying the
strength and phase of clock gene rhythms, as well as
conferring circadian transcriptional regulation to CCGs
[45,5153].
Outputs of the clock
Thus, through transcriptional and epigenetic modulation,
clock genes drive the expression of an extensive and diverse
set of CCGs, which in turn drive cascades of gene expression
that ultimately dictate rhythmic aspects of our behaviour
and physiology. The first line of CCGs directly responsive to
core clock gene regulation such as members of the PAR bZIP
family (e.g. DBP, TEF, HLF) [54] are themselves major
transcriptional regulators. Another group of CCGs which
link the clock to virtually all physiological processes in the
body includes members of the nuclear hormone receptor
(NR) family (Box 2). Many members of this family are
rhythmically regulated at the level of receptor expression
or via rhythmic ligand binding, with over half of the 48 NR
genes exhibiting rhythmic expression in a tissue-specific
manner [55]. Further, it is now evident that many NRs
can modulate clock gene expression (Figure 2).
Aside from their direct involvement in the clock machinery, REV-ERB and ROR are implicated in lipid metab-

Box 2. Nuclear hormone receptors

The human genome contains 48 nuclear hormone receptor (NR)
genes, comprising a large family of ligand-dependent transcription
factors. In contrast to most classic receptors, NRs bind directly to
DNA to modulate transcription, and ligand interactions occur
primarily within the cell cytosol or nucleus. NRs are key regulators
of most major physiological processes (e.g. development, reproduction, metabolism, inflammation and immunity), and NR ligands
include steroid and thyroid hormones, vitamin A and D derivatives,
oxysterols, and fatty-acid derivatives. The structure of NRs is
relatively well conserved, with an amino-terminal regulatory
domain, central DNA-binding domain, and carboxy-terminal ligand-binding domain. The receptors function as homodimers or
heterodimers binding at specific hormone response elements
(HSEs) within the gene promoter, and upon activation recruit coregulatory proteins to modulate transcription. Such co-regulatory
complexes often include proteins with intrinsic histone acetyltransferase (HAT) or histone deacetylase (HDAC) activity, which repress
or activate (respectively) transcription by altering the density of
DNAhistone interactions. Although the mechanism remains unclear, it is likely that NRs can also participate in non-genomic
signalling, evident by the fact that some ligand-mediated effects can
be observed within minutes of administration.
NRs are now recognised as key intermediaries between the
molecular clock machinery and a wide array of physiological
processes (Figure 2), and two NRs, REV-ERB and ROR are bonafide components of the clock. More than half of the NR family
exhibit rhythmic expression in a tissue-specific manner, and many
can feedback directly onto the clock itself [55,60]. For example,
glucocorticoids and retinoic acid can synchroniss and reset
peripheral clocks. Further, the core clock protein BMAL1 participates
in reciprocal transcriptional feedback with RORs, RER-ERBs, and
PPARs. ClockNR interactions are likely to contribute to circadian
dysfunction in disease, and represent targets for pharmacological
modulation.

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olism, adipogenesis, and the inflammatory response [56

58]. Until recently, REV-ERBa and REV-ERBb were considered to be constitutively active orphan receptors,
although heme has now been shown to bind reversibly
to both receptors and drive ligand-dependent activity
[59]. This implies that REV-ERB (and in turn clock
activity) are responsive to the cellular redox state and
perhaps gaseous signalling molecules (NO and CO)
through interactions with heme [60]. Similarly, glucocorticoids and retinoic acid can synchronise and reset peripheral clocks through their respective NRs [6163], and
PPARs, which are often rhythmically expressed in a
CLOCK/BMAL1-dependent manner, can modify BMAL1
expression [32,64]. PPARs bind fatty-acid derivatives, are
involved in lipid metabolism, and are also responsive to
energy status [65].
Consequently, NRs are not only important outputs
linking the clock to most physiological processes, but also
render the clock responsive to circulating hormones (e.g.
cortisol, estrogen) and metabolic signals (e.g. derivatives of
fatty acids and retinoids), as well as cellular energy and
redox status (Figure 2). Interestingly, many NRs with the
capacity to alter clock function are centrally involved in
energy metabolism and the immune system. In the following sections, we consider recent evidence linking circadian
dysfunction in these two physiological systems.
Circadian gating of the inflammatory response
Several inflammatory diseases exhibit a circadian
element to their symptoms. For example, patients with
rheumatoid arthritis report daily variations in their symptoms, experiencing greater joint pain, stiffness and functional disability in the mornings [66]. Some asthma
patients experience night-time exacerbations (nocturnal
asthma) that can be attributed (at least in part) to daily
variations in lung physiology (i.e airway narrowing), but
also increased bronchial responsiveness at night [67].
Circadian influences on the expression and circulating
level of immunomodulatory factors (hormones, cytokines)
have also been documented [68]. These no doubt contribute to fluctuations in symptom severity, yet more intimate
feedback between the molecular clock and inflammatory
pathways are now being uncovered.
At this point, there is a relative paucity of data directly
linking core clock proteins with inflammatory pathways.
Nonetheless, evidence from in-vivo studies suggest that a
systemic inflammatory stimulus (i.e. lipopolysaccharide
(LPS) administration) can modulate the expression of clock
genes (including per1/2, bmal1) in the SCN, PVN and
peripheral tissues, although some discrepancies exist between studies [6971]. In addition, it has been demonstrated through microarray analysis that a group of
immunoregulatory genes show a strong circadian pattern
of expression in the mouse liver, and this rhythmic expression is lost in clock mutant mice [37]. Direct modulation of
the immune response by the clock is also suggested by
studies showing that the induction of pro-inflammatory
cytokines IFNg and IL-1b after LPS challenge are
decreased in per2 / mice compared with wild-type mice
[72]. Furthermore, polymorphisms in per3 have been
associated with circulating levels of IL-6 [73], and mice

Review
experiencing repeated phase shifts (to mimic shift-work in
humans) exhibit heightened responses to subsequent
inflammatory challenge [74].
The mechanisms through which immune and inflammatory cells might be influenced or entrained by the SCN
are not presently clear, although a likely possibility is via
secretion of glucocorticoids and melatonin. Importantly,
inflammatory responses also appear to be gated at a local
level, within the mediating cells themselves. For example,
peritoneal macrophages exhibit rhythmic clock gene
expression, are capable of autonomous gene oscillation
in culture, and exhibit circadian gating in their responses
to LPS challenge [7577]. Gene microarray studies demonstrate that numerous genes involved in LPS response
pathways are rhythmically expressed in mouse macrophages, suggesting a direct influence of the clock on inflammatory responses [76].
An important pathway through which the circadian
clock may modify immune/inflammatory responses is the
NF-kB signalling cascade. The NF-kB pathway regulates
the immune response to infection by controlling transcription of target inflammatory genes. In non-stimulated cells,
NF-kB dimers are sequestered in the cytoplasm by IkBs
which mask the nuclear localisation signal; upon activation IkB is degraded to allow NFkB to enter the nucleus
and activate target genes. Importantly, bmal1 knockdown
in mouse peritoneal macrophages using siRNA can reduce
cytokine expression in concert with reduced activity of NFkB [75]. Of note, SIRT1 has also been shown to modify the
activity of NF-kB and the release of TNFa after LPS
treatment of macrophages [78].
The impact of the clock on the immune and inflammatory response may be indirect and involve downstream
CCGs such as the NRs. A link between NRs and inflammation has been established. In particular, through the
use of animal models of allergic airway disease (ovalbumin
challenge) and innate airway inflammation (LPS challenge), RORa, PPARa and PPARg have been associated
with the pathogenesis of pulmonary inflammatory diseases
[7981]. A link between REV-ERBa and the pulmonary
innate immune response has also been established. We
recently demonstrated that Rev-erba / mice exhibit a
heightened inflammatory response to LPS administration
(significantly increased release of specific cytokines and
enhanced neutrophil recruitment to the lung) and that
application of a REV-ERB ligand to human alveolar macrophages significantly reduces the LPS-driven release of IL-6
[77]. Moreover, pharmacological targeting of NRs (including LXR and PPAR) has been successful in demonstrating their involvement in pulmonary inflammation,
and highlighted their potential as pharmaceutical targets.
For example, the PPAR ligands fenofibrate and rosiglitazone reduce pulmonary inflammation (recruitment of
inflammatory cells and cytokine production) after LPS
administration to mice [79,82].
As yet, there is limited evidence to indicate the mechanisms through which these receptors affect inflammatory
pathways. LXR and REV-ERBa can interact to affect
expression of the pattern recognition receptor Toll-like
receptor 4 (involved in the innate immune response)
[83], but this is the only known nuclear receptor/receptor

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interaction reported to date. Several NRs are likely to

modulate the inflammatory response through direct interactions with the NF-kB signalling pathway [80,8486]. For
example, experiments in human primary smooth muscle
cells indicate that RORa1 directly induces IkBa via a
response element in its promoter [83].
Clock dysfunction in the metabolic syndrome
Several recent studies suggest that disruption of daily
metabolic rhythms is an exacerbating factor in the metabolic syndrome (obesity, diabetes, cardiovascular disease)
[8790]. The contribution of the circadian system in regulating metabolism has received increasing attention over
recent years [9195]. Many metabolic processes exhibit
coordinated circadian oscillation, such as feeding behaviour and the metabolism of glucose and lipids [9698],
and many genes involved in metabolic control are rhythmically expressed [32,33,36,99101]. Further, shift-work
and sleep deprivation are known to dampen rhythms in
growth hormone and melatonin, reduce insulin sensitivity,
and elevate circulating cortisol levels [102]. These changes
favour weight gain, obesity, and development of the metabolic syndrome. The importance of a functional circadian
system in the regulation of metabolism is also evident from
studies of animals with disrupted clock gene expression or
function [103106]. For example, clock mutant mice exhibit
a reduced metabolic rate and obesity [103].
Metabolic processes are readily decoupled from the
primarily light-driven SCN when food intake is desynchronised from normal daily patterns of activity. This has been
extensively modelled in rodents using restricted feeding
schedules (RFS) [107,108]. Under RFS, numerous physiological and metabolic functions become entrained to the
availability of food, e.g. locomotor activity, insulin and
corticosterone release. Therefore, rhythmic feeding
appears to be the dominant Zeitgeber for peripheral circadian oscillators [31], presumably to ensure optimal synchrony between metabolic processes and food intake. For
example, clock gene rhythms in the liver can entrain to
RFS within two days even though SCN activity remains
locked to lightdark cues throughout the duration of RFS
[109]. This implies that internal de-synchronisation
(decoupling of peripheral clocks from the SCN) could result
from lifestyles that oppose natural circadian rhythms.
Scheer and colleagues recently examined the effects of
such internal de-synchrony in humans by placing subjects
on a 28-hour daily routine for 10 days [110]. Similar to
observations made using animal models, rhythms in body
temperature remain tied to a 24-hour cycle; while others
(such as leptin and insulin) adhered to the new 28 hourbased cycles of food intake. Interestingly, circadian (24hour) and behavioural (28-hour) misalignment caused a
suppression of circulating leptin, an elevation of blood
glucose, and hypertension. Therefore, similar to changes
observed with chronic sleep deprivation [102], misalignment triggers a perceived state of energy deficit, altered
glucose homeostasis, and decreased insulin sensitivity, all
of which predispose to the metabolic syndrome. Sleep
restriction can also increase levels of the orexigenic hormone ghrelin, which has been strongly implicated in food
anticipation and meal entrainment [111].
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The mechanisms involved in clock entrainment to metabolic signals remain unclear. The direct influence of cellular
energy and redox status on clock genes has been demonstrated. For example, the activities of CLOCK/BMAL1 and
SIRT1 are responsive to the intracellular ratio of reduced-tooxidized nicotinamide adenine dinucleotide (NAD) cofactors, a ratio which is closely tied to cellular energy metabolism [97,112,113], and fluctuations in glucose itself can
modulate and entrain circadian oscillations in cells grown
in culture [114]. Further, as mentioned above, the clock
machinery is responsive to several genes which are themselves responsive to cellular and global energy status, including SIRT1, the PPARs, and PGC-1a. Feedback from
these genes would therefore render the clock responsive to
metabolic cues (Figure 2). The PPARs and PGC-1a regulate
genes involved in many aspects of energy homeostasis,
including the metabolism of glucose and lipids [115,116],
and their expressions and activities are responsive to energy
status and feeding cues [65]. In mice, PGC-1a is rhythmically expressed, and stimulates bmal1 and REV-ERBa
transcription through association of RORa [117]. Pgc1a / mice display metabolic and circadian abnormalities,
including altered weight gain, muscle dysfunction, hepatic
steatosis, as well as altered daily rhythms of activity, body
temperature, and metabolic rate [115,117]. Interestingly,
PGC-1a knockout mice appear to have a reduced ability to
phase-reset liver clock gene expression in response to a shift
from night-restricted to day-restricted feeding [117],
suggesting that feedback between PGC-1a and core clock
genes may be required for optimal entrainment of peripheral clocks to energy-related cues.
The sensitivity of different body clocks to metabolic
input may be dictated to a great extent by the local
(tissue-specific) expression of energy-responsive genes
(e.g. PPARa, PGC-1a, SIRT1). Therefore, imposition of
chronic and inappropriate metabolic inputs onto the clock
through metabolic regulators such as PGC-1a might contribute to damping of metabolic rhythms observed in
obesity. Additionally, the uncoupling of peripheral circadian oscillators like those in the liver from the SCN during
altered energy status raises the distinct possibility that
abnormal energy supply (including unrestricted hypercalorific food intake and feeding schedules that are out
of synchrony with normal patterns of behaviour) may be
effective at dampening the hypothalamic control of metabolism. Therefore, therapeutic strategies aimed at strengthening clock synchrony, minimising periods of internal desynchrony experienced during repeated behavioural phase
shifting (shift-work), and reinforcing circadian rhythms in
patients with metabolic syndrome should be pursued.
Future perspectives
Circadian dysfunction is clearly linked to human pathophysiology whether as a contributing factor or consequence. Nevertheless, clinical implications of clock
gene polymorphisms and mutations have been identified
and are driving the development of novel therapeutics. The
challenge remains to determine what impact the disruption of circadian rhythms per se has on disease states such
as cancer and the metabolic syndrome, rather than the
pleiotropic effects of clock genes independent of their role
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in circadian timing. Nevertheless, targeting the circadian

clock as a mechanism for strengthening inherent homeostatic and defence mechanisms would seem an important
and potentially fruitful therapeutic aim. Key sites for
therapeutic targeting include primary CCGs, particularly
those capable of feeding back onto the clock (i.e. NRs), as
well as clock-associated enzymes such as CK-1, AMPK, and
SIRT1. Several pharmaceutical tools have recently been
developed which target all three enzymes [118], and it will
be interesting to see if these agents may be useful in
modulating clock activity in vivo.
Disclosure Statement
DAB, JEG, and ASIL have no conflicts of interest relating
to the content, writing or publication of this work. Our
work is supported by the Biotechnology and Biological
Sciences Research Council (BBSRC), UK.
References
1 Reppert, S.M. and Weaver, D.R. (2002) Coordination of circadian
timing in mammals. Nature 418, 935941
2 Schernhammer, E.S. et al. (2001) Rotating night shifts and risk of
breast cancer in women participating in the nurses health study.
J. Natl. Cancer Inst. 93, 15631568
3 Schernhammer, E.S. et al. (2003) Night-shift work and risk of
colorectal cancer in the nurses health study. J. Natl. Cancer Inst.
95, 825828
4 Davis, S. et al. (2001) Night shift work, light at night, and risk of breast
cancer. J. Natl. Cancer Inst. 93, 15571562
5 Levi, F. and Schibler, U. (2007) Circadian rhythms: mechanisms and
therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 47, 593628
6 Sahar, S. and Sassone-Corsi, P. (2007) Circadian clock and breast
cancer: a molecular link. Cell Cycle 6, 13291331
7 Fu, L. et al. (2002) The circadian gene Period2 plays an important role in
tumor suppression and DNA damage response in vivo. Cell 111, 4150
8 Matsuo, T. et al. (2003) Control mechanism of the circadian clock for
timing of cell division in vivo. Science 302, 255259
9 Takahashi, J.S. et al. (2008) The genetics of mammalian circadian
order and disorder: implications for physiology and disease. Nat. Rev.
Genet. 9, 764775
10 Sawaki, Y. et al. (1984) Transplantation of the neonatal
suprachiasmatic nuclei into rats with complete bilateral
suprachiasmatic lesions. Neurosci. Res. 1, 6772
11 Meyer-Bernstein, E.L. et al. (1999) Effects of suprachiasmatic
transplants on circadian rhythms of neuroendocrine function in
golden hamsters. Endocrinology 140, 207218
12 Ralph, M.R. et al. (1990) Transplanted suprachiasmatic nucleus
determines circadian period. Science 247, 975978
13 Silver, R. et al. (1996) A diffusible coupling signal from the
transplanted suprachiasmatic nucleus controlling circadian
locomotor rhythms. Nature 382, 810813
14 Guo, H. et al. (2006) Suprachiasmatic regulation of circadian rhythms
of gene expression in hamster peripheral organs: effects of
transplanting the pacemaker. J. Neurosci. 26, 64066412
15 Sujino, M. et al. (2003) Suprachiasmatic nucleus grafts restore
circadian behavioral rhythms of genetically arrhythmic mice. Curr.
Biol. 13, 664668
16 LeSauter, J. and Silver, R. (1998) Output signals of the SCN.
Chronobiol. Int. 15, 535550
17 Buijs, R.M. and Kalsbeek, A. (2001) Hypothalamic integration of
central and peripheral clocks. Nat. Rev. Neurosci. 2, 521526
18 Bartness, T.J. et al. (2001) SCN efferents to peripheral tissues:
implications for biological rhythms. J. Biol. Rhythms 16, 196204
19 Vujovic, N. et al. (2008) Sympathetic input modulates, but does not
determine, phase of peripheral circadian oscillators. Am. J. Physiol.
Regul. Integr. Comp. Physiol. 295, R355360
20 Bando, H. et al. (2007) Vagal regulation of respiratory clocks in mice.
J. Neurosci. 27, 43594365
21 Saper, C.B. et al. (2005) Hypothalamic regulation of sleep and
circadian rhythms. Nature 437, 12571263

Review
22 Ruiter, M. et al. (2006) Hormones and the autonomic nervous system
are involved in suprachiasmatic nucleus modulation of glucose
homeostasis. Curr. Diabetes Rev. 2, 213226
23 Berthoud, H.R. (2002) Multiple neural systems controlling food intake
and body weight. Neurosci. Biobehav. Rev. 26, 393428
24 Cailotto, C. et al. (2008) Daily rhythms in metabolic liver enzymes and
plasma glucose require a balance in the autonomic output to the liver.
Endocrinology 149, 19141925
25 Kalsbeek, A. et al. (2007) Minireview: Circadian control of metabolism
by the suprachiasmatic nuclei. Endocrinology 148, 56355639
26 Abe, M. et al. (2002) Circadian rhythms in isolated brain regions. J.
Neurosci. 22, 350356
27 Cermakian, N. et al. (2002) Light induction of a vertebrate clock gene
involves signaling through blue-light receptors and MAP kinases.
Curr. Biol. 12, 844848
28 Granados-Fuentes, D. et al. (2004) The suprachiasmatic nucleus
entrains, but does not sustain, circadian rhythmicity in the
olfactory bulb. J. Neurosci. 24, 615619
29 Lamont, E.W. et al. (2005) The central and basolateral nuclei of the
amygdala exhibit opposite diurnal rhythms of expression of the clock
protein Period2. Proc. Natl. Acad. Sci. U. S. A. 102, 41804184
30 Reick, M. et al. (2001) NPAS2: an analog of clock operative in the
mammalian forebrain. Science 293, 506509
31 Schibler, U. et al. (2003) Peripheral circadian oscillators in mammals:
time and food. J. Biol. Rhythms 18, 250260
32 Panda, S. et al. (2002) Coordinated transcription of key pathways in
the mouse by the circadian clock. Cell 109, 307320
33 Storch, K.F. et al. (2002) Extensive and divergent circadian gene
expression in liver and heart. Nature 417, 7883
34 Yoo, S.H. et al. (2004) PERIOD2::LUCIFERASE real-time reporting
of circadian dynamics reveals persistent circadian oscillations in
mouse peripheral tissues. Proc. Natl. Acad. Sci. U. S. A. 101, 5339
5346
35 Lamia, K.A. et al. (2008) Physiological significance of a peripheral
tissue circadian clock. Proc. Natl. Acad. Sci. U. S. A. 105, 1517215177
36 Akhtar, R.A. et al. (2002) Circadian cycling of the mouse liver
transcriptome, as revealed by cDNA microarray, is driven by the
suprachiasmatic nucleus. Curr. Biol. 12, 540550
37 Oishi, K. et al. (2003) Genome-wide expression analysis of mouse liver
reveals CLOCK-regulated circadian output genes. J. Biol. Chem. 278,
4151941527
38 Oishi, K. et al. (2005) Genome-wide expression analysis reveals 100
adrenal gland-dependent circadian genes in the mouse liver. DNA
Res. 12, 191202
39 Miller, B.H. et al. (2007) Circadian and CLOCK-controlled regulation
of the mouse transcriptome and cell proliferation. Proc. Natl. Acad.
Sci. U. S. A. 104, 33423347
40 McCarthy, J.J. et al. (2007) Identification of the circadian
transcriptome in adult mouse skeletal muscle. Physiol. Genomics
31, 8695
41 Preitner, N. et al. (2002) The orphan nuclear receptor REV-ERBalpha
controls circadian transcription within the positive limb of the
mammalian circadian oscillator. Cell 110, 251260
42 Emery, P. and Reppert, S.M. (2004) A rhythmic Ror. Neuron 43, 443
446
43 Nakahata, Y. et al. (2007) Signaling to the circadian clock: plasticity
by chromatin remodeling. Curr. Opin. Cell Biol. 19, 230237
44 Doi, M. et al. (2006) Circadian regulator CLOCK is a histone
acetyltransferase. Cell 125, 497508
45 Etchegaray, J.P. et al. (2003) Rhythmic histone acetylation underlies
transcription in the mammalian circadian clock. Nature 421, 177
182
46 Michan, S. and Sinclair, D. (2007) Sirtuins in mammals: insights into
their biological function. Biochem. J. 404, 113
47 Asher, G. et al. (2008) SIRT1 regulates circadian clock gene expression
through PER2 deacetylation. Cell 134, 317328
48 Nakahata, Y. et al. (2008) The NAD+-dependent deacetylase SIRT1
modulates CLOCK-mediated chromatin remodeling and circadian
control. Cell 134, 329340
49 Rodgers, J.T. et al. (2008) Metabolic adaptations through the PGC-1
alpha and SIRT1 pathways. FEBS Lett. 582, 4653
50 Hirayama, J. et al. (2007) CLOCK-mediated acetylation of BMAL1
controls circadian function. Nature 450, 10861090

Trends in Pharmacological Sciences

Vol.31 No.5

51 Curtis, A.M. et al. (2004) Histone acetyltransferase-dependent

chromatin remodeling and the vascular clock. J. Biol. Chem. 279,
70917097
52 Naruse, Y. (2004) Circadian and light-induced transcription of clock
gene Per1 depends on histone acetylation and deacetylation. Mol. Cell
Biol. 24, 62786287
53 Ripperger, J.A. and Schibler, U. (2006) Rhythmic CLOCK-BMAL1
binding to multiple E-box motifs drives circadian Dbp transcription
and chromatin transitions. Nat. Genet. 38, 369374
54 Gachon, F. et al. (2006) The circadian PAR-domain basic leucine
zipper transcription factors DBP, TEF, and HLF modulate basal
and inducible xenobiotic detoxification. Cell Metabol. 4, 2536
55 Yang, X. et al. (2006) Nuclear receptor expression links the circadian
clock to metabolism. Cell 126, 801810
56 Chawla, A. and Lazar, M.A. (1993) Induction of Rev-ErbA alpha, an
orphan receptor encoded on the opposite strand of the alpha-thyroid
hormone receptor gene, during adipocyte differentiation. J. Biol.
Chem. 268, 1626516269
57 Fontaine, C. et al. (2003) The orphan nuclear receptor Rev-Erbalpha is
a peroxisome proliferator-activated receptor (PPAR) gamma target
gene and promotes PPARgamma-induced adipocyte differentiation.
J. Biol. Chem. 278, 3767237680
58 Lau, P. et al. (2008) The orphan nuclear receptor, RORalpha,
regulates gene expression that controls lipid metabolism: staggerer
(SG/SG) mice are resistant to diet-induced obesity. J. Biol. Chem. 283,
1841118421
59 Raghuram, S. et al. (2007) Identification of heme as the ligand for the
orphan nuclear receptors REV-ERBalpha and REV-ERBbeta. Nat.
Struct. Mol. Biol. 14, 12071213
60 Teboul, M. et al. (2009) How nuclear receptors tell time. J. Appl.
Physiol. 107, 19651971
61 Balsalobre, A. et al. (2000) Resetting of circadian time in peripheral
tissues by glucocorticoid signaling. Science 289, 23442347
62 McNamara, P. et al. (2001) Regulation of CLOCK and MOP4 by
nuclear hormone receptors in the vasculature: a humoral
mechanism to reset a peripheral clock. Cell 105, 877889
63 Gibbs, J.E. et al. (2009) Circadian timing in the lung; a specific role for
bronchiolar epithelial cells. Endocrinology 150, 268276
64 Lemberger, T. et al. (1996) Expression of the peroxisome proliferatoractivated receptor alpha gene is stimulated by stress and follows a
diurnal rhythm. J. Biol. Chem. 271, 17641769
65 Kersten, S. et al. (1999) Peroxisome proliferator-activated receptor
alpha mediates the adaptive response to fasting. J. Clin. Invest. 103,
14891498
66 Straub, R.H. and Cutolo, M. (2007) Circadian rhythms in rheumatoid
arthritis: implications for pathophysiology and therapeutic
management. Arthritis Rheum. 56, 399408
67 Ferraz, E. et al. (2006) Comparison of 4 AM and 4 PM bronchial
responsiveness to hypertonic saline in asthma. Lung 184, 341346
68 Cutolo, M. et al. (2003) Circadian rhythms in RA. Ann. Rheum. Dis. 62,
593596
69 Okada, K. et al. (2008) Injection of LPS causes transient suppression
of biological clock genes in rats. J. Surg. Res. 145, 512
70 Murphy, B.A. et al. (2007) Acute systemic inflammation transiently
synchronizes clock gene expression in equine peripheral blood. Brain
Behav. Immun. 21, 467476
71 Takahashi, S. et al. (2001) Physical and inflammatory stressors
elevate circadian clock gene mPer1 mRNA levels in the
paraventricular nucleus of the mouse. Endocrinology 142, 49104917
72 Liu, J. et al. (2006) The circadian clock Period 2 gene regulates gamma
interferon production of NK cells in host response to
lipopolysaccharide-induced endotoxic shock. Infect. Immun. 74,
47504756
73 Guess, J. et al. (2009) Circadian disruption, Per3, and human cytokine
secretion. Integr. Cancer Ther. 8, 329336
74 Preuss, F. et al. (2008) Adverse effects of chronic circadian
desynchronization in animals in a challenging environment. Am.
J. Physiol. Regul. Integr. Comp. Physiol. 295, R20342040
75 Hayashi, M. et al. (2007) Characterization of the molecular clock in
mouse peritoneal macrophages. Biol. Pharm. Bull. 30, 621626
76 Keller, M. et al. (2009) A circadian clock in macrophages controls
inflammatory immune responses. Proc. Natl. Acad. Sci. U. S. A. 106,
2140721412

197

Review
77 Gibbs, J.E. et al. (2009) A role for REV-ERBa in pulmonary
inflammation. In Congress of the European Biological Rhythms
Society, S1414
78 Shen, Z. et al. (2009) Role of SIRT1 in regulation of LPS- or two
ethanol metabolites-induced TNF-alpha production in cultured
macrophage cell lines. Am. J. Physiol. Gastrointest. Liver Physiol.
296, G10471053
79 Delayre-Orthez, C. et al. (2005) PPARalpha downregulates airway
inflammation induced by lipopolysaccharide in the mouse. Respir.
Res. 6, 91
80 Stapleton, C.M. et al. (2005) Enhanced susceptibility of staggerer
(RORalphasg/sg)
mice
to
lipopolysaccharide-induced
lung
inflammation. Am. J. Physiol. Lung Cell Mol. Physiol. 289, L144152
81 Jaradat, M. et al. (2006) Modulatory role for retinoid-related orphan
receptor alpha in allergen-induced lung inflammation. Am. J. Respir.
Crit. Care Med. 174, 12991309
82 Birrell, M.A. et al. (2004) PPAR-gamma agonists as therapy for
diseases involving airway neutrophilia. Eur. Respir. J. 24, 1823
83 Fontaine, C. et al. (2008) The nuclear receptor Rev-erbalpha is a liver
X receptor (LXR) target gene driving a negative feedback loop on
select LXR-induced pathways in human macrophages. Mol.
Endocrinol. 22, 17971811
84 Delerive, P. et al. (2001) The orphan nuclear receptor ROR alpha is a
negative regulator of the inflammatory response. EMBO Rep. 2, 4248
85 Zhang-Gandhi, C.X. and Drew, P.D. (2007) Liver X receptor and
retinoid X receptor agonists inhibit inflammatory responses of
microglia and astrocytes. J. Neuroimmunol. 183, 5059
86 Migita, H. et al. (2004) Rev-erbalpha upregulates NF-kappaBresponsive genes in vascular smooth muscle cells. FEBS Lett. 561,
6974
87 Gallou-Kabani, C. et al. (2007) Lifelong circadian and epigenetic drifts
in metabolic syndrome. Epigenetics 2, 137146
88 Karlsson, B. et al. (2001) Is there an association between shift work
and having a metabolic syndrome? Results from a population based
study of 27,485 people. Occup. Environ. Med. 58, 747752
89 Chaput, J.P. et al. (2006) Relationship between short sleeping hours
and childhood overweight/obesity: results from the Quebec en Forme
Project. Int. J. Obesity 30, 10801085
90 Gangwisch, J.E. et al. (2005) Inadequate sleep as a risk factor for
obesity: analyses of the NHANES I. Sleep 28, 12891296
91 Bechtold, D.A. (2008) Energy-responsive timekeeping. J. Genet. 87,
447458
92 Laposky, A.D. et al. (2008) Sleep and circadian rhythms: key
components in the regulation of energy metabolism. FEBS Lett.
582, 142151
93 Ramsey, K.M. et al. (2007) The clockwork of metabolism. Annu. Rev.
Nutr. 27, 219240
94 Kohsaka, A. and Bass, J. (2007) A sense of time: how molecular clocks
organize metabolism. Trends Endocrinol. Metab. 18, 411
95 Wijnen, H. and Young, M.W. (2006) Interplay of circadian clocks and
metabolic rhythms. Annu. Rev. Genet. 40, 409448
96 Kaasik, K. and Lee, C.C. (2004) Reciprocal regulation of haem
biosynthesis and the circadian clock in mammals. Nature 430, 467
471
97 Rutter, J. et al. (2002) Metabolism and the control of circadian
rhythms. Annu. Rev. Biochem. 71, 307331
98 Tu, B.P. and McKnight, S.L. (2006) Metabolic cycles as an underlying
basis of biological oscillations. Nat. Rev. Mol. Cell Biol. 7, 696701
99 Duffield, G.E. et al. (2002) Circadian programs of transcriptional
activation, signaling, and protein turnover revealed by microarray
analysis of mammalian cells. Curr. Biol. 12, 551557
100 Kornmann, B. et al. (2007) Regulation of circadian gene expression in
liver by systemic signals and hepatocyte oscillators. Cold Spring
Harb. Symp. Quant Biol. 72, 319330
101 Walker, J.R. and Hogenesch, J.B. (2005) RNA profiling in circadian
biology. Meth. Enzymol. 393, 366376
102 Spiegel, K. et al. (2009) Effects of poor and short sleep on glucose
metabolism and obesity risk. Nat. Rev. Endocrinol. 5, 253261
103 Turek, F.W. et al. (2005) Obesity and metabolic syndrome in circadian
Clock mutant mice. Science 308, 10431045
104 Bechtold, D.A. et al. (2008) Metabolic rhythm abnormalities in mice
lacking VIP-VPAC2 signaling. Am. J. Physiol. Regul. Integr. Comp.
Physiol. 294, R344351

198

Trends in Pharmacological Sciences Vol.31 No.5

105 Oishi, K. et al. (2006) Disrupted fat absorption attenuates obesity
induced by a high-fat diet in Clock mutant mice. FEBS Lett. 580,
127130
106 Kudo, T. et al. (2008) Clock mutation facilitates accumulation of
cholesterol in the liver of mice fed a cholesterol and/or cholic acid
diet. Am. J. Physiol. Endocrinol. Metab. 294, E120130
107 Mistlberger, R.E. (1994) Circadian food-anticipatory activity: formal
models and physiological mechanisms. Neurosci. Biobehav. Rev. 18,
171195
108 Stephan, F.K. (2002) The other circadian system: food as a
Zeitgeber. J. Biol. Rhythms 17, 284292
109 Stokkan, K.A. et al. (2001) Entrainment of the circadian clock in the
liver by feeding. Science 291, 490493
110 Scheer, F.A. et al. (2009) Adverse metabolic and cardiovascular
consequences of circadian misalignment. Proc. Natl. Acad. Sci.
U. S. A. 106, 44534458
111 LeSauter, J. et al. (2009) Stomach ghrelin-secreting cells as foodentrainable circadian clocks. Proc. Natl. Acad. Sci. U. S. A. 106,
1358213587
112 Rutter, J. et al. (2001) Regulation of clock and NPAS2 DNA binding by
the redox state of NAD cofactors. Science 293, 510514
113 Sauve, A.A. et al. (2006) The biochemistry of sirtuins. Annu. Rev.
Biochem. 75, 435465
114 Hirota, T. et al. (2002) Glucose down-regulates Per1 and Per2 mRNA
levels and induces circadian gene expression in cultured Rat-1
fibroblasts. J. Biol. Chem. 277, 4424444251
115 Leone, T.C. et al. (2005) PGC-1alpha deficiency causes multi-system
energy metabolic derangements: muscle dysfunction, abnormal
weight control and hepatic steatosis. PLoS Biol. 3, e101
116 Lin, J. et al. (2005) Metabolic control through the PGC-1 family of
transcription coactivators. Cell Metab. 1, 361370
117 Liu, C. et al. (2007) Transcriptional coactivator PGC-1alpha integrates
the mammalian clock and energy metabolism. Nature 447, 477481
118 Pillarisetti, S. (2008) A review of Sirt1 and Sirt1 modulators in
cardiovascular and metabolic diseases. Rec. Pat. Cardiovasc. Drug
Disc. 3, 156164
119 Lowrey, P.L. and Takahashi, J.S. (2004) Mammalian circadian
biology: elucidating genome-wide levels of temporal organization.
Annu. Rev. Genomics Hum. Genet. 5, 407441
120 Gallego, M. et al. (2006) An opposite role for tau in circadian rhythms
revealed by mathematical modeling. Proc. Natl. Acad. Sci. U. S. A.
103, 1061810623
121 Meng, Q.J. et al. (2008) Setting clock speed in mammals: the CK1e tau
mutation in mice accelerates the circadian pacemaker by selectively
destabilizing PERIOD proteins. Neuron 58, 7888
122 Sack, R.L. et al. (2007) Circadian rhythm sleep disorders: part II,
advanced sleep phase disorder, delayed sleep phase disorder, freerunning disorder, and irregular sleep-wake rhythm. An American
Academy of Sleep Medicine review. Sleep 30, 14841501
123 Jones, C.R. et al. (1999) Familial advanced sleep-phase syndrome: A
short-period circadian rhythm variant in humans. Nat. Med. 5, 1062
1065
124 Reid, K.J. et al. (2001) Familial advanced sleep phase syndrome. Arch.
Neurol. 58, 10891094
125 Toh, K.L. et al. (2001) An hPer2 phosphorylation site mutation in
familial advanced sleep phase syndrome. Science 291, 10401043
126 Xu, Y. et al. (2005) Functional consequences of a CKIdelta mutation
causing familial advanced sleep phase syndrome. Nature 434, 640644
127 Vanselow, K. et al. (2006) Differential effects of PER2
phosphorylation: molecular basis for the human familial advanced
sleep phase syndrome (FASPS). Genes Dev. 20, 26602672
128 Xu, Y. et al. (2007) Modeling of a human circadian mutation yields
insights into clock regulation by PER2. Cell 128, 5970
129 Ralph, M.R. and Menaker, M. (1988) A mutation of the circadian
system in golden hamsters. Science 241, 12251227
130 Loudon, A.S. et al. (2007) The biology of the circadian Ck1epsilon tau
mutation in mice and Syrian hamsters: a tale of two species. Cold
Spring Harb. Symp. Quant Biol. 72, 261271
131 Etchegaray, J.P. et al. (2009) Casein kinase 1 delta regulates the pace
of the mammalian circadian clock. Mol. Cell. Biol. 29, 38533866
132 Walton, K.M. (2009) Selective inhibition of casein kinase 1 epsilon
minimally alters circadian clock period. J. Pharmacol. Exp. Ther. 330,
430439