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Jurnal Reading

Circardian Rhytm



OLEH:
Rio Jaya Abadi

PEMBIMBING:
dr. Oedayati Sp.KK



KEPANITERAAN KLINIK ILMU PENYAKIT KULIT DAN KELAMIN
RUMAH SAKIT MARDI RAHAYU KUDUS
PERIODE 9 Juni 2014 12 Juli 2014
FAKULTAS KEDOKTERAN UKRIDA

Circadian rhythm of adrenal glucocorticoid: Its regulation and clinical implications
Sooyoung Chung, Gi Hoon Son, Kyungjin KimCorresponding author contact information, E-mail the
corresponding author
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DOI: 10.1016/j.bbadis.2011.02.003
Under an Elsevier user license
Open Archive
Abstract
Glucocorticoid (GC) is an adrenal steroid hormone that controls a variety of physiological
processes such as metabolism, immune response, cardiovascular activity, and brain function. In
addition to GC induction in response to stress, even in relatively undisturbed states its circulating
level is subjected to a robust daily variation with a peak around the onset of the active period of the
day. It has long been believed that the synthesis and secretion of GC are primarily regulated by the
hypothalamuspituitaryadrenal (HPA) neuroendocrine axis. However, recent chronobiological
research strongly supports the idea that multiple regulatory mechanisms along with the classical
HPA neuroendocrine axis underlie the diurnal rhythm of circulating GC. Most notably, recent studies
demonstrate that the molecular circadian clockwork is heavily involved in the daily GC rhythm at
multiple levels. The daily GC rhythm is implicated in various human diseases accompanied by
abnormal GC levels. Patients with such diseases frequently show a blunted GC rhythmicity and, more
importantly, circadian rhythm-related symptoms. In this review, we focus on recent advances in the
understanding of the circadian regulation of adrenal GC and its implications in human health and
disease.

Research highlights
Current understanding of circadian control of the adrenal gland. Multiple regulatory
mechanisms underlying the daily rhythm of glucocorticoid (GC). Role of the adrenal local
clockwork in circadian GC production. Importance of GC rhythm in human health and diseases.

Keywords
Glucocorticoid; Adrenal gland; HPA axis; Circadian rhythm; Biological clock
1. Introduction
Circadian rhythms are comprised of a ubiquitous biological oscillation of approximately 24-h
periods that are highly conserved from cyanobacteria to humans. This daily rhythm is not a simple
response to alternating changes of day and night. It arises from an innate and genetically operated
timekeeping system referred to as a biological clock *1] and [2]. This internal timekeeping system
allows organisms to anticipate and prepare for changes in their physical environments, thereby
enabling them to behave appropriately at the right time of day. The biological clock also greatly
contributes to ensuring that certain physiological processes take place in coordination with others
[3]. In mammals, the suprachiasmatic nucleus (SCN) of the anterior hypothalamus functions as the
master circadian pacemaker, driving overt circadian rhythms such as the rest-activity cycle, daily
variations in metabolism and body temperature, and the rhythmic secretion of hormones [4].

Glucocorticoid (GC) is an adrenal steroid hormone that plays a crucial role in the adaptive
responses to various types of stress and is under the control of the hypothalamuspituitaryadrenal
gland (HPA) neuroendocrine axis. In addition to its stress reactivity, robust daily variation in the
circulating level is another key feature of this hormone. It is widely accepted that the daily GC
rhythm is also under the control of circadian timing because its rhythmicity is completely blunted by
disruption of the SCN harboring the master oscillator [5]. It is well known that chronic dysregulation
of GC, i.e. either hyper- or hyposecretion, induces the onset of diverse pathological conditions by
disrupting carbohydrate and lipid metabolism, immune response, cardiovascular activity, mood, and
cognitive/brain functions. A growing body of evidence suggests that not only the level of circulating
GC but also its rhythmic activity plays a significant role in human health and disease [6] and [7].
Therefore, understanding the regulatory mechanisms of the daily GC rhythm and its physiological
relevance can provide novel insight into both the molecular basis and clinical treatment of human
diseases involving abnormal GC secretion. Here, we review recent progress in circadian clock
research and focus on the roles of the circadian timing system in the daily GC rhythm and its clinical
implications.

2. Circadian timing system and molecular clockwork
2.1. The mammalian circadian clockwork
Because of the earth's rotation, almost all organisms function under 24-h daynight cycles. To
adapt to and anticipate external daily cycles, organisms have evolved an internal timekeeping
system. This daily timekeeping system is referred to as the circadian clock from the Latin circa
diem, which literally meaning approximately a day. It is both autonomous and self-sustainable
but is also continuously entrained by external time cues called zeitgeber. The mammalian
circadian timing system consists of 3 basic components: 1) input signals (environmental cues), 2) a
circadian oscillator as an intrinsic rhythm generator and 3) output rhythms. The hypothalamic SCN
has generally been considered to be the central circadian oscillator both anatomically and
functionally; it receives photic information from the eyes via the retino-hypothalamic tract, and then
synchronizes the circadian timing system with environmental time [4] and [8]. This notion is strongly
supported by findings that selective ablation of the SCN leads to a complete loss of circadian
rhythmicity, whereas transplantation of an intact SCN into arrhythmic mutant animals restores
circadian rhythmicity [9] and [10]. The circadian rhythm generated in the SCN is believed to be
converted into neuronal or hormonal signals that affect metabolic processes, physiology and
behavior (Fig. 1).


Fig. 1.
Hierarchical organization of the mammalian circadian timing system. The suprachiasmatic
nucleus (SCN), which resides in the ventral hypothalamus, functions as the central clock responsible
for the coordination of multiple clock networks in the body. It communicates with and synchronizes
local clockworks in other tissues, including both peripheral tissues and extra-SCN regions of the
brain. Examination of the tissue-specific modulation of the clock machinery revealed the
autonomous role of each local clock (also see the text), and the adrenal peripheral clock in particular
is involved in the daily rhythms of GC and exerts an impact on the synchronization of other
peripheral clocks and the regulation of physiological systems, including metabolism.
The autonomous and self-sustaining nature of the circadian timing system primarily depends on
the presence of a genetic mechanism known as the molecular circadian clockwork. Clock genes are
required for the generation and maintenance of the circadian rhythm in an organism and even
within individual cells [11] and [12]. The clock genes and their gene products cooperatively promote
rhythmic gene expression by two interlocked positive and negative transcription/translation
feedback loops that are core and auxiliary (Fig. 2). In the principal or core feedback loop, members
of the basic helixloophelixPeriod-ARNT-single-minded (bHLH-PAS) transcription factor
superfamily, such as CLOCK and BMAL1, form heterodimers to activate the transcription of their
target genes containing E-box elements in the cis-regulatory regions of those genes [13], [14] and
[15]. These target genes include their negative regulators such as the Periods (PERs: PER1, PER2 and
PER3) and the Cryptochromes (CRYs: CRY1 and CRY2). The concentration of BMAL1 is adjusted by an
auxiliary or stabilizing feedback loop formed by the clock-controlled nuclear receptors REV-ERB and
ROR *16+, *17+, *18+ and *19+. The self-sustaining feedback loops described in Fig. 2 constitute the
circadian molecular clock machinery in an approximate 24-h period.


Fig. 2.
Molecular circadian clockwork. The mammalian circadian oscillator is composed of 2 interlocking
transcriptional/translational feedback loops: core and auxiliary. The CLOCK/BMAL1 heterodimer, the
integral component of the core loop, induces E-box-mediated transcription of the negative
regulators Periods (PERs) and Cryptochromes (CRYs). Accumulated PER and CRY proteins intensively
repress E-box-mediated transcription until their levels have sufficiently decreased. Additionally,
CLOCK and BMAL1 also control the transcription of nuclear receptors ROR and Rev-erb, which
modulate Bmal1 mRNA levels by competitive actions on the RRE element residing in the Bmal1
promoter. Collectively, the cycling of the clock components also determines the levels of the clock-
controlled gene (CCGs) by transcription via the E-box and/or RRE to achieve their oscillating patterns
and thus to generate rhythmic physiological output.
In addition to core regulation at the level of transcription/translation, circadian clock proteins are
also subjected to extensive post-translational modifications that appear to control their protein
stability, nuclear localization and functional activity. For example, casein kinase 1 and are known
to be critical factors that regulate the turnover of PERs and CRYs in mammals [20], [21] and [22].
BMAL1 is rhythmically simulated in vivo and the simulation promotes its interaction with CLOCK,
exclusive nuclear accumulation in promyelocytic leukemia (PML) nuclear bodies, transactivation and
ubiquitin-dependent degradation [23], [24] and [25]. BMAL1 is also regulated by acetylation so as to
have a role in the maintenance of circadian rhythmicity [26]. In addition, the Ca2+-dependent
protein kinase C (PKC)-mediated phosphorylation of CLOCK and subsequent recruitment of cofactors
to the CLOCK/BMAL1 heterodimer appear to be important for the phase resetting of the mammalian
circadian clock [27] and [28]. Post-translational regulation of the clock proteins and its functional
significance are extensively reviewed elsewhere [11] and [12].

2.2. Central and peripheral clocks in rhythmic physiological outputs
The mammalian circadian system is organized in a hierarchical manner. At the top of the
mammalian circadian timing system, the SCN is composed of densely packed neurons that have self-
sustaining rhythmic capacity [29]. It is striking that not only the SCN but also most tissues and
peripheral organs express their own clock genes. It has been shown that even cultured cells in vitro
retain their rhythmicity at the single cell level; thus, a high concentration of serum or synthetic GC
agonist is able to synchronize individual rhythms so as to exhibit a robust cyclic clock gene
expression at the cell population level [30], [31], [32] and [33]. Furthermore, it has been established
that most mammalian cells possess their own circadian clocks. These clocks have a molecular
makeup similar to that in SCN pacemaker neurons, but are referred to as peripheral or local clocks to
distinguish them from the master clock in the SCN. Therefore, the SCN serves as the center for
harmonizing the circadian rhythm in mammals by coordinating the rhythms of the peripheral clocks
scattered throughout the body ( Fig. 1). The SCN maintains continuous communication with the
peripheral clocks through a variety of neural and humoral signals [34]. In addition to the time
information transmitted by the SCN, other zeitgebers, such as feeding times and body temperature
rhythms, play an important role in the resetting of these peripheral timekeepers [4]. In this context,
it should be noted that GC is an attractive candidate for the key hormonal link between the SCN and
the peripheral clocks. This issue will be discussed in a later section of the present article.

A variety of physiological processes in mammals, including the sleepwake cycle, body
temperature, renal plasma flow and cardiovascular activity are influenced by circadian regulation [3].
Although the rhythmic features of these physiological processes require SCN involvement, the
presence of ubiquitous peripheral oscillators strongly supports their contribution to the
manifestation of circadian rhythms in a variety of cellular processes. Considerable evidence has been
obtained from transcriptome-profiling studies. For example, 510% of all mRNA species display a
circadian expression pattern in the liver [35], [36], [37] and [38]. A comparison of the transcriptome
profiles in different tissues [38] revealed that most circadian transcripts are expressed in a tissue-
specific fashion, which is in keeping with the idea that different functions are controlled by different
tissues' own local circadian clockwork. However, the roles of the peripheral clocks and the central
pacemaker in governing the circadian functions in a given organ are rarely distinguished. In this
context, selective modulation of certain peripheral clock machinery has been recently examined for
the possible roles of peripheral clocks in physiology and metabolism. Takahashi et al. investigated
the functional rescue of certain tissues in BMAL1 knockout mice, thus showing the requirement of
brain BMAL1 activation for circadian behavioral rhythms [39]. In another study, liver-specific
abrogation of Bmal1 resulted in a dysfunction in glucose and lipid metabolism [40] and [41] as well
as pancreatic disruption of the local clock that led to diabetes mellitus because of defective -cell
function [42]. Endothelial BMAL1 appears to affect the response to thrombogenic stimuli and blood
pressure in the cardiovascular system [43]. Notably, disruption of the adrenal local clock influenced
the daily GC profiles [44] and [45], indicating the importance of the adrenal peripheral clock in the
robust circadian rhythm of the steroid hormone.

3. Neuroendocrine regulation of the adrenal GC
3.1. HPA axis and physiological roles of GC
The HPA axis is a major neuroendocrine circuit of the stress response system, and adrenal GC
synthesis and secretion are known to be tightly regulated by upstream hormones secreted from the
hypothalamus and the pituitary (Fig. 3). Briefly, certain neurochemical signals reach the
hypothalamus and then neurons in the paraventricular nucleus (PVN) of the hypothalamus release
corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) to induce
adrenocorticotropic hormone (ACTH) synthesis and secretion from the pituitary. ACTH then induces
adrenal synthesis and secretion of GC, which interacts with specific receptors in various target
tissues in the brain and periphery. Circulating GC ultimately turns off the HPA neuroendocrine
activity and restores a steady state via negative feedback [46].


Fig. 3.
Neuroendocrine regulation of adrenal GC and its physiological roles. GC is primarily regulated by
the hypothalamuspituitaryadrenal gland (HPA) axis, a major neuroendocrine circuit of the stress
response system. When certain neurochemical signals reach the hypothalamus as the result of stress
or circadian input, a subset of neurosecretory cells in the PVN of the hypothalamus releases CRH and
AVP to induce ACTH synthesis and secretion from the pituitary. ACTH then induces the
adrenocortical cells to produce and secrete GC. Circulating GC turns off the HPA neuroendocrine axis
by negative feedback mechanisms. In addition, GC exerts widespread actions in the body as needed
to restore and maintain various physiological homeostasis.
As a final effector of the stress-responsive HPA neuroendocrine axis, GC exerts widespread
effects in the body to maintain homeostasis and enable the organism to prepare to respond to and
cope with physical and emotional stresses [47]. For examples, GC promotes the breakdown of
carbohydrate and protein and modulates lipid deposition and breakdown. GC is also an important
regulator in numerous immune and inflammatory responses [48]. Furthermore, it raises blood
pressure, has diverse effects on bone, elicits both positive and negative effects on cell growth, and is
proapoptotic in certain cell types, including certain neuronal cells. In addition to providing negative
feedback to the HPA axis, GC influences both neuronal and glial cells in the central nervous system
(CNS) to mediate important organizational events in the developing brain and neural plasticity and
degeneration in adulthood. Other central influences include changes in mood and behavior, the
modulation of food intake, body temperature and nociception [49].

3.2. Adrenal GC biosynthesis
GC is mainly synthesized from a subset of adrenocortical cells in response to ACTH by the
steroidogenic processing of cholesterol (Fig. 4). The mammalian adrenal cortex is composed of cells
that are segregated into separate zones with distinct functions, the zona glomerulosa (ZG), zona
fasciculata (ZF) and zona reticularis (ZR), and distinct sets of steroidogenic genes are expressed in
each zone [50]. GC is mainly produced in the ZF, where the ACTH receptor (ACTHR; melanocortin
receptor 2, MC2R) is also highly expressed. During activation of the HPA axis, ACTH binds to the
ACTHR, activates heterotrimeric Gs protein, and subsequently stimulates adenylyl cyclase [51].
Intracellular cAMP then activates protein kinase A (PKA) nuclear transcription factors, such as cAMP
response element (CRE) binding protein (CREB) and CRE modulator (CREM). These transcription
factors modulate the expression of genes involved in adrenal GC biosynthesis by binding to the CRE
residing in the promoter regions of those genes [52] and [53].


Fig. 4.
Adrenal steroidogenesis and its hormonal regulation. GC is mainly synthesized in a subset of
adrenocortical steroidogenic cells by successive enzymatic modifications of cholesterol in the
mitochondria. The transferring of cholesterol from the cytosol into mitochondrial compartments by
StAR serves as the rate-limiting step. The ACTH secreted in response to stress induces adrenal GC
production by promoting steroidogenic gene expression through activation of the
ACTHR/cAMP/PKA/CREB signaling cascades.
Various sets of steroidogenic genes are known to be involved in adrenal GC biosynthesis. First,
cholesterol has to be transferred from the cytosol to the inner mitochondrial membrane, where it
can be converted to pregnenolone, a common steroid precursor. Steroidogenic acute regulatory
protein (StAR), the expression of which rapidly responds to hormonal stimulation, mediates the
delivery of cholesterol to the site of its first enzymatic conversion of cholesterol to pregnenolone by
CYP11A1 (cholesterol side chain cleavage monooxygenase). Hence, it constitutes a rate-limiting and
hormonally regulated step in steroidogenesis [52]. As described in Fig. 4, pregnenolone is then
subjected to the sequential actions of several steroid hydrogenases (cytochrome P450 and heme-
containing proteins) and HSD3Bs (3-hydroxysteroid dehydrogenases), ultimately leading to GC
production. CYP17 (17-hydroxylase) is present only in cortisol-producing species such as humans
but not in corticosterone-producing species such as rats and mice. It mediates 17-hydroxylation
and the cleavage of pregnenolone and progesterone, thus constituting an additional pathway to
cortisol biosynthesis [54 and references therein].


4. Circadian regulation of GC biosynthesis and secretion
In addition to the response to stress, another key characteristic of GC is its robust daily rhythm.
Circulating GC levels are higher during the activity period (day for diurnal species and night for
nocturnal species) and peak levels are linked to the beginning of the activity period. Although the
circadian rhythm of GC was reported several decades ago, its molecular basis is still not fully
understood. A growing body of evidence resulting from recent advances in chronobiology has shown
that the daily variation is generated by multimodal forms of regulation: the driving role of the SCN
via the neuroendocrine axis and autonomic nervous system as well as intrinsic mechanisms involving
the adrenal local clockwork appear to coincide with the generation of the robust GC circadian
rhythm in the circulation [55] and [56]. Moreover, GC is considered as a key mediator for
synchronicity of the circadian timing system [31]. In this section, we will discuss the multiple
regulatory mechanisms involved in the GC circadian rhythm and its physiological relevance.

4.1. SCN regulation occurs through the HPA axis and the autonomic nervous system
The oscillatory profiles of circulating GC have primarily been attributed to SCN modulation of the
HPA axis [57, Fig. 5]. Observations that SCN abrogation eliminates the rhythms of plasma ACTH and
GC strongly support this notion. From the neuroanatomical aspect, SCN pacemaker neurons seem to
indirectly control the hypothalamic ACTH secretagogue-producing neurons in the parvocellular
division of the PVN, projecting into the neighboring area of the PVN, the subparaventricular zone,
and the dorsomedial nucleus of the hypothalamus [58]. Since the morning (trough) corticosterone
(CS) levels are reported to increase after SCN ablation in rats, strong inhibition of basal GC release by
the SCN seems evident [59]. AVP produced by a subset of SCN neurons is considered one of the main
neurotransmitters mediating this inhibition [60]. However, several lines of evidence suggest
relatively restricted roles for the upstream hormonal regulators of the HPA axis and the involvement
of multiple inputs into the adrenal gland. First, the daily rhythm in non-stress levels of plasma CS
usually displays a 5- to 10-fold higher amplitude from the trough to peak levels in rodents, whereas
the plasma ACTH rhythm is relatively lower (up to 2-fold) or even frequently not significantly
different throughout the day [44], [61], [62], [63] and [64]. Despite only a modest rhythm in ACTH,
circulating CS levels exhibit a robust rhythm, implying that additional regulation is likely involved.
Second, the plasma CS rhythm persists even in hypophysectomized rats receiving ACTH pellets,
demonstrating that the GC rhythm does not solely depend on the rhythmic release of ACTH [65].
Third, it is also of importance to note that even in the absence of SCN inhibitory signals, plasma CS
levels did not reach a peak level, and there was an apparent discrepancy between the decrease in
the inhibitory regulation from the SCN and the afternoon increase in the circulating CS levels in rats
[59] and [66]. Thus, after a series of disinhibition experiments, Buijs et al. suggested that additional
signals with a delay of several hours after the major inhibitory signal, but preceding the peak CS
level, appear to be required [66] and [67].



Fig. 5.
Working model for the diurnal regulation of GC secretion and biosynthesis. Daily variations in
circulating GC levels are achieved by multiple regulatory mechanisms. The suprachiasmatic nucleus
(SCN) regulates the adrenal rhythm by modulating HPA axis activity. The rhythmic production of
arginine vasopressin by SCN neurons is involved in this regulation. In an alternative pathway,
splanchnic nerve innervation of the adrenal gland in the SCN-autonomic nervous system (ANS)
contributes to circadian GC secretion as well as a resetting of the adrenal local clock. In addition to
the central mechanisms exerted by the master clock in the SCN, adrenal intrinsic mechanisms
involving the adrenal local clockwork underlie the GC rhythm. Although the adrenal local clock along
with the ANS was postulated to gate adrenal sensitivity to ACTH, it is more important that this local
clock is tightly linked with the steroidogenic pathway. Cyclic expression of StAR, a rate-limiting gene
of steroid biosynthesis, is directly controlled by the CLOCK:BMAL1 heterodimer as an adrenal gland-
specific clock-controlled gene; consequently, the resulting daily oscillation in steroidogenesis
contributes to the generation of the robust GC rhythm.
Recently, the influence of the central pacemaker in the SCN via splanchnic nerve innervation to
the adrenal gland has been reportedly implicated [[68], [69] and [70], Fig. 5]. Diurnal control of GC
secretion by this autonomic SCN-adrenal pathway is supported by the following 2 lines of evidence.
First, sympathetic innervation of the adrenal gland directly transmits light information to the gland
that leads to increased CS release, independent of HPA axis activation. Adrenaline release by the
adrenal medulla is responsible for the transmission of the photic signal to the adrenal cortex [69].
Second, autonomic control of the GC rhythm is related to modulation of adrenal sensitivity to ACTH
[68], [70] and [71]. Adrenal responsiveness to ACTH in nocturnal rodents exhibits a daily rhythm,
with a higher sensitivity leading to higher CS release in the evening [44] and [72]. It has been shown
that the sensitivity of the adrenal gland to ACTH stimulation is regulated via splanchnic nerve
innervations from the central clock of the hypothalamic SCN [66], [67], [68] and [70]. However,
discrepancies remain regarding the daily alterations in adrenal responsiveness in the HPA axis. For
instance, it has been suggested that the diurnal changes in non-stress CS involve splanchnic nerve
integrity, but are not mediated by differential responsiveness to ACTH [73]. More recently, it was
also shown that responses to mild stress in rats were not different between the early light and dark
phases, so there is some doubt about the diurnal variation in the responsiveness of the HPA axis
[74]. Furthermore, splanchnic nerve transection resulted in only a partial decrease in peak CS
circulation levels in rats, showing that SCN-derived neural inputs are still insufficient to completely
account for the GC circadian rhythm [70].

4.2. Adrenal intrinsic mechanisms: the involvement of adrenal oscillator
The GC circadian rhythm is thus not fully explained by the SCN-driven central mechanisms, as
described above. Therefore, it is likely that unidentified mechanisms remain, especially those that
are adrenal-intrinsic. Interestingly, restricted daytime feeding of nocturnal animals can dissociate
the phases of the SCN central pacemaker and other peripheral clocks, presumably by food-
entrainable oscillators [75]; under this daytime feeding regime, the daily GC profiles are split into 2
peaks each day [76] and [77], implying the presence of adrenal-intrinsic mechanisms. In this regard,
it is noteworthy that the adrenal gland harbors its own circadian clockwork, as has been shown by
several independent groups [44], [45], [69] and [78]. The molecular clockwork of the adrenocortical
steroidogenic cells works autonomously, and it can be entrained by the activation of the autonomic
SCN-adrenal pathway. Global analyses of the adrenal transcriptome support this notion that this
local clock machinery is linked to key cellular pathways in the adrenal gland [44], [69] and [78]. They
include genes encoding proteins involved in cholesterol biosynthesis and transport, which may
control the availability of the precursor for GC biosynthesis. Several of the components implicated in
ACTHR-signaling also exhibit periodic expression, although it is still elusive whether they are under
the direct control of the local adrenal clock. Based on these findings, as well as evidence obtained
from the well-designed transplantation experiments, Oster et al. proposed a gating mechanism:
the local clock machinery in the adrenal gland contributes to the diurnal rhythm of GC by controlling
the daily variation in the adrenal sensitivity to ACTH [44]. Considering that splanchnic innervation
can entrain the adrenal local clockwork [69], it is plausible that the adrenal clock mediates the
autonomic SCN-adrenal pathway so as to produce the robust GC rhythm (Fig. 5).

However, early pioneering works which demonstrated the rhythmic nature of adrenal GC
biosynthesis and secretion in cultivated adrenal glands without any humoral or neural input imply
that a further adrenal-autonomous mechanism still remains [79], [80] and [81]. Cyclic accumulation
of steroidogenic genes and accompanying steroid production, which are linked with the adrenal
peripheral clock, would seem to be most likely candidates. Our recent study demonstrated that
StAR, a rate-limiting gene in the regulation of steroidogenesis [82] and [83], is an adrenal-specific
clock-controlled gene, which resides under the transcriptional control of a core clock component,
the CLOCK:BMAL1 heterodimer [45]. It was shown that StAR mediates molecular clock-evoked
steroid production, and its periodicity is found even under constant darkness. It should be noted
that both the adrenal StAR mRNA and protein levels increase in the late daytime in accordance with
the adrenal and plasma CS profiles. This StAR expression profile seems to be distinct from that of
other previously suggested steroidogenesis-related genes, which reach their deduced peaks several
hours after subjective light-off time [44]. The transcriptional regulation of the StAR gene expression
by the local clockwork appears to be evolutionarily conserved in both rodent and avian species [84]
and [85]. Our recent unpublished observations indicate that human StAR promoter activity is also
regulated by the CLOCK:BMAL1 heterodimer. Daily variations in adrenal StAR expression are
maintained even when the neural input into the gland is attenuated by splanchnic denervation,
supporting the idea that the adrenal local clock is the primary determinant of cyclic StAR expression
[70]. However, it is noteworthy that adrenal gland-specific ablation of the molecular clockwork
produces results in flattened adrenal CS content and a partially dampened circulating CS profile in a
mouse model [45]. Therefore, it is reasonable to speculate that rhythmic steroid production intrinsic
to the gland contributes to the robust daily rhythm in the circulating GC levels in cooperation with
the central modulation effected by hormonal and neural input (Fig. 5).

4.3. Rhythmic GC in the circadian timing system
Several features of the GC circadian rhythm strongly suggest its potential importance in overall
circadian physiology and metabolism. For example, the diverse actions of GC on physiological
processes [86] and [87], such as the clock-resetting activity of the hormone [4] and [31], support this
notion. The daily GC rhythm is heavily involved in behavioral rhythms; flattening of the GC rhythm by
either genetic abrogation of the adrenal clock or the administration of exogenous GC attenuates
circadian locomotor activity [45], [88] and [89]. Since the rhythmicity of the body temperature is not
significantly affected by this dampened GC rhythm [45], GC may have an organizing effect on the
specific brain functions underlying the periodic locomotor behaviors, presumably by coordinating
motor functions or maintaining the sleepwake cycle [45] and [49]. Circadian cell proliferation
rhythms in many tissues are also candidates for the circadian output influenced by GC [90]. Circadian
cell cycle rhythms in zebrafish larvae were severely attenuated in the absence of GC signaling,
implying a role of the steroid hormone as a systemic input crucial for cell proliferation at the right
time [91], although homologous functions in mammalian species have not yet been identified.

An acute administration of GC can induce phase synchronization in a wide range of peripheral
clocks both in vivo and in vitro [31]. Such clock-resetting activity by GC can be also considered in
terms of the circadian cyclicity of the hormone. Indeed, an attenuated GC rhythm leads to a blunted
cyclic accumulation of Per1 mRNA in several peripheral organs such as the liver, kidney, and
pancreas, but not in the SCN [45]. Conversely, chronic administration of a synthetic GC completely
abolished circadian Per1 expression in peripheral organs by a mechanism associated with its
constitutive overexpression in spite of the presence of an intact molecular oscillator [88]. The
periodic clock gene expression in certain discrete brain regions also requires rhythmic GC signaling,
implying that even higher brain functions can be directly influenced by the adrenal rhythm [89] and
[92]. It might be supposed that the GC circadian rhythm by itself can produce the rhythmic
physiological outputs from other tissues in a more direct fashion via classical GC signaling, and thus
contribute to the overt pattern of the rhythms considering the observations that the expression of at
least 10% of all genes are influenced by GC [86]. Moreover, there are two GC receptor types, with
distinctive affinities and capacities, and these are believed to be differentially activated at the
circadian peak and nadir of the circulating ligand levels [86]. This idea is strongly supported by the
observations that the rhythmic expression of a large number of genes in the liver is more dependent
on an intact adrenal gland and/or GC signaling rather than the hepatic oscillator [93] and [94].
Therefore, it is likely that the circulating GC rhythm influences some number of gene cycling
patterns, as well as periodic metabolic activity and behavior by a more direct actions on them.

On the other hand, accumulating evidence also suggests that there are stabilizing effects of GC on
established physiological rhythms in vivo. GC inhibits the daytime feeding-induced phase shift of
peripheral oscillators by GR-dependent mechanism in rats [77]. Ablation of the adrenal gland or GR
expression in target tissues facilitates phase dissociation of the peripheral clocks from the SCN
central clock. More importantly, GC exhibits stabilizing feedback effects on the central rhythm
during the resynchronization. Ablation of the entire adrenal gland or the adrenal clock facilitated re-
entrainment of the SCN-driven behavioral rhythm to a shifted lightdark cycle in a zeitgeber time-
dependent manner [95] and [96]. Daily CS oscillations in rats are involved in regulating the photic
entrainment of the locomotor activity rhythm [95]. Upon advancing the GC rhythm by the
application of metyrapone, a GC biosynthesis inhibitor, it results in a faster re-entrainment of the
locomotor rhythm in the same direction, as revealed in a mouse model of jet lag [96]. Taken
together, it is most likely that rhythmic GC contributes to the circadian timing system by harmonizing
diverse circadian output pathways and providing resistance to sporadic environmental changes so as
to avoid uncoordinated shifts.

5. Circadian rhythm of GC in human health and disease
Dysregulated GC secretion is responsible for numerous pathological conditions [7], [46], [47],
[48], [49], [86] and [87]. Alterations in its rhythmicity are frequently found in many human diseases,
including Cushing's syndrome, mood disorders, Alzheimer's disease, and metabolic syndrome [7],
[97], [98] and [99]. Importance of rhythmic GC has been well recognized in the course of its clinical
applications; tonic replacement at a constant dosage is not as successful as expected, and in fact is
related to cardiovascular mortality, disturbed daily glucose homeostasis and bone loss [100].
Uncoupling of the ACTH and the GC levels observed in the circadian regulation of the HPA axis is also
an important issue; such uncoupling during the phase of GC level increase can arise from either
autonomic or extrinsic causes. Notably, mismatches between circulating ACTH and cortisol often
occur in conditions such as chronic fatigue syndrome, sepsis, post-traumatic stress disorder, and
some cases of alcoholism [101], [102] and [103]. We will briefly review several of the human
diseases closely related to GC dysregulation and circadian rhythmicity.



5.1. Cushing's syndrome
Cushing's syndrome, a clinical syndrome of endogenous cortisol excess due to various causes,
occurs with a substantially high prevalence. The long-term consequences of severe hypercortisolism
include diabetes mellitus, osteoporosis, bone fractures, hypertension, dyslipidemia, recurrent
infections, sleep disorder, and increased mortality [7]. Mortality in Cushing's disease is usually 25
times higher than expected in the matched control population [104], [105] and [106], and even mild
hypercortisolism has harmful effects on long-term health because of decreased insulin sensitivity
and altered glucose tolerance [107] and [108]. Cushing's syndrome can be separated into the
categories of ACTH-dependent and ACTH-independent. In ACTH-dependent Cushing's syndrome,
inappropriately high levels of plasma ACTH secretion caused by corticotropin-producing tumors
persistently stimulate the adrenal cortex. In contrast, excessive production of cortisol by abnormal
adrenocortical tissue induces ACTH-independent Cushing's syndrome, suppressing the secretion of
both CRH and ACTH by a negative feedback mechanism [109].
It is well known that Cushing's syndrome is associated with a disturbed circadian rhythm; patients
with Cushing's syndrome show increased basal cortisol levels as well as an altered daily rhythm
(Table 1 and references therein). Therefore, some diagnostic tests for Cushing's syndrome are
designed to evaluate the circadian rhythm of cortisol, for instance, determination of the 24-hr free
cortisol and late-night cortisol levels [7 and Table 1]. Sleep disorders are another circadian feature of
Cushing's syndrome. They are associated with an increased frequency of sleep apnea or sleep
fragmentation [110] and [111]. These symptoms appear to be related to altered GC rhythms [112]
and [113], but the exact causes remain unclear.

Table 1.
Altered daily cortisol rhythms in patients with Cushing's syndrome or chronic fatigue syndrome.
Disease Patients Measurement Daily profiles References
Cushing's syndrome 7 Plasma cortisol, 24 h No diurnal rhythm [130]
7 Plasma cortisol, 24 h No diurnal rhythm [131]
39 Late-night salivary cortisol Higher levels at 23:00 h [132]
103 Plasma cortisol at 2 points No difference between 00:00 and 08:00 h [133]
120 Late-night salivary cortisol Higher levels at 22:00 h [134]
Chronic fatigue syndrome 30 Serum cortisol Lower levels in the morning [135]
7 Plasma cortisol, 24 h Low peak levels [121]
14 Salivary cortisol in the morning and evening Lower levels [136]

The cAMP/PKA signaling pathway tends to be enhanced in adrenal GC-producing cells in both
ACTH-dependent and -independent Cushing's syndrome. Excess ACTH strongly increases cAMP
production by adenylyl cyclase in association with its receptors, and persistent activation of the PKA
pathway induces the production and secretion of cortisol from the adrenal gland [114]. In addition,
investigation of the molecular cause of bilateral adrenocortical hyperplasia leading to ACTH-
independent Cushing's syndrome reveals certain prevalent mutations in the regulatory subunit
type1- of protein kinase A (PRKAR1A) and phosphodiesterase-11A (PDE11A) [115]. These mutations
reinforce cAMP/PKA signaling by constitutive PKA activation and cAMP degradation blockade. In this
context, a recent publication which reported that rhythmic cAMP/PKA signaling is a prerequisite for
normal cycling and functioning of the cellular clockwork is noteworthy [116]. It can, therefore be
speculated that the disruption of GC rhythmicity in Cushing's syndrome may involve dysregulated
cAMP/PKA signaling in many cases. This possibility needs to be further investigated in the near
future.

5.2. Adrenocortical insufficiency and GC replacement therapy
Adrenocortical insufficiency which arises from Addison's disease (an autoimmune disorder
causing degeneration of the adrenal cortex), congenital adrenal hyperplasia (an inherited defect in
adrenocortical steroidogenesis) or certain pituitary diseases (secondary adrenal insufficiency) is
commonly characterized by vulnerability to stress, white blood cell elevation, lymphoid tissue
hypertrophy, hypotension, mood disturbances, weight loss, and hypoglycemia [117]. Major
symptoms and signs of the diseases are mainly due to insufficient adrenal GC, and thus GC
replacement therapy is commonly employed. Although cortisol rhythmic activity is often observed in
patients with adrenal insufficiency, the amplitude of the cortisol rhythms is usually dampened due to
a reduction in the peak levels of circulating GC [118]. In this context, it should be noted that some
symptoms of GC insufficiency are closely related to circadian disorders; for example, sleep
disturbances in association with increased fatigue during the daytime were reported [100]. Since
simple replacement with a constitutive dose of GC was not as effective at alleviating symptoms as
expected and often exacerbated cardiovascular and metabolic disturbances [100] and [117], the
rhythmic nature of cortisol has become an important issue in the design of GC replacement therapy
regimens.
Oral administration of conventional immediate-release hydrocortisone (HC; the generic
pharmaceutical name of cortisol) two or three times a day is a widely accepted regimen to manage
adrenal insufficiency, in which dose is set higher in the morning and lower in the evening to mimic
daily cortisol rhythm. Although such conventional HC replacements have some benefit, the mortality
and morbidity risks are still higher than in the normal population primarily due to a short half-life of
the hormone in circulation. Furthermore, the under-replacement of cortisol often leads to the onset
of malaise, hypotension, weight loss, abdominal pain, electrolyte abnormalities and an impaired
stress response. On the other hand, overdosing can result in Cushingoid symptoms such as glucose
intolerance, hypertension, cardiovascular disease and mood disorders [100] and [119]. As a result,
the ideal GC replacement therapy would mimic the normal physiological state as closely as possible.
Several physiological hormone therapy regimens such as circadian infusion or more conveniently,
delayed and sustained release oral formulations of HC have been introduced over the past few years
[100] and [120]. In particular, an approach with a modified-release HC tablet has emerged that
allows a delayed and thus sustained rise in the circulating HC level so as to reach its peak at
approximately the morning time of awakening when taken at nighttime [119] and [120]. Therefore, a
better understanding of the rhythmic nature of GC and the development of new drug-delivery
technologies may provide improved hormone replacement regimens for adrenal insufficiency, which
would be more simplified and efficient to relieve symptoms, but have less adverse effects on
physiology.

5.3. Chronic fatigue syndrome
Chronic fatigue syndrome (CFS) is a disorder characterized by profound disabling chronic fatigue
in association with a number of other symptoms. Operationally defined, the fatigue should be severe
enough to cause a significant loss of physical and social function for a minimum of 6 months, and 4
of the following symptoms must also be present: sleep disturbance, impaired concentration, muscle
pain, multijoint pain, headaches, post-exertional exacerbation of fatigue, sore throat, tender lymph
nodes and depression [101]. CFS is a common and disabling problem that may be related to certain
psychosocial factors, but the nature of the pathophysiological components of this disease remains
unclear. In many cases, patients with CFS exhibit alterations in the HPA axis, including mild
hypocortisolism and reinforced negative feedback (Table 1). Many studies with serial measures of
unstimulated cortisol in a variety of biological fluids have reported reduced cortisol levels,
particularly the peak levels, suggesting that the GC circadian rhythm can be attenuated in a large
proportion of CFS patients [101 and references therein]. Reduced activity and sleep disturbance
imply disruption of behavioral rhythms, but daily variations of core body temperature and pituitary
hormone levels are surprisingly normal in CFS patients [121]. Although it is still debatable whether
disturbed HPA function is a cause or a consequence of CFS, the reported effectiveness of low-dose
GC therapy in CFS patients suggests that attenuated GC may be related to some of the syndromes to
some degree [122]. Interestingly, these features are comparable with the phenotypes observed in
transgenic mice with attenuated GC circadian rhythms because of adrenal-specific abrogation of
clock machinery: the mutant mice exhibited dampened GC rhythms and hypo-locomotion during the
activity period, but a normal temperature rhythm [45].

5.4. Clinical consequences of environmentally disrupted GC rhythm
Common environmental stimuli such as those associated with shift-work, sleep deprivation,
night-time eating and jet lag can alter or disrupt normal circadian physiology. In those cases, the
body tries to adapt to or endure such disruptions by adjusting the internal timekeeping system, but
chronic disruption may lead to persistent dysregulation of the circadian timing system. For example,
shift work and night-time eating are strongly associated with the onset of metabolic syndrome, a
cluster of health risk factors characterized by the impairment of carbohydrate and lipid metabolism
and normal functioning of adipose tissue and the cardiovascular, and hemostatic systems [123].
Chronic jet lag may influence malignant tumor growth [124] and even cognitive impairments
associated with reduced brain temporal lobe [125] and [126]. Accordingly, chronic
desynchronization of circadian rhythmicity in laboratory animals significantly increases mortality
often by cardiomyopathic heart disease [127] and [128].
GC is one of the key factors in the pathogenesis of metabolic syndrome, and its symptoms share
many features with those of other human disease related with dysregulation of GC, such as
Cushing's syndrome. In addition, several lines of evidence suggest that patients with metabolic
syndrome are characterized by hyperactivity of the HPA axis, leading to hypercortisolism [129]. It is
also of importance to mention that increased cortisol levels are closely related with cognitive deficits
in airline flight crews repeatedly exposed to jet lag [125] and [126]. As mentioned earlier, GC has an
influence on circadian outputs during the adaptation to new zeitgeber cues, including changes in the
lightdark schedule and feeding times. Therefore, chronic disruption of the GC circadian rhythm may
be involved in both the adaptation/entrainment and pathophysiological consequences of
environmental disruption of the circadian timing system.

6. Conclusion
In conclusion, the current understanding of the circadian control of the adrenal GC and human
diseases related to disruptions of this temporal regulation is here reviewed. Periodic GC secretion
and biosynthesis are tightly regulated by coincident multiple mechanisms at different levels of the
circadian timing system. The master clock in the SCN directly drives the GC circadian rhythm both by
modulating the HPA neuroendocrine axis and via sympathetic splanchnic innervation of the adrenal
gland. However, a growing body of evidence points to the importance of local clockwork in the
adrenal gland itself. The oscillating adrenal clock machinery plays a crucial role in maintaining the
rhythm by controlling the capacity and responsiveness of adrenal GC secretion and biosynthesis to
ACTH. Therefore, the next questions are related to determining how these multiple mechanisms are
coordinated with the robust cyclicity of the secretion of the hormone, and then how GC target cells
sense and process this rhythmic information. Another important question regarding the GC rhythm
concerns its role in physiology and pathophysiology. Although the importance of the rhythmic GC
has been appreciated for some time, the specific physiological relevance of the rhythm, particularly
in human health and disease, remains to be further elucidated. Recent advances in our knowledge
on the molecular and cellular basis of the GC circadian rhythm should help provide novel insights
and breakthroughs to resolve these as yet outstanding issues.

Acknowledgments
This work was supported by grants from the Korea Ministry of Education, Science and Technology
(MEST) through the Brain Research Center for the 21st Century Frontier R&D Program in
Neuroscience. Sooyoung Chung was supported by the Brain Korea 21 Research Fellowships from the
MEST.

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Irama circardian terhadap glukortikoid adrenal : regulasi dan implikasi klinis
Abstrak
Glukokortikoid (GC) adalah hormon steroid adrenal yang mengendalikan berbagai proses
fisiologis metabolisme, respon imun, aktivitas kardiovaskular dan fungsi otak. Sebagai
tambahan terhadap induksi Glukokortikoid sebagai respon terhadap stres, bahkan dalam
kondisi yang tidak terganggu kadar sirkulasi nya tergantung pada variasi peningkatan setiap
hari dengan puncaknya di sekitar awal masa aktif harian. Hal ini telah lama diyakini bahwa
sintesis dan sekresi Glukokortikoid terutama diatur oleh sumbu neuroendokrin hipotalamus-
pituitary-adrenal (HPA). Namun, penelitian kronobiologi terbaru sangat mendukung gagasan
bahwa beberapa mekanisme regulasi dengan sumbu neuroendokrin HPA klasik mendasari
irama diurnal sirkulasi Glukokortikoid. Terutama, studi terbaru menunjukkan bahwa masa
kerja sirkardian sangat berhubungan dengan irama glukokortikoid harian pada beberapa
tingkatan. Irama harian Glukokortikoid berefek dalam berbagai penyakit pada manusia
dengan disertai abnormalitas tingkat Glukokortikoid. Pasien dengan penyakit tersebut sering
menunjukan irama Glukokortikoid yang datar dan, lebih penting lagi, gejala-gejala yang
berhubungan dengan ritme sirkadian. Dalam tinjauan ini, kita fokus pada kemajuan terbaru
dalam pemahaman tentang regulasi sirkadian glukokortikoid adrenal dan implikasinya dalam
kesehatan dan penyakit.
Yang perlu di perhatikan dalam penelitian ini
Pemahaman sekarang terhadap kontrol sirkardian kelenjar adrenal. Beberapa
mekanisme regulasi yang mendasari irama harian glukokortikoid (GC). Peran pada masa
kerja adrenal lokal terhadap produksi Glukokortikoid sirkardian. Pentingnya irama
glukokortikoid dalam kesehatan dan penyakit manusia.
Kata kunci
Glukortikoid; Kelenjar adrenal ; sumbu HPA; Irama sirkardian; Jam biologis
1. Introduksi
Ritme sirkadian terdiri atas osilasi biologis dengan periode sekitar 24 jam yang sangat
dikonservasikan dari cyanobacteria terhadap manusia. Irama harian ini bukanlah respon
sederhana terhadap perubahan alternatif siang dan malam. Hal ini muncul dari sistem
timekeeping bawaan genetik,yang disebut sebagai jam biologis. Time keeping internal ini
mengijinkan organisme untuk mengantisipasi dan mempersiapkan diri terhadap perubahan
dalam lingkungan fisik mereka, sehingga memungkinkan mereka untuk berperilaku
sebagaimana seharusnya pada waktu yang tepat. Jam biologis juga sangat memberikan
kontribusi untuk memastikan bahwa proses fisiologis tertentu berlangsung dalam koordinasi
dengan yang lain. Pada mamalia, nucleus suprachiasmatic dari hipotalamus anterior, berfungi
sebagai pacemaker sirkardian utama,yang mendorong ritme sirkadian terbuka seperti siklus
aktivitas-istirahat, variasi harian dalam metabolism dan suhu tubuh, dan irama sekresi
hormon [4].
GC adalah hormon steroid adrenal yang memainkan peranan penting dalam respon
adaptasi terhadap variasi tipe stress dan berada di bawah kendali aksis neuroendokrin
hipotalamus-hipofisis-glandula adrenal. Sebagai tambahan terhadap reaktivitas stress, variasi
harian dalam tingkat sirkulasi adalah fitur kunci lain dari hormon ini. Hal ini diterima secara
luas bahwa ritme GC harian juga berada di bawah kendali waktu sirkadian karena iramanya
yang benar-benar datar oleh gangguan dari SCN menyimpan osilator induk. Hal ini juga
diketahui bahwa disregulasi kronis GC, yaitu baik hiper atau hiposekresi, menginduksi
timbulnya kondisi patologis yang beragam dengan mengganggu metabolisme karbohidrat dan
lipid, respon imun, aktivitas kardiovaskular, suasana hati, dan fungsi kognitif / otak. Semakin
banyak bukti menunjukkan bahwa tidak hanya tingkat sirkulasi GC tetapi juga aktivitas irama
memainkan peran penting dalam kesehatan manusia dan penyakit. Oleh karena itu,
memahami mekanisme regulasi irama GC harian dan relevansi fisiologis dapat memberikan
wawasan baru terhadap kedua dasar molekul dan pengobatan klinis penyakit manusia yang
melibatkan sekresi GC abnormal. Di sini, kita meninjau kemajuan terbaru dalam penelitian
jam sirkadian dan fokus pada peran sistem waktu sirkadian di irama GC harian dan implikasi
klinisnya.
2. Sistem waktu sirkardian dan waktu kerja molekuler
2 1 Waktu kerja sirkardian pada mamalia
Oleh karena rotasi bumi, hamper semua fungsi organisme berada dalam siklus 24 jam
siang-malam. Untuk beradaptasi dan mengantisipasi siklus harian eksternal, organisme telah
mengembangkan sebuah sistem timekeeping internal. Sistem timekeeping harian ini disebut
sebagai waktu sirkadian dari Bahasa Latin circa diem di mana secara literatur berarti
sekitar sehari. Keduanya otonom dan mandiri tetapi juga secara kontinu tertahan oleh syarat
waktu eksternal yang disebut "zeitgeber. Sistem waktu sirkadian mamalia terdiri dari 3
komponen: 1. Input sinyal (syarat lingkungan), 2. Osilator sirkadian sebagai generator irama
intrinsik, dan 3. Irama output. SCN hipotalamus secara umum telah dianggap sebagai pusat
osilator sirkadian baik secara anatomic dan fungsional; menerima informasi photic dari mata
melalui traktus retino-hipotalamus dan kemudian mengsinkronisasi sistem waktu sirkadian
dengan waktu lingkungan. Anggapan ini didukung kuat oleh temuan bahwa ablasi selektif
dari SCN mengarah pada hilangnya irama sirkadian secara total, sedangkan transplantasi dari
SCN intak terhadap mutasi hewan aritmik mengembalikan ritmisitas sirkadian. Ritme
sirkadian yang dihasilkan dalam SCN diyakini diubah menjadi sinyal saraf atau hormon yang
mempengaruhi proses metabolisme, fisiologi dan perilaku. (Gambar. 1).

Organisasi hirarki untuk sistem waktu sirkadian mamalia. SCN yang tinggal dalam ventral
hipotalamus, berfungsi sebagai pusat waktu bertanggung jawab terhadap koordinasi jaringan
waktu multipel pada tubuh. SCN berkomunikasi dengan dan mengsinkronkan waktu kerja
lokal pada jaringan lain, termasuk kedua jaringan peripheral dan region ekstra-SCN pada
otak. Pemeriksaan terhadap modulasi jaringan spesifik dari mesin waktu mengungkapkan
peran otonom masing-masing waktu lokal dan waktu peripheral adrenal secara khusus terlibat
dalam irama harian GC dan memberikan dampak pada sinkronisasi waktu peripheral lain dan
regulasi dari sistem fisiologis, termasuk metabolisme.
Sistem otonom dan kemampuan dasar untuk mempertahankan diri sistem waktu sirkadian
secara primer bergantung pada keberadaan mekanisme genetic dikenal sebagai waktu kerja
sirkadian molecular. clock genes dibutuhkan untuk generasi dan mempertahankan ritme
sirkadian dalam suatu organisme dan bahkan dalam sel individual. Clock genes dan produk
gen tersebut secara kooperatif mempromosikan ekspresi gen ritmik oleh dua transkripsi
positif dan negatif/translasi umpan balik yang saling bertautan yaitu inti dan tambahan.
Dalam prinsip atau inti putaran umpan balik, anggota dari dasar helixloophelixPeriod-
ARNT-single-minded (bHLH-PAS) faktor transkripsi superfamily seperti CLOCK and
BMAL1, membentuk heterodimer untuk mengaktivasi transkripsi dari target gen meliputi
elemen E-box dalam regio regulasi-cis gen teresbut. Target gen ini termasuk regulator negatif
seperti Periods (PERs: PER1, PER2 and PER3) dan kriptokrom (CRYs: CRY1 and CRY2).
Konsentrasi BMAL1 disesuaikan oleh umpan balik tambahan atau stabilisasi yang dibentuk
oleh reseptor nuklir REV-ERB dan ROR terkontrol waktu. Umpan balik mandiri
dideskripsikan pada Gambar 2, merupakan mesin waktu sirkadian molecular dalam perkiraan
periode 24 jam.


Gambar 2.
Waktukerja sirkadian molecular. Osilator sirkadian mamalia terdiri dari 2 umpan balik
transkripsi / translasi yang saling bertautan: inti dan tambahan. CLOCK/BMAL1
heterodimer, komponen integral dari inti menginduksi transkripsi E-box-mediated dari
Periode regulator negatif (PERs) dan Kriptokrom (CRYs). Akumulasi protein PER dan CRY
secara intensif menekan transkripsi E-box-mediated sampai tingkat mereka sudah cukup
menurun, sebagai tambahan, CLOCK and BMAL1 juga mengontrol transkripsi reseptor
nuclear ROR and Rev-erb, di mana memodulasi tingkat Bmal1mRNA dengan tindakan
kompetitif pada elemen RRE berada di promotor Bmal1. Secara kolektif, siklus dari
komponen waktu juga mendeterminasi tingkat dari gen waktu terkontrol (CCGs) dengan
transkripsi melalui E-box and/or RRE untuk meraih pola osilasi mereka dan untuk
menghasilkan output fisiologis ritmik.
Sebagai tambahan untuk regulasi inti pada tingkat transkripsi/translasi, protein waktu
sirkadian juga mengalami modifikasi pasca-translasi yang luas yang muncul untuk
mengendalikan stabilitas protein mereka, lokalisasi nuklir dan aktivitas fungsional. Sebagai
contoh, casein kinase 1 and diketahui sebagai faktor penting yang mengatur perputaran
PERs dan Crys pada mamalia.
BMAL1 disimulasi in vivo secara berirama dan simulasi ini mempromosikan interaksi
dengan CLOCK, akumulasi nuklir yang eksklusif di dalam nukleus leukemia promyelocytic
(PML), transaktivasi dan degradasi yang bergantung pada ubiquitin]. BMAL1 juga diatur
oleh acetylation sehingga memiliki peran dalam pemeliharaan irama sirkardian. Tambahan
lagi, mediasi forsforilasi protein kinase C (PKC) tergantung ca2+ terhadap CLOCK dan
pengumpulan kofaktor yang berhubungan terhadap heterodimer CLOK/BMAL1 penting
untuk mengatur ulang fase waktu sirkardian mamalia. Regulasi Post-Translasi dari protein
CLOCK dan fungsi nya secara signifikan diteliti secara ekstensif ditempat lain.
2.2. Waktu utama dan perifer dalam output irama fisiologis
Sistem sirkardian mamalia diatur secara hirarki. Pada puncak waktu sistem sirkardian
mamalia,SCN terdiri dari saraf yang padat yang memilik kapasitas ritmik yang mandiri.
Sangat jelas bahwa bukan saja SCN tetapi hampir seluruh jaringan dan organ perifer
menunjukan waktu gen tersendiri. Ini telah dibuktikan bahwa kultur sel in vitro juga
mempertahankan irama sirkardian pada tingkat sel tunggal ; bahkan, konsentrasi tinggi dari
serum atau GC agonis sintetik mampu untuk mensinkronisasi irama individual sehingga
mampus mengekspresi siklus waktu gen pada tingkat populasi sel. Selain itu, sudah di
buktikan bahwa kebanyakan sel mamalia memilki waktu sirkardian tersendiri. Irama ini
menunjukan tampilan molekular yang sama dengan yang terdapat di saraf pacemaker
SCN,tetapi di kenal sebagai irama lokal atau perifer untuk membedakanya dari irama utama
di SCN. Oleh karena itu, SCN berfungsi sebagai pusat untuk menyelaraskan ritme sirkadian
di mamalia dengan mengkoordinasi irama waktu perifer yang tersebar di seluruh tubuh
(Gambar. 1). SCN mempertahankan komunikasi terus menerus dengan waktu perifer melalui
berbagai sinyal saraf dan humoral. Sebagai tambahan,terhadap waktu informasi yang
ditransmisikan oleh SCN, zeitgebers lain, seperti waktu makan dan irama suhu tubuh,
memainkan peran penting dalam mengatur ulang timekeepers perifer. Dalam konteks ini,
perlu diperhatikan bahwa GC adalah calon yang sesuai untuk hubungan hormon penting
antara SCN dan waktu perifer. Masalah ini akan dibahas dalam bagian selanjutnya dari jurnal
ini.
Berbagai proses fisiologis di Mamalia, termasuk siklus bangun tidur, suhu tubuh, aliran
plasma ginjal dan aktivitas kardiovaskular dipengaruhi oleh regulasi sirkadian. Meskipun
gambaran irama dari proses fisiologis ini memerlukan keterlibatan SCN, keberadaan osilaor
perifer sangat mendukung kontribusi mereka terhadap manifestasi irama sirkardian didalam
berbagai proses selular. Banyak bukti telah diperoleh dari studi profil transcriptome.
Misalnya, 5%-10% dari semua spesies mRNA menunjukan pola ekspresi sirkadian di hati.
Perbandingan profile transcriptome di berbagai jaringan mengungkapkan bahwa kebanyakan
transkripsi sirkardian di tunjukkan dalam bentuk mode jaringan spesifik, yang sesuai dengan
gagasan bahwa fungsi yang berbeda dikendalikan oleh jaringan yang berbeda dari waktu
kerja sirkardian lokal. Namun, peran irama perifer dan pacemaker pusat dalam mengatur
fungsi sirkadian dalam organ tertentu jarang dibedakan. Dalam konteks ini,modulasi selektif
dari mesin waktu perifer tertentu baru-baru ini telah dikaji untuk mengetahui kemungkinan
peran irama perifer secara fisiologis dan metabolisme. Takahashi et al. menyelidiki fungsi
penyelamatan jaringan tertentu pada BMAL1 tikus mati, menunjukan kebutuhan aktivasi
BMAL1 otak untuk perilaku irama sirkardian. Dalam studi lain, ekstraksi spesifik hati dari
Bmal1 mengakibatkan disfungsi metabolisme glukosa dan metabolisme lipid serta gangguan
pankreas yang menyebabkan diabetes melitus karena fungsi sel-B2 rusak. Endotel BMAL1
mepengaruhi respon terhadap rangsangan thrombogenic dan tekanan darah dalam sistem
kardiovaskular. Terutama, gangguan waktu adrenal lokal mempengaruhi profil GC harian,
menunjukkan pentingnya waktu adrenal perifer di irama sirkadian hormon steroid.



3. Regulasi neuroendokrin kelenjar GC adrenal
3.1. HPA axis dan peranan fisiologis GC
Sumbu HPA adalah rangkaian neuroendokrin utama dari sistem respon stres, dan adrenal
GC sintesis dan sekresi dikenal ketat diatur oleh hormon yang dikeluarkan dari hipotalamus
dan hipofisis (Gambar. 3). Secara umumnya, sinyal neurokimia tertentu mencapai
hipotalamus dan kemudian neuron di nukleus paraventrikular (PVN) hipotalamus
mengeluarkan corticotrophin-releasing hormon (CRH) dan arginin vasopresin (AVP) untuk
merangsang sintesis dan sekresi hormon adrenokortikotropik (ACTH dari hipofisis.
Kemudian ACTH menginduksi sintesis adrenal dan sekresi GC, yang berinteraksi dengan
reseptor spesifik di berbagai jaringan target di otak dan perifer. Sirkulasi GC akhirnya
mengehentikan aktivitas HPA neuroendokrin dan mengembalikan kesetimbangan melalui
umpan balik negatif.

Gambar 3
Pengaturan neuroendokrin terhadap adrenal GC dan peran fisiologisnya. GC terutama
diatur oleh sumbu hipotalamus hipofisis kelenjar adrenal (HPA), rangkaian neuroendokrin
utama dari sistem respons stres. Ketika sinyal neurokimia tertentu mencapai hipotalamus
sebagai hasil dari stres atau sirkadian input, sebuah subset dari sel-sel neurosecretory dalam
PVN hipotalamus mengeluarkan CRH dan AVP untuk menginduksi sintesis ACTH dan
sekresi dari hipofisis. ACTH kemudian menginduksi sel adrenocortical untuk memproduksi
dan mensekresi GC. Sirkulasi GC menghentikan sumbu neuroendokrin HPA dengan
mekanisme umpan balik negatif. Selain itu, GC diberikan efek yang luas dalam tubuh yang
diperlukan untuk mengembalikan dan mempertahankan berbagai homeostasis fisiologis.

Sebagai sumbu akhir efektor HPA responsif stres neuroendokrin, GC diberikannya efek
yang dalam tubuh untuk mempertahankan homeostasis dan memampukan organisme untuk
mempersiapkan untuk menanggapi dan mengatasi stres fisik dan emosional. Sebagai contoh,
GC mempromosikan pemecahan karbohidrat dan protein dan memodulasi endapan lipid dan
pemecahanya. GC juga penting sebagai regulator dalam berbagai response imun dan
inflamasi. Selanjutnya, GC meningkatkan tekanan darah, memiliki beragam efek pada tulang,
memunculkan efek positif dan negatif pada pertumbuhan sel, dan proapoptosis dalam jenis
sel tertentu, termasuk sel-sel saraf tertentu. Selain menyediakan umpan balik negatif untuk
sumbu HPA, GC mempengaruhi sel-sel neuronal dan glial dalam sistem saraf pusat (SSP)
untuk menjembatani proses organisasi yang penting dalam perkembangan otak dan plastisitas
neural dan degenerasi di masa dewasa. Pengaruh utama lainnya termasuk perubahan dalam
suasana hati dan perilaku, modulasi dari asupan makanan,, modulasi asupan makanan, suhu
tubuh dan nosiseptive.




3.2 Biosintesis GC adrenal
GC terutama disintesis dari subset dari sel-sel adrenocortical dalam menanggapi ACTH
oleh pengolahan steroidogenic kolesterol (gambar 4). Korteks adrenal mamalia terdiri dari
sel-sel yang dipisahkan menjadi zona yang terpisah dengan fungsi yang berbeda, zona
glomerulosa (ZG), zona fasciculata (ZF) dan zona reticularis (ZR), dan set yang berbeda dari
gen steroidogenic diekspresikan dalam setiap zona [50]. GC terutama diproduksi di ZF,
dimana reseptor ACTH (ACTHR; melanocortin reseptor 2, MC2R) juga sangat
diekspresikan. Selama aktivasi sumbu HPA, ACTH mengikat ACTHR, mengaktifkan
heterotrimeric Gs protein, dan kemudian merangsang adenylyl cyclase. CAMP intrasel
kemudian mengaktifkan protein kinase A (PKA) nuklir transkripsi faktor, seperti cAMP
respon elemen (CRE) mengikat protein (CREB) dan CRE modulator (CREM). Faktor-faktor
transkripsi memodulasi ekspresi gen yang terlibat dalam biosintesis GC adrenal dengan
mengikat CRE yang tinggal di daerah promotorgen-gen.


Gambar 4.
Adrenal steroidogenesis dan pengaturan hormon. GC disintesis terutama dalam subset dari
sel-sel steroidogenic adrenocortical oleh modifikasi enzimatik kolesterol dalam mitokondria
yang berturur-turut. Pemindahan kolesterol dari sitosol ke kompartemen mitokondria oleh
StAR berfungsi sebagai langkah membatasi tingkat. ACTH dikeluarkan sebagai response
untuk menginduksi produksi GC adrenal dengan mempromosikan ekspresi gen steroidogenic
melalui aktivasi cascades sinyal ACTHR/cAMP/PKA/CREB.
Berbagai set gen steroidogenic dikenal untuk terlibat dalam biosintesis GC adrenal.
Pertama, kolesterol dipindahkan dari sitosol ke dalam membran mitokondrial, dimana dapat
dikonversi ke pregnenolone, prekursor steroid umum. Pengaturan steroidogenik akut protein
(StAR), ekspresi yang cepat sebagai tanggapan terhadap rangsangan hormonal, menjembatani
pengiriman kolesterol ke situs konversi enzimatik pertama kolesterol untuk pregnenolone
oleh CYP11A1 (kolesterol sisi jaringan pembelahan monooxygenase). Oleh karena itu, ini
merupakan langkah yang membatasi tingkat dan hormon yang diatur dalam steroidogenesis.
Seperti yang dijelaskan dalam gambar 4, pregnenolone kemudian diberikan tindakan yang
berurutan dari beberapa hydrogenases steroid (sitokrom P450 dan protein yang mengandung
heme) dan HSD3Bs (3 -hydroxysteroid dehydrogenases), akhirnya mengarah ke GC
produksi. CYP17 (17 -hidroksilase) yang hanya ada untuk memproduksi kortisol spesies
seperti manusia tetapi tidak dalam memproduksi kortikosterone spesies seperti tikus. Hal ini
menjembatani 17 -hidroksilasi dan pembelahan pregnenolone dan progesteron, sehingga
merupakan tambahan jalur untuk biosintesis kortisol.
4. Pengaturan sirkardian untuk biosintesis dan sekresi GC
Selain respon terhadap stres, karakteristik kunci lain dari GC adalah irama harian yang
kuat. Tingkat sirkulasi GC lebih tinggi selama periode aktivitas (siang untuk spesies diurnal
dan malam untuk spesies malam) dan tingkat puncak terhubung ke awal periode aktivitas.
Walaupun irama sirkardian GC dilaporkan beberapa dekade yang lalu, dasar molekul nya
masih belum dipahami sepenuhnya. Bukti-bukti yang dihasilkan dari kemajuan terbaru dalam
chronobiology telah menunjukkan bahwa variasi harian dibentuk oleh peraturan multimodal
:peran dari SCN yang memicu melalui sumbu neuroendokrin dan sistem saraf otonom serta
mekanisme intrinsik yang melibatkan waktu kerja kelenjar adrenal secara lokal menunjukkan
adanya hubungan dengan pembentukan ritme GC sirkardian didalam sirkulasi. Selain itu, GC
dianggap sebagai kunci mediasi bagi penghubungan dari sistem waktu sirkadian . Dalam
bagian ini, kita akan membahas beberapa mekanisme regulasi terkait irama sirkardian GC
dan fisiologis.
4.1. Regulasi SCN mengacu pada sumbu HPA dan sistem saraf otonom
Profil osilasi dalam sirkulasi GC terutama telah dikaitkan dengan modulasi SCN sumbu
HPA, Gambar 5]. Pengamatan bahwa pembatalan SCN menghilangkan irama plasma ACTH
dan GC sangat mendukung gagasan ini. Dari segi neuroanatomis, pacemaker neuron SCN
tampaknya tidak langsung mengontrol hipotalamus ACTH memproduksi secretagogue
neuron dalam divisi parvocellular PVN, memproyeksikan ke daerah tetangga PVN, zona
subparaventricular dan nukleus hipotalamus [58] dorsomedial. Karena tingkat kortikosterone
(CS) pagi dilaporkan meningkat setelah ablasi SCN pada tikus, kekuatan hambatan pada
basal Gc yang dikeluarkan oleh SCN tampaknya jelas. AVP diproduksi oleh sekumpulan
neuron SCN dianggap salah satu neurotransmitter utama dalam mediasi penghambatan ini.
Namun, beberapa menyarankan peran yang relatif terbatas untuk regulator hormon sumbu
HPA dan keterlibatan beberapa masukan ke dalam kelenjar adrenal. Pertama, irama harian
bebas-stres pada kadar plasma CS biasanya menampilkan 5 - untuk 10 kali lipat lebih
tinggi dari palung untuk tingkat puncak dalam tikus, sedangkan irama plasma ACTH relatif
lebih rendah (hingga 2-kali lipat) atau bahkan sering tidak signifikan perbedaanya. Meskipun
hanya irama sederhana di ACTH,tingkat sirkulasi CS memperlihatkan irama yang kuat,
yang menyiratkan regulasi tambahan. Kedua, irama plasma CS bertahan walau dalam
keadaan tikus yang telah di hipofisektomi tetap menerima butir ACTH , menunjukkan bahwa
irama GC tidak semata-mata tergantung pada irama pelepasan ACTH. Ketiga, hal ini juga
penting untuk dicatat bahwa bahkan dalam ketiadaan SCN penghambatan sinyal, kadar
plasma CS tidak mencapai tingkat puncak, dan ada perbedaan yang jelas antara penurunan
pengaturan penghambatan dari SCN dan peningkatan tingkat CS saat sore pada tikus.
Dengan demikian, setelah serangkaian percobaan disinhibisi, Buijs et al. menyarankan bahwa
perlunya sinyal tambahan dengan penundaan beberapa jam setelah sinyal penghambatan
utama, tapi sebelum tingkat CS puncak.

Gambar 5.
Model kerja dalam regulasi diurnal sekresi dan biosintesis GC. Variasi harian dalam
tingkat sirkulasi GC dicapai oleh beberapa mekanisme regulasi. Nukleus suprakiasmatik
(SCN) mengatur irama adrenal dengan modulasi aktivitas sumbu HPA. Irama produksi
arginin vasopresin oleh neuron SCN yang terlibat dalam peraturan ini. Di jalur lain, saraf
splanknikus yang mempersarafi kelenjar adrenal dalam sistem saraf otonom SCN (oz)
berkontribusi terhadap sekresi sirkardian dari GC serta mengatur ulang waktu lokal dari
adrenal. Selain pusat mekanisme yang diberikan oleh waktu utama di SCN, mekanisme
intrinsik adrenal melibatkan waktu kerja lokal adrenal yang mendasari irama GC. Meskipun
waktu lokal adrenal bersama dengan ANS mendalilkan gerbang adrenal yang sensitif
terhadap ACTH, lebih penting bahwa waktu lokal ini terkait erat dengan jalur steroidogenic.
Ekspresi siklik StAR, sebuah gen yang membatasi tingkat dari steroid biosintesis,secara
langsung dikendalikan oleh CLOCK: BMAL1 heterodimer sebagai kelenjar adrenal khusus
gen; Akibatnya, osilasi harian yang dihasilkan dalam steroidogenesis berkontribusi generasi
irama GC kuat.
Baru-baru ini, pengaruh dari pacemaker pusat di SCN melalui persarafan splanchnikus ke
kelenjar adrenal telah dilaporkan terlibat [gambar 5]. Kontrol sekresi GC diurnal oleh jalur
SCN-adrenal otonom ini didukung oleh 2 hal. Pertama, saraf simpatis kelenjar adrenal
langsung mengirimkan informasi ringan ke kelenjar tersebut yang mengarah ke peningkatan
CS , bebas dari aktivasi sumbu HPA. Penghasilan adrenalin oleh medula adrenal bertanggung
jawab untuk transmisi sinyal fotic ke korteks adrenal. Kedua, kontrol otonom terhadap irama
GC terkait modulasi sensitivitas adrenal terhadap ACTH. Responsitivitas adrenal terhdap
ACTH pada tikus nokturnal memperlihatkan irama harian, dengan sensitivitas tinggi yang
mengarah pengeluaran CS yang lebih tinggi di malam hari. Telah terbukti bahwa sensitivitas
dari kelenjar adrenal terhadap rangsangan ACTH bergantung pada persarafan splanknikus
dari waktu pusat SCN dihipotalamus. Namun, perbedaan tetap mengenai perubahan harian di
response adrenal di sumbu HPA. Misalnya, telah diusulkan bahwa perubahan diurnal bebas-
stres CS melibatkan integritas splanchnic saraf, tapi tidak dimediasi oleh diferensial
responsivitas terhadap ACTH . Baru-baru ini, itu juga menunjukkan bahwa tanggapan stres
ringan pada tikus tidak berbeda antara fase awal terang dan malam, sehingga ada sedikit
keraguan tentang variasi diurnal terhadap respon sumbu HPA. Selain itu, transeksi saraf
splanknikus mengakibatkan penurunan tingkat sirkulasi CS puncak pada tikus secara
sebagian, menampilkan bahwa input neural terhadap SCN masih belum cukup untuk benar-
benar memperhitungkan irama sirkadian GC
4.2. Mekanisme intrinsik adrenal: keterlibatan osilator adrenal
Irama sirkardian GC tidak sepenuhnya dijelaskan oleh mekanisme pusat kendali SCN,
seperti yang dijelaskan di atas. Oleh karena itu, ada kemungkinan bahwa mekanisme yang
tidak dikenal pasti , terutama mereka adrenal intrinsik. Menariknya, pembatasan makanan
disiang hari pada hewan nokturnal dapat memisahkan fase pacemaker SCN pusat dan waktu
perifer lain, kemungkinan oleh entrainable makanan osilator; di bawah rezim makan pada
siang hari, profil GC harian terbagi menjadi 2 puncak setiap hari, menyiratkan adanya
mekanisme adrenal intrinsik. Dalam hal ini, sangat penting bahwa kelenjar adrenal pelabuhan
clockwork sirkadian sendiri, seperti yang telah ditunjukkan oleh beberapa kelompok bebas.
Waktu kerja molekuler dari sel steroidogenic adrenocortical bekerja secara otonom, dan itu
bisa berjalan oleh aktivasi dari jalur SCN-adrenal otonom. Analisis global dari transkriptom
adrenal mendukung gagasan bahwa mesin waktu lokal ini berhubungan dengan kunci jalur
selular di kelenjar adrenal. Mereka termasuk pengkodean protein gen yang terlibat dalam
biosintesis kolesterol dan transportasi, yang dapat mengontrol ketersediaan prekursor untuk
biosintesis GC. Beberapa komponen-komponen yang terlibat dalam ACTHR-signaling juga
menunjukkan ekspresi periodik, meskipun masih sulit dipahami Apakah mereka berada di
bawah kontrol langsung waktu lokal adrenal. Berdasarkan Temuan ini, serta bukti-bukti yang
diperoleh dari percobaan transplantasi yang dirancang dengan baik, Oster et al. Mengusulkan
gating mechanism: mesin waktu lokal di kelenjar adrenal berkontribusi terhadap irama
diurnal GC dengan mengendalikan variasi harian pada sensitivitas adrenal terhadap ACTH.
Mengingat bahwa persarafan splanchnikus dapat turut serta dalam waktu kerja lokal adrenal,
ini masuk akal bahwa waktu adrenal memediasi jalur SCN-adrenal otonom sehingga
menghasilkan irama GC yang kuat (GB. 5).
Namun,kerja awal yang menunjukkan sifat irama biosintesi GC adrenal dan sekresi di
dibudidayakan kelenjar adrenal tanpa setiap humoral atau input saraf menyiratkan bahwa
mekanisme otonom adrenal lanjutan masih tetap ada. Akumulasi siklik gen steroidogenik dan
produksi steroid yang menyertainya, yang dikaitkan dengan waktu perifer adrenal, tampaknya
akan menjadi kandidat yang paling mungkin. Studi terbaru kami menunjukkan bahwa StAR,
gen yang kadar nya terbatas dalam regulasi steroidogenesis,merupakan gen adrenal spesifik
terkontrol waktu, yang berada di bawah kendali komponen transkripsional dari inti komponen
waktu, CLOCK: BMAL1 heterodimer. Itu menunjukkan bahwa StAR memediasi molekul
pembangkit waktu produksi steroid, dan periodisitas ditemukan bahkan di bawah kegelapan
tetap. Perlu dicatat bahwa kedua StAR mRNA adrenal dan tingkat protein meningkatkan di
akhir siang hari sesuai dengan profil adrenal dan plasma CS. Profil ekspresi StAR ini
tampaknya berbeda dengan gen terkait dengan steroidogenesis yang sudah disarankan
sebelumnya, yang mencapai puncak mereka beberapa jam setelah waktu henti subyektif.
Peraturan transcriptional StAR gen di ekspresikan oleh waktu kerja lokal tampaknya
evolusioner dilestarikan di spesies tikus dan burung. Observasi terbaru yang tidak diterbitkan
menunjukkan bahwa aktivitas promotor StAR manusia juga diatur oleh CLOCK: BMAL1
heterodimer.Variasi harian dalam ekspresi StAR adrenal dipertahankan bahkan ketika input
saraf ke dalam kelenjar dilemahkan oleh denervasi splanchnic, mendukung gagasan bahwa
waktu lokal adrenal adalah penentu utama ekspresi StAR siklik. Namun, sangat penting
bahwa ablasi kelenjar adrenal khusus pada waktu kerja molekul menghasilkan isi CS adrenal
yang rata dan sebagian memperkecil profil CS yang beredar di model tikus. Oleh karena itu,
sangat wajar untuk berspekulasi bahwa irama produksi steroid intrinsik untuk kelenjar
berkontribusi terhadap irama harian yang kuat di tingkat peredaran GC dengan kerjasama
dengan modulasi pusat yang dipengaruhi oleh hormon dan input saraf (GB. 5).
4.3. Irama GC dalam sistem waktu sirkardian
Beberapa fitur irama sirkardian GC sangat menyarankan kepentingan potensialnya di
keseluruhan fisiologi dan metabolisme sirkardian. Sebagai contoh, beragam tindakan GC
pada proses fisiologis, seperti mengatur ulang jam aktivitas hormon, mendukung gagasan ini.
Irama GC harian yang sangat terlibat dalam perilaku irama; perataan irama GC baik
pemecahan genetik dari waktu adrenal atau administrasi GC eksogen melemahkan aktivitas
lokomotor sirkardian. Oleh karena irama suhu tubuh tidak secara signifikan dipengaruhi oleh
pengurangan irama GC, GC mungkin memiliki efek pengorganisasian pada fungsi otak
tertentu yang mendasari perilaku lokomotor periodik,mungkin dengan mengkoordinasikan
fungsi motor atau mempertahankan siklus bangun tidur. Irama proliferasi sel sirkardian dalam
banyak jaringan juga calon output sirkadian dipengaruhi oleh GC. Irama siklus sel sirkadian
di larva ikan zebra sangat dilemahkan dalam ketiadaan sinyal GC, menunjukkan peran
hormon steroid sebagai masukan sistemik yang penting untuk proliferasi sel pada waktu yang
tepat , meskipun fungsi homolog dalam spesies mamalia belum diidentifikasi.
Administrasi akut dari GC dapat menginduksi tahap sinkronisasi berbagai macam jam
perifer baik in vivo dan in-vitro. Aktivitas pengaturan ulang waktu oleh GC dapat dianggap
juga dalam hal siklus sirkadian hormon. Memang, irama GC yang lemah dapat menyebabkan
akumulasi siklik yang tumpul dari peR-1 mRNA dalam beberapa organ-organ perifer seperti
hati, ginjal, dan pankreas, tapi tidak di SCN. Sebaliknya, administrasi kronis dari GC sintetis
sepenuhnya menghapus ekspresi Per1 sirkardian di organ-organ perifer oleh mekanisme yang
terkait dengan konstitutif yang berlebihan walaupun dengan kehadiran dari osilator molekul
yang utuh. Ekspresi waktu gen periodik di bagian diskrit otak tertentu juga memerlukan
sinyal berirama GC, menunjukan bahwa fungsi otak yang lebih tinggi dapat secara langsung
dipengaruhi oleh irama adrenal. Mungkin seharusnya bahwa irama GC sirkadian dengan
sendirinya dapat menghasilkan output fisiologis berirama dari jaringan lain dalam mode
langsung melalui signaling GC klasik, dan dengan demikian berkontribusi terhadap pola
irama yang jelas mempertimbangkan pengamatan bahwa ekspresi setidaknya 10% dari semua
gen dipengaruhi oleh GC. Selain itu, ada dua jenis reseptor GC, dengan afinitas dan kapasitas
yang khas, dan ini diyakini diaktifkan terpisah di puncak sirkadian dan titik nadir dari tingkat
peredaran ligan. Ide ini sangat didukung oleh pengamatan bahwa ekspresi berirama sejumlah
besar gen dalam hati lebih bergantung pada sinyal kelenjar adrenal utuh dan/atau GC
daripada osilator hepatik. Oleh karena itu, ada kemungkinan bahwa peredaran irama GC
mempengaruhi sejumlah pola siklus gen, serta aktivitas metabolisme periodik dan perilaku
oleh tindakan langsung lain pada mereka.
Di sisi lain, akumulasi bukti juga menunjukkan bahwa ada yang efek stabilisasi dari GC
pada pembentukan irama fisiologis in vivo. GC menghambat pergeseran fasa induksi makan
pada siang hari dari osilator perifer oleh mekanisme tergantung GR pada tikus. Ablasi
kelenjar adrenal atau ekspresi GR dalam jaringan target memfasilitasi fase disosiasi jam
perifer dari jam utama SCN. Lebih penting lagi, GC menstabilkan efek umpan balik pada
irama utama selama sinkronisasi ulang. Ablasi seluruh kelenjar adrenal atau menduduki
fasilitas waktu adrenal difasilitasi kembali oleh irama perilaku bergeser ke arah siklus terang
gelap dengan cara bergantung pada waktu zeitgeber. Osilasi CS harian pada tikus yang
terlibat dalam pengaturan aktivitas irama lokomotor. Berdasarkan kemajukan irama GC oleh
aplikasi metyrapone, inhibitor biosintesis GC, hasilnya mempercepat entrainment dari irama
lokomotor dalam arah yang sama, seperti yang dinyatakan dalam model tikus. Diambil
bersama-sama, ini kemungkinan bahwa irama GC berkontribusi pada sistem waktu sirkadian
dengan menyelaraskan jalur output sirkadian yang beragam dan memberikan perlawanan
terhadap perubahan lingkungan sporadis untuk menghindari pergeseran tidak terkoordinasi.
5. Irama sirkardian GC dalam kesehatan dan penyakit manusia
Sekresi GC yang tidak teratur ini bertanggung jawab untuk banyak kondisi patologis .
Perubahan dalam iramanya sering ditemukan dalam banyak penyakit manusia, termasuk
Cushing's sindrom, gangguan mood, penyakit Alzheimer dan sindrom metabolik. Pentingnya
irama GC telah diakui dalam aplikasi klinis; penggantian tonik pada dosis yang tetap tidak
memberkan hasil seperti yang diharapkan, dan bahkan berhubungan dengan kematian
kardiovaskular, homeostasis harian glukosa menjadi terganggu dan kehiangan kepadatan
tulang. Pemisahan dari ACTH dan tingkat GC diamati di regulasi sirkardian sumbu HPA juga
merupakan masalah penting; seperti pemisahan selama fase peningkatan tingkat GC bisa
timbul dari penyebab yang otonom atau ekstrinsik. Terutama, ketidak cocokan antaraa
sirkulasi ACTH dan kortisol sering terjadi dalam kondisi seperti sindrom kelelahan kronis,
sepsis, pasca-traumatic stress disorder, dan beberapa kasus alkohol. Kami secara singkat akan
meninjau beberapa penyakit manusia yang lekat dengan GC disregulasi dan irama sirkadian.
5.1. Cushing's syndrome
Cushing's syndrome,adalah sindrom klinis kelebihan kortisol endogen karena berbagai
penyebab, terjadi dengan prevalensi yang tinggi. Konsekuensi jangka panjang dari
hiperkortisolisme berat termasuk diabetes melitus, osteoporosis, patah tulang, hipertensi,
dyslipidemia, infeksi berulang, gangguan tidur, dan peningkatan mortalitas. Kematian pada
penyakit Cushing ini biasanya 2-5 kali lebih tinggi daripada diharapkan dalam populasi yang
terkontrol, dan hiperkortisolisme ringan bahkan memiliki efek yang merugikan pada
kesehatan jangka panjang karena sensitifitas terhadap insulin berkurang dan perubahan
toleransi glukosa. Cushing's sindrom dapat dipisahkan ke dalam kategori tergantung ACTH
dan tidak tergantung ACTH. Pada Cushing's sindrom yang tergantung ACTH, sekresi ACTH
plasma tinggi yang tidak wajar disebabkan oleh tumor yang memproduksi kortikotropin yang
terus-menerus merangsang korteks adrenal. Sebaliknya, produksi berlebihan kortisol oleh
jaringan adenokortikal abnormal menginduksi Cushing's sindrom yang tidak tergantung
ACTH, menekan sekresi CRH dan ACTH oleh mekanisme umpan balik negatif.
Diketahui bahwa Cushing's sindrom dikaitkan dengan irama sirkadian yang terganggu;
pasien dengan Cushing's sindrom menunjukkan peningkatan tingkat kortisol basal serta
perubahan irama harian (Tabel 1 dan referensi di dalamnya). Karena itu, beberapa tes
diagnostik untuk Cushing's sindrom dirancang untuk mengevaluasi ritme sirkadian kortisol,
misalnya, penentuan tingkat bebas kortisol 24-jam dan tingkat kortisol larut malam tingkat [
tabel 1]. Gangguan tidur adalah fitur sirkardian lain dari Cushing's sindrom. Mereka
berhubungan dengan peningkatan frekuensi apnea tidur atau fragmentasi tidur. Gejala ini
nampaknya berhubungan dengan peruubahan irama GC, tetapi penyebab pasti tetap tidak
jelas.



Table 1.
Altered daily cortisol rhythms in patients with Cushing's syndrome or chronic fatigue
syndrome.
Disease Patients Measurement Daily profiles References
Cushing's syndrome 7 Plasma cortisol, 24 h No diurnal rhythm [130]
7 Plasma cortisol, 24 h No diurnal rhythm [131]
39 Late-night salivary cortisol Higher levels at 23:00 h [132]
103 Plasma cortisol at 2 points No difference between 00:00 and 08:00 h [133]
120 Late-night salivary cortisol Higher levels at 22:00 h [134]
Chronic fatigue syndrome 30 Serum cortisol Lower levels in the morning [135]
7 Plasma cortisol, 24 h Low peak levels [121]
14 Salivary cortisol in the morning and evening Lower levels [136]
cAMP/PKA menandakan jalur cenderung ditingkatkan dalam sel adrenal yang
memproduksi GC dalam Cushing's sindrom yang tergantung ACTH maupun tidak. Kelebihan
ACTH sangat meningkatkan produksi cAMP oleh adenylyl cyclase dalam hubungannya
dengan reseptornya, dan aktivasi terus menerus dari jalur PKA menginduksi produksi dan
sekresi kortisol dari kelenjar adrenal. Selain itu, penyelidikan penyebab molekul dari
hiperplasia adrenocortical bilateral menuju ke arah cushing sindrom yang tidak tergantung
ACTH mengungkapkan mutasi-mutasi lazim tertentu dalam regulasi subunti tipe 1- dari
protein kinase A(PRKAR1A) dan phosphodiesterase-11A (PDE11A). Mutasi-mutasi ini
memperkuat sinyal cAMP PKA dengan aktivasi PKA konstitutif dan degradasi blok cAMP.
Dalam konteks ini, sebuah publikasi terbaru melaporkan bahwa sinyal cAMP PKA sinyal
berirama merupakan prasyarat untuk siklus normal dan berfungsi pada waktu kerja selular
adalah penting. Hal ini dapat, karena itu berspekulasi bahwa gangguan irama GC pada
Cushing's sindrom mungkin melibatkan dysregulasi sinyal cAMP/PKA s dalam banyak
kasus. Kemungkinan ini perlu diselidiki lebih lanjut dalam waktu dekat.
5.2. Kekurangan adrenokortikal dan terapi substiusi GC
Insufisiensi adrenocortical yang muncul dari penyakit Addison (gangguan autoimun yang
menyebabkan degenerasi korteks adrenal), hiperplasia adrenal bawaan (defek pada
steroidegenesis adrenocortical yang diwarisi) atau penyakit tertentu hipofisis ( insufisiensi
adrenal sekunder) biasanya ditandai dengan kerentanan terhadap stres, elevasi sel darah putih,
hipertrofi jaringan limfoid, hipotensi, gangguan mood,penurunan berat badan, dan
hipoglikemia. Gejala utama dan tanda-tanda penyakit ini terutama disebabkan oleh
kekurangan GC adrenal, dan dengan demikian terapi penggantian GC umum digunakan.
Meskipun aktivitas ritmik kortisol sering diamati pada pasien dengan insufisiensi adrenal,
amplitudo dari irama kortisol biasanya menurun karena pengurangan tingkat puncak
peredaran GC. Dalam konteks ini, perlu dicatat bahwa beberapa gejala insufisiensi GC
berkaitan erat dengan gangguan sirkadian; sebagai contoh, gangguan tidur dalam
hubungannya dengan peningkatan kelelahan selama siang hari telah dilaporkan . Karena
penggantian sederhana dengan dosis konstitutif GC tidak efektif untuk mengurangi gejala
sebagai diharapkan dan sering diperburuk dengan gangguan kardiovaskular dan metabolik,
sifat berirama kortisol telah menjadi isu penting dalam desain rejimen terapi penggantian GC.
Pemberian secara oral hidrokortison yang cepat dilepaskan(HC; nama farmasi generik
kortisol) dua atau tiga kali sehari adalah rejimen yang diterima secara luas untuk mengelola
insufisiensi adrenal, dalam dosis yang ditetapkan lebih tinggi di pagi hari dan menurunkan di
malam hari untuk menselaraskan irama kortisol setiap hari. Meskipun penggantian HC
konvensional tersebut memiliki beberapa manfaat, risiko angka mortalitas dan morbiditas
masih lebih tinggi daripada populasi primer normal karena waktu paruh pendek hormon
beredar. Selain itu, penggantian kortisol yang kurang sering menyebabkan timbulnya malaise,
hipotensi,penurunan berat badan, sakit perut, gangguan keseimbangan elektrolit dan
gangguan respon stres. Di sisi lain, kelebihan dosis dapat mengakibatkan gejala Cushingoid
seperti intoleransi glukosa, tekanan darah tinggi, penyakit jantung dan gangguan mood .
Akibatnya, terapi penggantian GC yang ideal dapat menyamai keadaan fisiologis normal
sedekat mungkin. Beberapa rejimen terapi hormon fisiologis seperti infusi sirkardian atau
lebih baik lagi, formulasi HC oral yang lambat dan berkelnajutan telah diperkenalkan selama
beberapa tahun ini. Secara khusus, pendekatan dengan tablet HC-modified release telah
memungkinkan penundaan peningkatan tingkat HC yang beredar untuk mencapai puncaknya
pada sekitar pagi saat bangun ketika diambil pada waktu malam. Oleh karena itu, pemahaman
yang lebih baik dari sifat irama GC dan pengembangan teknologi penyampaian obat baru
dapat memberikan peningkatan terapi pengganti hormon untuk insufisiensi adrenal, yang
akan lebih sederhana dan efisien untuk meringankan gejala, tetapi memiliki efek yang lebih
sedikit merugikan pada fisiologi.

5 3 Sindrom kelelahan kronis
Sindrom kelelahan kronik adalah gangguan yang ditandai dengan kelelahan kronis yang
mendalam,dalam hubungannya dengan beberapa gejala lain. Didefinisikan secara
operasional, kelelahan ini harus cukup parah untuk menyebabkan kerugian yang signifikan
dari fungsi fisik dan sosial selama minimal 6 bulan, dan 4 gejala berikut juga harus hadir:
gangguan tidur, gangguan konsentrasi, nyeri otot, nyeri sendi, sakit kepala, kelelahan setelah
bekerja berat, sakit tenggorokan, sakit pada kelenjar getah bening dan depresi. Sindrom ini
juga umum dan masalah kelumpuhan yang mungkin berkaitan dengan faktor-faktor
psikososial tertentu, tetapi sifat komponen patofisiologi dari penyakit ini masih belum jelas.
Dalam banyak kasus, pasien dengan sindrom ini menunjukkan perubahan dalam sumbu HPA,
termasuk hypokortisolisme ringan dan umpan balik negatif yang kuat (Tabel 1). Banyak studi
dengan beberapa ukuran kortisol yang tidak di rangsang dalam berbagai cairan biologis
dilaporkan dapat mengurangi tingkat kortisol, terutama tingkat puncak, menunjukkan bahwa
ritme sirkadian GC dapat dilemahkan dalam proporsi besar pada pasien dengan sindrom ini.
Pengurangan aktivitas dan gangguan tidur menyiratkan gangguan irama perilaku, tetapi setiap
variasi dari suhu tubuh dan tingkat hormon pituitari mengejutkan normal dalam pasien dalam
sindrom ini. Meskipun hal ini masih diperdebatkan apakah gangguan fungsi HPA adalah
penyebab atau konsekuensi dari sindroma ini, efektivitas dari terapi GC dosis rendah telah di
laporkan pada pasien dengan sindrom ini menunjukkan bahwa GC yang dilemahkan mungkin
berhubungan dengan beberapa sindrom untuk beberapa derajat. Menariknya, fitur ini
sebanding dengan fenotipe yang diamati dalam embrio tikus dengan irama sirkadian GC yang
dilemahkan disebabkan gangguan mesin waktu spesifik adrenal: tikus mutant menunjukan
pengurangan irama GC dan hypo-locomotion selama periode aktivitas, tetapi irama suhu
normal.
5.3. Konsekuensi klinis dari gangguan lingkungan irama GC
Rangsangan lingkungan yang umum seperti yang berkaitan dengan kerja shift, kurang
tidur, makan malam dan jet lag dapat mengubah atau mengganggu fisiologi sirkadian normal.
Dalam kasus tersebut, tubuh mencoba untuk beradaptasi atau bertahan dari gangguan tersebut
dengan menyesuaikan sistem pengaturan waktu internal, tetapi gangguan kronis dapat
menyebabkan dysregulaasi tetap dari sistem waktu sirkadian. Misalnya, kerja shift dan makan
malam sangat terkait dengan terjadinya sindrom metabolik, sekelompok faktor risiko
terhadap kesehatan yang ditandai dengan penurunan karbohidrat dan metabolisme lemak dan
fungsi normal dari jaringan adiposa dan sistem kardiovaskular, dan hemostatik. Mabuk
pascaterbang kronis dapat mempengaruhi pertumbuhan tumor ganas dan bahkan gangguan
kognitif yang terkait dengan lobus temporal otak yang berkurang. Dengan
demikian,desikronisasi kronis dari irama sirkadian pada hewan laboratorium secara signifikan
meningkatkan mortalitas sering dengan penyakit jantung kardiomiopati.
GC adalah salah satu faktor kunci dalam patogenesis sindrom metabolik, dan gejala-
gejalanya membagikan banyak fitur dengan penyakit manusia lain yang berkaitan dengan
dysregulation dari GC, seperti Cushing's sindrom. Selain itu, beberapa menyarankan bahwa
pasien dengan sindrom metabolik ditandai dengan hiperaktivitas sumbu HPA, mengarah ke
hyperkortisolisme. Hal ini juga penting untuk menyebutkan bahwa tingkat peningkatan
kortisol terkait erat dengan defisit kognitif di kru penerbangan maskapai berulang kali terkena
mabuk pascaterbang. Seperti disebutkan sebelumnya, GC memiliki pengaruh terhadap output
sirkadian selama adaptasi baru isyarat zeitgeber, termasuk perubahan dalam jadwal terang
dan gelap dan waktu makan. Oleh karena itu, gangguan kronis terhadap ritme sirkadian GC
mungkin terkait dalam adaptasi maupun konsekuensi patofisiologi gangguan lingkungan
terhadap sistem waktu sirkadian.
6. Kesimpulan
Kesimpulannya, pengertian saat ini mengenai kontrol sirkadian GC adrenal dan penyakit
manusia yang berkaitan dengan gangguan peraturan temporal di tinjau di sini. Periodik GC
sekresi dan biosintesis sangat erat diatur oleh kebetulan beberapa mekanisme pada tingkat
yang berbeda dari sistem waktu sirkadian. Waktu utama di SCN secara langsung
mengemudikan irama sirkardian GC keduanya melalu memodulasi sumbu neuroendokrin
HPA maupun melalui persarafan simpatik splanchnic kelenjar adrenal. Namun, bukti
pertumbuhan badan menunjukkan pentingnya waktu kerja lokal di kelenjar adrenal itu
sendiri. Mesin waktu osilasi adrenal memainkan peran penting dalam menjaga irama dalam
mengontrol kapasitas dan responsif dari sekresi dan biosintesis GC adrenal terhadap ACTH.
Oleh karena itu, pertanyaan berikutnya yang berhubungan dengan menentukan bagaimana
beberapa mekanisme ini dikoordinasi dengan peningkatan siklus dari sekresi hormon, dan
kemudian bagaimana GC sel target GC mengesankan dan memproses informasi irama ini.
Pertanyaan penting lain mengenai irama GC mengutamakan perannya dalam Fisiologi dan
Patofisiologi. Walaupun pentingnya irama GC telah dihargai untuk beberapa waktu, relevansi
fisiologis tertentu irama, terutama dalam kesehatan dan penyakit, tetap lebih lanjut perlu
diperjelas. Kemajuan pengetahuan kita terkini pada basis molekuler dan selular irama
sirkardian GC harus membantu memberikan wawasan baru dan terobosan untuk mengatasi
isu-isu yang luar biasa ini.
Ucapan terima kasih
Karya ini didukung oleh hibah dari Korea Departemen Pendidikan, Sains dan teknologi
(MEST) melalui pusat penelitian otak untuk abad ke-21 Frontier R & amp; D Program di
Neuroscience. Sooyoung Chung didukung oleh Korea 21 Research Fellowships dari MEST.