1. Adaptive Medicine 3(2): 85-90, 2011 85
DOI: 10.4247/AM.2011.ABB006
Review
Maladaptation in the Circadian System
Robert Joseph Thomas
Division of Pulmonary, Critical Care and Sleep, Beth Israel Deaconess Medical Center and Harvard Medical School,
330 Brookline Avenue, Boston, MA 02215, USA
Circadian rhythms are pervasive processes through a evidence supports that shift work is associated with
range of body functions. While the earlier focus was on increased risk for obesity, diabetes, and cardiovascular
effect on sleep and performance, significant current disease (25, 63). Shift workers often maintain a state
interest is turning to the effects of circadian factors in of chronic circadian misalignment. Forced desyn-
metabolic and cardiovascular regulation. This review
chrony studies in normal healthy subjects lead to
will address clinical and experimental data demonstrat-
altered cardiometabolic function (52). Misalignment
ing metabolic and cardiovascular effects of circadian
maladaptation. This maladaptation likely occurs as between the circadian system and behavioral cycles,
circadian stressors are extremely new on the evolutionary as occurs in DSPS and other circadian stress condi-
pressure/time scale – environmental light control, shift tions such as shift-work and so-called social jet-lag,
work and jet-lag effects did not previously exist. therefore, could result in increased cardiometabolic
risk.
Key Words: circadian, maladaptation, metabolic, car-
diovascular Circadian Misalignment and
Metabolic Dysregulation
Introduction
Perturbations of the internal clock system and sleep
Life forms have developed adaptive responses to constitute risk factors for disorders including obe-
a variety of environmental stressors. These include sity, diabetes mellitus, and metabolic syndrome (32).
responses to gravity, temperature, hypoxia, hyper- Peripheral clocks including those in the liver con-
carbia, sodium load, and nutrient/caloric restriction. tributes to glucose homeostasis (21) and can be
These stressors have been pervasive through evolution. entrained by restricted feeding (62). There is cross-
The Earth’s 24-h light/dark cycle has had a profound talk between circadian and metabolic regulatory
effect on innate biological rhythms. However, this pathways (4, 5, 32), utilizing pathways that involve
cycle has been invariant and thus not provided real the peroxisome proliferator-activated receptor-gamma
challenges to adaptation. coactivator-1 transcriptional coactivators (23) and
Circadian rhythm disorders have been so far Rev-erb-α (71). In a rat model for “shift-work”,
characterized primarily as sleep disorders, resulting based on daily 8-h activity schedules during the resting
in sleep loss, circadian mismatch, and clinical symp- phase, the major abnormalities induced (internal de-
toms of sleepiness, fatigue, dysphoric mood, and at- synchrony, flattened glucose and locomotor rhythms,
tentional difficulty. Delayed sleep phase syndrome abdominal obesity) were observed when food intake
(DSPS) is the most common circadian rhythm disorder occurred during the rest phase (51). Alternatively,
in the sleep clinic, and has been associated with de- shifting food intake to the normal activity phase
pression and attention deficit hyperactivity disorder. prevented body weight increase and reverted metabolic
It is unknown if this disorder is associated with and rhythmic disturbances of the shift work animals
pathological effects in other systems known to be to control values.
regulated by circadian mechanisms. Several circadian mutants show abnormal
The severity of many diseases follows circadian metabolic regulation including the metabolic
variation. For example, asthma is often worse at syndrome: the CLOCK mutant (66) and the BMAL1
night and there is an increased incidence of car- knockout mouse (49). Clock genes’ expression in
diovascular events in the morning. Epidemiological human adipose tissue is associated with metabolic
Corresponding author: Robert Joseph Thomas, M.D., Assistant Professor of Medicine, Division of Pulmonary, Critical Care and Sleep, Beth
Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. Tel: +1-617-667-5864,
Fax: +1-617-667-4849, E-mail: rthomas1@bidmc.harvard.edu
Received: May 5, 2011; Accepted: June 21, 2011.
2011 by The Society of Adaptive Science in Taiwan and Airiti Press Inc. ISSN : 2076-944X. http://www.sast.org.tw

2. 86 Thomas
syndrome parameters: hPer2 expression level in Inflammatory mediators are likely under circadian
visceral fat is inversely correlated to waist circum- regulation and thus misalignment in the circadian
ference, while BMAL1, Per2 and Cry1 are all nega- system may result in increased systemic inflammation,
tively correlated with total cholesterol and LDL a possible contributor to increased cardiometabolic
cholesterol (12). risk. A diurnal rhythm in plasma concentration in
Direct evidence of the effect of circadian many components involved in the systemic inflam-
misalignment on metabolism is available in humans matory response (such as cytokines and hormones)
from experimental, epidemiologic, and genetic studies. has been observed. These rhythms may be entrained
In a 10-day laboratory-based protocol in 10 subjects, by the central clock in the suprachiasmatic nucleus
hourly plasma leptin, insulin, glucose, and cortisol, (54). In mice however, spleen, lymph nodes, and
every 2 h urinary catecholamines, blood pressure, peritoneal macrophages are under autonomous
heart rate, cardiac vagal modulation, oxygen consump- regulation of intrinsic circadian clocks that coordinate
tion, respiratory exchange ratio, core body tempera- circadian rhythms in innate immune function (18).
ture, and daily polysomnographic sleep were measured Endotoxin stimulation of isolated spleen cells at
(52). Circadian misalignment—when subjects ate different circadian times showed a circadian pattern
and slept approximately 12 h out of phase from their to tumor necrosis factor-alpha (TNF-α) and inter-
habitual times—systematically decreased leptin leukin-6 (IL-6) secretion, controlled by a circadian
(-17%), increased glucose (+6%) despite increased clock localized to splenic macrophages (18).
insulin (+22%), completely reversed the daily cortisol In humans, increased inflammation has been
rhythm, increased mean arterial pressure (+3%), and proposed as a potential mechanism of the increased
reduced sleep efficiency (-20%). Simulated and real cardiometabolic risk profiles seen in shift workers. In
shift workers show relatively impaired glucose and a large cross sectional European study comparing
lipid tolerance with feeding during the biological 877 day workers with 474 rotating shift workers, shift
night vs. day (2, 13, 34, 46). Many studies demonstrate workers not only had higher BMI, waist circumference,
an increased risk of metabolic syndrome in shift- diastolic blood pressure and Homeostasis Model
workers. In a prospective study of night-shift nurses, Assessment index (HOMA), but were also found to
initially free from components of metabolic syndrome, have increased leukocyte counts, independent of age
followed over four years and compared to a control and smoking (58).
group of day-shift nurses, the relative risk of devel-
oping metabolic syndrome was five times higher in Circadian Misalignment and
the night workers (44). In a retrospective study of Endothelial Function
females working rotating shifts, there was an increased
risk of progression to metabolic syndrome (24). Shift The circadian clock also influences vascular cell
work is associated with higher body mass index, signaling and function. In a prospective study in
waist to hip ration, excess weight gain, obesity, and humans evaluating a possible circadian pattern to
markers of insulin resistance (including hyperglyce- vascular dysfunction, brachial flow mediated dilation
mia, increased triglycerides, and low HDL cholesterol) was found to be blunted in early as compared to late
(15, 16, 37, 39). Impaired glucose tolerance also morning (post-waking) hours and independently
occurs in adolescent circadian rhythm disorders (65). predictive of adverse cardiovascular risk in healthy
A genetic variant of the melatonin receptor is as- subjects (14). Rodent studies offer further support for
sociated with the risk of type 2 diabetes (7, 48). specific circadian roles in vascular regulation and
At a population level, individuals with strong dysfunction. Endothelial cells, smooth muscle cells
morning or evening circadian preferences could be at and fibroblasts follow circadian rhythms (50). Mouse
increased risk for chronic and variable circadian Bmal-1 knockout and Clock mutants have abnormal
cardiac, vascular and metabolic misalignment. While nitric oxide signaling and endothelial function (3)
this may be less extreme than shift-workers with and the Bmal-1 knockout mouse demonstrates
variable work schedules, these individuals also evidence of chronic vascular impairment with altered
frequently suffer from chronic sleep debt and daytime angiogenesis, vascular remodeling, and vascular
fatigue. The proposed study will assess effects of stiffness (3).
circadian misalignment in subjects with delayed
circadian phase on sympathetic regulation, glucose Circadian Misalignment and
and insulin homeostasis, postprandial metabolism, Cardiovascular Function
and endothelial function, using this disorder as a
potential model of body-wide circadian effects. There are known circadian patterns to cardiovascular
risk. Epidemiological evidence shows the peak in-
Circadian Misalignment and Inflammation cidence of cardiovascular events (angina, myocardial

3. Circadian Maladaptation 87
infarction, stroke, and sudden cardiac death) occurs In addition to cardiovascular and metabolic risks,
during morning hours (8, 29, 33, 35, 47, 69). The circadian misalignment has been associated with
physiologic pattern of blood pressure dipping during malignancy, gastrointestinal disorders and early aging
sleep is considered cardio-protective, while the effects. Vinogradova et al., using a rat model of vari-
absence of blood pressure dipping is an independent ous light and dark regimens from age 25 days until
cardiovascular risk factor (61). The cardiomyocyte natural death, found that the rats exposed to both
exhibits a robust circadian time-keeping system; 10- natural light and constant light routines (as opposed
15% of all myocardial genes oscillate in a time-of- to a standard 12:12 h light dark cycle) developed
day dependent manner (10). This clock is important metabolic syndrome, spontaneous tumors, and a
for normal myocardial metabolism and contractile reduced life-span (68).
function (6, 9, 11, 56). Cardiac gene oscillations take
5-8 days to re-entrain after a 12-h shift of the light- Sleep Quality, Quantity, and Cardiometabolic
dark cycle (9). Circadian desynchrony leads to Risk
impaired cardiac function and phenotypes. Circadian
misalignments augment pressure overload induced Insufficient sleep quantity and inadequate quality
myocardial dysfunction (31). Under conditions of have been linked to cardiometabolic dysfunction.
circadian misalignment, the heterozygous tau mutant Studies suggest that poor sleep increases cardiovas-
hamster develops heart failure (30). In experimental cular risk (26, 27). Two independent studies of 24-h
ischemia-reperfusion, clock genes show decreased total sleep deprivation in humans demonstrated
amplitude of oscillations in the ischemic tissue (20). increased diastolic blood pressure and decreased
Mice with genetic ablation of the BMAL1 display sympathetic activity (MSNA) (17, 41), suggesting
premature aging and a prothrombotic phenotype (57). that either a peripheral mechanism contributing to
Circulating von Willebrand Factor, fibrinogen and altered vascular tone, or a central component resulting
plasminogen activator inhibitor-1 (PAI-1) are sig- in resetting of the baroreflex, explain the change in
nificantly elevated in BMAL1 (-/-) mice. CLOCK diastolic blood pressure. Sleep deprivation studies
and Bmal-1 directly regulate the activity of vWF demonstrate changes in sympathetic activation,
promoter, and the lack of Bmal-1 results in up- cortisol, thyrotropin, inflammatory mediators, leptin
regulation of vWF both at mRNA and protein level. levels, and insulin sensitivity in normal, healthy
Evidence suggests that abnormal circadian function subjects (19, 36, 59, 67). Studies of selective sleep
contributes to essential hypertension. Patients with stage suppression and partial sleep restriction also
hypertension demonstrate decreased daytime- resulted in cardiometabolic effects. Increased diabetes
nighttime rhythms of sympathovagal balance (38) risk and sympathetic activation were demonstrated in
while those with coronary artery disease show an a selective sleep stage restriction study. Using the
abnormal pattern of endothelial-dependant vasodila- Minimal Model analysis (42) of the frequently sampled
tation with loss of diurnal variation seen in controls IV glucose tolerance test, Tasali et al. demonstrated
(55). A small randomized double-blind placebo- reduced insulin sensitivity and reduced disposition
controlled crossover study in 16 males with untreated index (D I ) [the product of insulin sensitivity index
hypertension (essential) found that daily melatonin (SI) and the acute insulin response to glucose (AIRg)]
over three weeks lowered systolic and diastolic blood after 3 nights of selective slow wave sleep (SWS)
pressure during sleep and increased the amplitude suppression compared to baseline sleep (7.5 h, 11pm-
of the diurnal blood pressure rhythm (53). 7:30 am) (64). DI is a validated marker of diabetes
Shift-work has been associated with adverse risk (28, 43, 70). Also seen was an increase in the
cardiovascular outcomes (1, 45). Mechanisms im- normalized LF/HF ratio (low frequency to high fre-
plicated include stress, sleep deprivation, depression, quency ratio, a marker of sympathovagal balance)
and circadian misalignment. Derangements in the after selective SWS suppression upon assessment of
biological time-keeping mechanisms which are active heart rate variability of daytime electrocardiogram
in the cardiovascular system may contribute to the recordings (64) suggesting that sympathetic activation
notable increase in cardiovascular pathology in this is increased after selective SWS suppression. Further,
population. A simulated shift work forced desyn- a moderate length study (6 nights) of limited sleep
chrony study in healthy humans found a 3% increase time (4-h/night) followed by recovery sleep showed
in mean arterial blood pressure and complete reversal a statistically significant decrease in oral glucose
of the cortisol rhythm during circadian misalignment- tolerance in the sleep debt condition compared to
when subjects ate and slept 12 h out of phase from post-exposure recovery (59).
their habitual times (52). Epidemiologic studies suggest that insomnia
may be a risk factor for diabetes and cardiovascular
Circadian Misalignment and General Health disease (40, 71) . Normotensive subjects with chronic

4. 88 Thomas
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