There is considerable epidemiological evidence that shift work is associated with increased risk for obesity, diabetes, and cardiovascular disease, perhaps the result of physiologic maladaptation to chronically sleeping and eating at abnormal circadian times. To begin to understand underlying mechanisms, we determined the effects of such misalignment between behavioral cycles (fasting/ feeding and sleep/wake cycles) and endogenous circadian cycles on metabolic, autonomic, and endocrine predictors of obesity, diabetes, and cardiovascular risk. Ten adults (5 female) underwent a 10-day laboratory protocol, wherein subjects ate and slept at all phases of the circadian cycle-achieved by scheduling a recurring 28-h ''day.'' Subjects ate 4 isocaloric meals each 28-h ''day.'' For 8 days, plasma leptin, insulin, glucose, and cortisol were measured hourly, urinary catecholamines 2 hourly (totaling Ϸ1,000 assays/ subject), and blood pressure, heart rate, cardiac vagal modulation, oxygen consumption, respiratory exchange ratio, and polysomnographic sleep daily. Core body temperature was recorded continuously for 10 days to assess circadian phase. Circadian misalignment, when subjects ate and slept Ϸ12 h out of phase from their habitual times, systematically decreased leptin (؊17%, P < 0.001), increased glucose (؉6%, P < 0.001) despite increased insulin (؉22%, P ‫؍‬ 0.006), completely reversed the daily cortisol rhythm (P < 0.001), increased mean arterial pressure (؉3%, P ‫؍‬ 0.001), and reduced sleep efficiency (؊20%, P < 0.002). Notably, circadian misalignment caused 3 of 8 subjects (with sufficient available data) to exhibit postprandial glucose responses in the range typical of a prediabetic state. These findings demonstrate the adverse cardiometabolic implications of circadian misalignment, as occurs acutely with jet lag and chronically with shift work. autonomic nervous system ͉ diabetes ͉ glucose metabolism ͉ leptin ͉ obesity A pproximately 8.6 million Americans perform shift work (1), which is associated with increased risk of obesity, diabetes, and cardiovascular disease (2-6). The endogenous circadian timing system, including the suprachiasmatic nucleus (SCN) in the hypothalamus and peripheral oscillators in vital organs, optimally regulates much of our physiology and behavior across the 24-h day when it is properly aligned with the sleep/wake cycle. However, shift work is generally associated with chronic misalignment between the endogenous circadian timing system and the behavioral cycles, including sleep/wake and fasting/ feeding cycles (7,8). Shift workers often experience symptoms akin to jet lag, with gastrointestinal complaints, fatigue, and sleepiness during the scheduled wake periods, and poor sleep during the daytime sleep attempts (9). Moreover, chronic circadian misalignment has been proposed to be the underlying cause for the adverse metabolic and cardiovascular health effects of shift work (10, 11). The SCN regulates circadian rhythms in leptin, plasma glucose, glucose tolerance, corticosteroids, and ...

The risk of adverse cardiovascular events peaks in the morning (≈9:00 AM) with a secondary peak in the evening (≈8:00 PM) and a trough at night. This pattern is generally believed to be caused by the day/night distribution of behavioral triggers, but it is unknown whether the endogenous circadian system contributes to these daily fluctuations. Thus, we tested the hypotheses that the circadian system modulates autonomic, hemodynamic, and hemostatic risk markers at rest, and that behavioral stressors have different effects when they occur at different internal circadian phases. Twelve healthy adults were each studied in a 240-h forced desynchrony protocol in dim light while standardized rest and exercise periods were uniformly distributed across the circadian cycle. At rest, there were large circadian variations in plasma cortisol (peak-to-trough ≈85% of mean, peaking at a circadian phase corresponding to ≈9:00 AM) and in circulating catecholamines (epinephrine, ≈70%; norepinephrine, ≈35%, peaking during the biological day). At ≈8:00 PM, there was a circadian peak in blood pressure and a trough in cardiac vagal modulation. Sympathetic variables were consistently lowest and vagal markers highest during the biological night. We detected no simple circadian effect on hemostasis, although platelet aggregability had two peaks: at ≈noon and ≈11:00 PM. There was circadian modulation of the cardiovascular reactivity to exercise, with greatest vagal withdrawal at ≈9:00 AM and peaks in catecholamine reactivity at ≈9:00 AM and ≈9:00 PM. Thus, the circadian system modulates numerous cardiovascular risk markers at rest as well as their reactivity to exercise, with resultant profiles that could potentially contribute to the day/night pattern of adverse cardiovascular events.

We investigate if known extrinsic and intrinsic factors fully account for the complex features observed in recordings of human activity as measured from forearm motion in subjects undergoing their regular daily routine. We demonstrate that the apparently random forearm motion possesses dynamic patterns characterized by robust scale-invariant and nonlinear features. These patterns remain stable from one subject to another and are unaffected by changes in the average activity level that occur within individual subjects throughout the day and on different days of the week, since they persist during daily routine and when the same subjects undergo time-isolation laboratory experiments designed to account for the circadian phase and to control the known extrinsic factors. Further, by modeling the scheduled events imposed throughout the laboratory protocols, we demonstrate that they cannot account for the observed scaling patterns in activity fluctuations. We attribute these patterns to a previously unrecognized intrinsic nonlinear multi-scale control mechanism of human activity that is independent of known extrinsic factors such as random and scheduled events, as well as the known intrinsic factors which possess a single characteristic time scale such as circadian and ultradian rhythms.