The circadian system regulates daily rhythms in lipid metabolism and adipose tissue function. Although disruption of circadian clock function is associated with negative cardiometabolic end points, very little is known about interindividual variation in circadianregulated metabolic pathways. Here, we used targeted lipidomicsbased approaches to profile the time course of 263 lipids in blood plasma in 20 healthy individuals. Over a span of 28 h, blood was collected every 4 h and plasma lipids were analyzed by HPLC/MS. Across subjects, about 13% of lipid metabolites showed circadian variation. Rhythmicity spanned all metabolite classes examined, suggesting widespread circadian control of lipid-mediated energy storage, transport, and signaling. Intersubject agreement for lipids identified as rhythmic was only about 20%, however, and the timing of lipid rhythms ranged up to 12 h apart between individuals. Healthy subjects therefore showed substantial variation in the timing and strength of rhythms across different lipid species. Strong interindividual differences were also observed for rhythms of blood glucose and insulin, but not cortisol. Using consensus clustering with iterative feature selection, subjects clustered into different groups based on strength of rhythmicity for a subset of triglycerides and phosphatidylcholines, suggesting that there are different circadian metabolic phenotypes in the general population. These results have potential implications for lipid metabolism disorders linked to circadian clock disruption.metabolomics | chronobiology T he circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus regulates daily rhythms in behavior and physiology, ensuring that metabolic pathways are temporally coordinated with 24-h cycles of rest-activity and feeding (1). The circadian system controls lipid and carbohydrate homeostasis, thus optimizing energy storage and utilization across the day (2). In humans, this is reflected in part by diurnal variation in glucose tolerance (3, 4), as well as circadian rhythms of glucose, insulin, triglycerides, and adipose-derived hormones in blood (5, 6). At the cellular level, circadian rhythms are generated by transcriptional and posttranscriptional feedback loops, with daily rhythms of cell biology driven by core clock genes and their protein products. The SCN neural rhythm is normally entrained by the 24-h solar cycle, whereas the phase of rhythms in peripheral tissues is thought to be determined primarily by daily rest-activity and/or feeding cycles (7).Disruption of circadian rhythms has been implicated in metabolic syndrome and dyslipidemia (2), and chronic circadian misalignment is thought to contribute to increased risk of cardiovascular disease and obesity in shift workers (8, 9). Although the mechanisms have yet to be fully elucidated, consumption of meals at night is associated with higher postprandial triglyceride levels, compared with meals consumed during the daytime (10, 11). In nocturnal mice, the circadian timing of food intake contribut...

Some individuals show severe cognitive impairment when sleep deprived, whereas others are able to maintain a high level of performance. Such differences are stable and trait‐like, but it is not clear whether these findings generalize to physiologic responses to sleep loss. Here, we analyzed individual differences in behavioral and physiologic measures in healthy ethnic‐Chinese male volunteers (n = 12; aged 22–30 years) who were kept awake for at least 26 h in a controlled laboratory environment on two separate occasions. Every 2 h, sustained attention performance was assessed using a 10‐min psychomotor vigilance task (PVT), and sleepiness was estimated objectively by determining percentage eyelid closure over the pupil over time (PERCLOS) and blink rate. Between‐subject differences in heart rate and its variability, and electroencephalogram (EEG) spectral power were also analyzed during each PVT. To assess stability of individual differences, intraclass correlation coefficients (ICC) were determined using variance components analysis. Consistent with previous work, individual differences in PVT performance were reproducible across study visits, as were baseline sleep measures prior to sleep deprivation. In addition, stable individual differences were observed during sleep deprivation for PERCLOS, blink rate, heart rate and its variability, and EEG spectral power in the alpha frequency band, even after adjusting for baseline differences in these measures (range, ICC = 0.67–0.91). These findings establish that changes in ocular, ECG, and EEG signals are highly reproducible across a night of sleep deprivation, hence raising the possibility that, similar to behavioral measures, physiologic responses to sleep loss are trait‐like.

Exposure to light is a major determinant of sleep timing and hormonal rhythms. The role of retinal cones in regulating circadian physiology remains unclear, however, as most studies have used light exposures that also activate the photopigment melanopsin. Here, we tested the hypothesis that exposure to alternating red light and darkness can enhance circadian resetting responses in humans by repeatedly activating cone photoreceptors. In a between-subjects study, healthy volunteers (n = 24, 21–28 yr) lived individually in a laboratory for 6 consecutive days. Circadian rhythms of melatonin, cortisol, body temperature, and heart rate were assessed before and after exposure to 6 h of continuous red light (631 nm, 13 log photons cm−2 s−1), intermittent red light (1 min on/off), or bright white light (2,500 lux) near the onset of nocturnal melatonin secretion (n = 8 in each group). Melatonin suppression and pupillary constriction were also assessed during light exposure. We found that circadian resetting responses were similar for exposure to continuous versus intermittent red light (P = 0.69), with an average phase delay shift of almost an hour. Surprisingly, 2 subjects who were exposed to red light exhibited circadian responses similar in magnitude to those who were exposed to bright white light. Red light also elicited prolonged pupillary constriction, but did not suppress melatonin levels. These findings suggest that, for red light stimuli outside the range of sensitivity for melanopsin, cone photoreceptors can mediate circadian phase resetting of physiologic rhythms in some individuals. Our results also show that sensitivity thresholds differ across non-visual light responses, suggesting that cones may contribute differentially to circadian resetting, melatonin suppression, and the pupillary light reflex during exposure to continuous light.