Extensive diversity in circadian regulation of plasma lipids and evidence for different circadian metabolic phenotypes in humans

Abstract

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...

Lipidomics reveals diurnal lipid oscillations in human skeletal muscle persisting in cellular myotubes cultured in vitro

“…4). This value is similar to a study in human plasma, which showed 17.8% of oscillating lipid metabolites when analyzed on an individual basis (19). To unravel whether these metabolite oscillations are solely driven by diurnal cycles of rest-activity and food intake, or are controlled in a cellautonomous manner, we conducted a similar temporal analysis in primary human skeletal myotubes synchronized in vitro.…”

“…In humans, diurnal variations in glucose tolerance have long been described (18), and rhythmic profiles of plasma glucose, insulin, and triglycerides have been detected (19,20). Furthermore, a lipidomic analysis of human plasma has shown that ∼18% of all lipid profiles oscillate in a circadian manner independent of sleep and food intake (19).…”

“…Furthermore, a lipidomic analysis of human plasma has shown that ∼18% of all lipid profiles oscillate in a circadian manner independent of sleep and food intake (19). Similarly, metabolomics studies of plasma, saliva, and urine revealed that around 20% of all identified metabolites, among them many fatty acids, were oscillating (21-23).…”

Circadian regulation of lipid metabolism

“…In another study, lipidomics analyses revealed that about 17 % of lipids showed circadian oscillations in wild-type mice and in Per1 −/− /Per2 −/− mice fed ad libitum. Consistent with studies in human subjects (108) , TAG species were especially rhythmic, but their peak accumulation was shifted in clock gene-deficient animals (112) . Exposure to a high-fat diet also has a profound influence on diurnal variation in the liver metabolome (82,113) .…”

“…Therefore, future studies should examine the interaction of genetic and environmental factors on diurnal regulation of lipids and postprandial responses. If it were possible to identify prospectively individuals who are at increased risk of metabolic dysregulation caused by circadian misalignment and night eating, such information (108) .…”