Abstract
Daily, 24-h rhythms exist in nearly all physiological and behavioural processes, including metabolism. Research shows clear links between metabolism and the circadian system. Drivers for circulating metabolite rhythms can be endogenous ‘circadian’ or endogenously and exogenously derived ‘diurnal’ rhythms. The present studies aimed to investigate the endogenous and exogenous contribution to plasma metabolite profiles by characterising both circadian and diurnal metabolite rhythms using ‘constant routine (CR)’ or ‘entrained protocols’, respectively.
Firstly, a 40-h CR protocol in young, healthy participants (n = 30, 50% females) was used to reveal circadian rhythms in plasma metabolites. Metabolites from five chemical classes; amino acids, biogenic amines, acylcarnitines, glycerophospholipids and sphingolipids were measured using targeted LC-MS/MS (liquidchromatography-massspectroscopy) metabolomics. A subsequent study set out to elucidate ‘diurnal rhythms’ from ‘entrained protocols’ (n = 24 healthy, young participants, 50% females). Comparison between the CR and entrained protocol enabled assessment of the acute effect of exogenous factors (timed meals, sleep and fasting) on metabolite profiles. Finally, a pilot study in eight healthy young participants (3 females) was employed across three in-laboratory study days in both summer and winter to assess day-day consistency and seasonal differences in metabolites.
The results demonstrated that most metabolites (76% (n = 96/127)) exhibited sex differences in their levels, influenced by the metabolite class irrespective of rhythmicity. Only a small proportion of metabolites (27% (n = 34/127)) exhibited circadian rhythmicity. By contrast, most metabolites (75%) in exhibited diurnal rhythms. Amino acid profiles were acutely affected by timed meals, whilst most metabolite levels declined during fasting and sleep. The final study revealed that plasma metabolite levels and rhythms were mostly consistent across three days and between summer and winter. The findings from this thesis highlight the importance of acknowledging sex, time-of-day, feed/fasting, sleep/wake status and season as variables capable of affecting circulating metabolites.