Abstract
Biological rhythms, including circadian rhythms (with approximately 24-hour periodicity) and ultradian rhythms (periodicities from milliseconds to hours), play a crucial role in behavioural and physiological processes. The focus on circadian rhythms, however, has led to the underrepresentation of ultradian rhythms in chronobiology research. A link between ultradian rhythms and metabolic homeostasis has long been recognised but poorly understood.. In this thesis, we developed, tested and applied CAP, a dedicated signal analysis tool designed to detect ultradian rhythms in the presence of co-expressed circadian rhythms and noise. CAP's initial testing demonstrated high accuracy (98%) and low false positive rates (<5%) in detecting and characterising ultradian rhythms in various synthetic signals, even in highly noisy signals. CAP was then applied to high-resolution human plasma metabolomics timeseries data. We revealed significant ultradian rhythmicity in metabolic features (~10%) across the study population (N = 30 individuals; 15 females), with ultradian rhythms detected exhibiting an 8-hour periodicity and distinct sex-specific differences. Finally, to test the hypothesis that ultradian rhythms are enhanced by energy shortage, we designed the first cell culture model for ultradian rhythms using 3T3-L1 pre-adipocyte cells transduced with a destabilised luciferase reporter construct controlled by the Pdcd5 promoter region. In this model, we showed that ultradian rhythms could be enhanced by lowering glucose concentrations. Over 80% of cultures displayed ultradian rhythmicity, and reducing glucose levels resulted in increased amplitude and a shorter periodicity (8.2 h ± 2.7 h vs. 6.9 h ± 1.1 h, N = 12). In summary, the utilisation of CAP to demonstrate that 10% of human metabolites exhibit ultradian rhythms, alongside the observation of enhanced ultradian rhythms in metabolic processes due to negative energy balance in vitro, underscores the intricate relationship between ultradian rhythms and metabolism. These insights contribute to a more comprehensive and deeper understanding of the significance of ultradian rhythms in physiological functioning. Such knowledge enhances our understanding of the timing mechanisms within physiological processes, which is crucial for effective management of health and disease.