Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

Background: Recently, circannual gene expression rhythms have been described in timekeeping centres of the human brain. In the arctic ground squirrel, an increase in sensitivity to A1 adenosine receptor signaling corresponds with the winter onset of reduced physiological activity. In our preliminary survey of the human serum metabolome, we identified a highly significant shift in adenosine metabolism between summer & winter, which correlated with seasonal weight gain. These and other circannual distortions in human metabolism may have profound physiological consequences.

Goals: We will screen the human serum metabolome for metabolic pathways with significant circannual variation, and determine which correspond with seasonal physiological and behavioural phenomena:
1. Confirm a circannual rhythm in adenosine metabolism
2. Ascertain the scope of circannual variation in human metabolism
3. Identify specific metabolic shifts that predict physiological (metabolic rate, body composition, insulin sensitivity), behavioural (physical activity and sleep-wake cycle characteristics) and neurological biorhythms.

Study Design: We will recruit healthy medication-free adult participants to provide blood samples in 4 consecutive seasons. Fasting blood (12 hr) will be taken at 6 hours post mid-sleep point estimated using 24-hour actigraphy. We will control for diet and supplement use with gold-standard Food Frequency Questionnaires, and for sleep and physical activity using 2-week actigraphy. Resting metabolic rate will be assessed using 10 min continuous breath-by-breath sampling. Body mass and composition (percentage fat) will be assessed by dual X-ray absorptiometry. Insulin sensitivity will be assessed by the homeostatic model.

Assays: We will survey over 2000 metabolites using targeted, quantitative assays to inform each of the ~85 essential biosynthetic pathways (e.g. amino acids, sugars, alcohols, organic acids, other amines, phospholipids, sphingolipids, cholesteryl esters, free fatty acids, triglycerides, sterols oxylipins, plasmaologens, acylcarnitines, nucleosides/nucelotides, reducing sugars, carboxylates/central carbon metabolites, sulfur-containing compounds, and water-soluble and fat-soluble vitamins and trace metals). We will identify significant changes in metabolite patterns between seasons using multivariate empirical Bayes time-series analysis, and confirm circannual patterns by fitting concentrations to sine curves.

Impact: Small molecule metabolites are the summary products of all genomic, epigenomic, transcriptomic, miRNomic, microbiomic, proteomic, and environmental influences, and their complex interactions. This platform offers a unique biochemical field-of-view into the full scope of seasonal metabolic shifts and underlying circannual rhythmic phenomena in human physiology and behaviour.