Biological Clocks, Healthy, Metabolic Disturbance, Sleep Deprivation
Conditions
Brief summary
Metabolism is increasingly recognized as being highly regulated by anticipatory biological rhythms (circadian rhythms or biorhythms), which are driven by molecular feedback loops, and which are approximately 24 hours long (circa diem). These circadian rhythms exist both centrally, in the brain, but also in the periphery, and are specific to many tissues depending on their main biological function or functions. Whereas these circadian rhythms have been thoroughly characterized in other organisms, their role in humans remain poorly understood, partly because of the difficulty in studying these rhythms in peripheral tissues. The investigators therefore aim to characterize these rhythms in primarily skeletal muscle and adipose tissue in healthy young volunteers (using the so-called constant routine paradigm), and how these rhythms interact with one another at various genetic and molecular levels. At the same time, the investigators aim to study how an unhealthy vs. healthy diet can alter these circadian rhythms, and how they interact with circadian rhythms in other tissue compartments such as those expressed by blood cells.
Interventions
High-fat diet (5-7 days) preceding extended wakefulness under standardized conditions
Low-fat diet (5-7 days) preceding extended wakefulness under standardized conditions
Sponsors
The Swedish Research Council
Uppsala University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Masking description
In the crossover subgroup condition, participants will not be briefed about what diet they will receive before the actual onset of the dietary intervention
Intervention model description
Participants will be studied in a crossover design both after a healthy diet, and after an unhealthy diet
Eligibility
Sex/Gender
ALL
Age
18 Years to 32 Years
Healthy volunteers
Yes
Inclusion criteria
* Age 18-33 yr * Healthy (self-reported) and not on medication * BMI 18-28 kg/m2 (and waist circumference \<102 cm), and weight stable (±5% body weight in past 6 months) * Non-smoker and non-nicotine user * Regular sleep-wake pattern, with sleep duration of 7-9.25 hrs per night * Sedentary to moderately active with regular exercise habits the last 2 months * Regular daily meal pattern with 3 main meals
Exclusion criteria
* Major or chronic illness, e.g. diabetes, renal disease or inflammatory bowel disease * Current or history of endocrine or metabolic disorders * Psychiatric or neurological disorders (e.g. bipolar disorder, epilepsy) * Frequent gastrointestinal symptoms * Chronic medication * Any sleep disorder (e.g. irregular bedtimes, symptoms of insomnia) * Any issues with or allergies against the provided food items or utilized anesthesia * Shift work in the preceding three months or for a long duration * Time travel over two time zones in the preceding month * Too much weight gain or weight loss in the preceding 6 months * Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in clock gene & associated omic circadian rhythms | Measured repeatedly (every 6 hours for 24 hours) during a period of extended wakefulness, following each dietary intervention (i.e. over a total period of 6-7 weeks) | Changes in clock gene & associated clock-regulated & clock-independent metabolic and omic circadian rhythms (e.g. in epigenome, transcriptome, metabolites) in peripheral tissues (primarily skeletal muscle and adipose tissue), and interplay between these rhythms across the 24-h period and under the different dietary conditions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 24-h rhythms in blood | Measured repeatedly (every 2-3 hours over 24 hours) during a period of extended wakefulness and after subsequent recovery, following each dietary intervention (i.e. over a total period of 6-7 weeks) | Changes in rhythms in blood-borne cells, proteins and other molecular factors such as DNA, hormones, and proteins, due to the preceding dietary intervention, and relation to other rhythms measured across 24 hrs following the two dietary conditions |
| Diet-induced changes in gut microbiota and relation to circadian rhythms | Measured throughout study participation, i.e. on average over 6-7 weeks | Changes in gut microbiota (metagenomic, compositional) due to dietary intervention, and relation to circadian rhythms measured across 24 hrs in peripheral tissues following the two dietary conditions |
| Energy expenditure rhythms | Measured repeatedly (every 2 hours over 24 hours) during a period of extended wakefulness and after subsequent recovery, following each dietary intervention (i.e. over a total period of 6-7 weeks) | Changes in energy expenditure rhythms due to the preceding dietary intervention, and relation to other rhythms measured across 24 hrs following the two dietary conditions |
| Wakefulness-induced changes and subsequent recovery at omic levels | Following each dietary intervention (i.e. over a total period of 6-7 weeks), measured repeatedly (every 2-6 hours for 24 hours) during a period of extended wakefulness, and after recovery sleep | Changes at omic levels (e.g. DNA methylation, transcriptome, proteome, metabolome) in peripheral tissues (primarily skeletal muscle and adipose tissue), urine and feces samples due to extended wakefulness following subsequent recovery, following each dietary intervention |
| Rhythms of blood markers of damage to the central nervous system | Measured repeatedly (every 1-3 hours over 24 hours) during a period of extended wakefulness and after subsequent recovery, following each dietary intervention (i.e. over a total period of 6-7 weeks) | Assessment of rhythms in of blood markers of damage to the central nervous system (e.g. Olink Proseek multiplex panel, neuron-specific enolase, S-100b) across a 24-h period and following subsequent recovery sleep, following the two dietary conditions |
| 24-h rhythms in saliva | Measured repeatedly (every 2-3 hours over 24 hours) during a period of extended wakefulness and after subsequent recovery, following each dietary intervention (i.e. over a total period of 6-7 weeks) | Changes in rhythms in saliva-borne cells, proteins and other molecular factors such as DNA, hormones, and proteins, due to the preceding dietary intervention, and relation to other rhythms measured across 24 hrs following the two dietary conditions |
| Central circadian rhythms | Measured repeatedly (every 1-3 hours over 24 hours) during a period of extended wakefulness and after subsequent recovery, following each dietary intervention (i.e. over a total period of 6-7 weeks) | Changes in centrally driven circadian rhythms (e.g. temperature and melatonin), due to the preceding dietary intervention, and relation to other rhythms measured across 24 hrs following the two dietary conditions |
| Urine metabolite rhythms | Measured throughout study participation, i.e. on average over 6-7 weeks | Changes in levels of urine metabolites due to dietary intervention, and relation to circadian rhythms across 24 hrs in peripheral tissues following the two dietary conditions |
Countries
Sweden
Contacts
Primary ContactJonathan Cedernaes, M.D., Ph.D.
Backup ContactChristian Benedict, Ph.D.
Outcome results
None listed