Biorhythms in Metabolic Tissues

Biological Rhythms in Metabolic Tissues: Impact of Diet

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.

Study Overview

• Status: Unknown
• Conditions: Healthy; Sleep Deprivation; Metabolic Disturbance; Biological Clocks
• Intervention / Treatment: Other: Low-fat dietary intervention; Other: High-fat dietary intervention

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jonathan Cedernaes, M.D., Ph.D.; Phone Number: 0184714136; Email: jonathan.cedernaes@neuro.uu.se
• Study Contact Backup: Name: Christian Benedict, Ph.D.; Phone Number: 0184714136; Email: christian.benedict@neuro.uu.se

Study Locations

• Sweden
  • Uppsala, Sweden, 75324
    • Recruiting
    • Department of Neuroscience, Uppsala University
    • Contact: Jonathan Cedernaes, MD, PhD; Phone Number: +46184714102; Email: jonathan.cedernaes@neuro.uu.se
    • Contact: Christian Benedict, PhD; Phone Number: 46184714136; Email: christian.benedict@neuro.uu.se
    • Principal Investigator: Jonathan Cedernaes, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 32 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Healthy diet; 'Low-fat dietary intervention' to be administered to participants	Other: Low-fat dietary intervention; Low-fat diet (5-7 days) preceding extended wakefulness under standardized conditions
Experimental: Unhealthy diet; 'High-fat dietary intervention' to be administered to participants	Other: High-fat dietary intervention; High-fat diet (5-7 days) preceding extended wakefulness under standardized conditions

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in clock gene & associated omic circadian rhythms	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	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Wakefulness-induced changes and subsequent recovery at omic levels	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	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
24-h rhythms in blood	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	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)
Diet-induced changes in gut microbiota and relation to circadian rhythms	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	Measured throughout study participation, i.e. on average over 6-7 weeks
Energy expenditure rhythms	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	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)
Urine metabolite rhythms	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	Measured throughout study participation, i.e. on average over 6-7 weeks
Rhythms of blood markers of damage to the central nervous system	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	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)
24-h rhythms in saliva	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	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)
Central circadian rhythms	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	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)

Collaborators and Investigators

• Sponsor: Uppsala University
• Collaborators: The Swedish Research Council
• Investigators: Principal Investigator: Jonathan Cedernaes, Uppsala University

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2017
• Primary Completion (Anticipated): November 30, 2019
• Study Completion (Anticipated): December 31, 2019

Study Registration Dates

• First Submitted: August 28, 2017
• First Submitted That Met QC Criteria: September 7, 2017
• First Posted (Actual): September 8, 2017

Study Record Updates

• Last Update Posted (Actual): October 12, 2017
• Last Update Submitted That Met QC Criteria: October 10, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Dyssomnias; Sleep Wake Disorders; Neurologic Manifestations; Sleep Deprivation
• Other Study ID Numbers: CircHFJC2017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No