Effects of Microbouts of Activity on Metabolic Health

Study Overview
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Brief Summary
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Population studies suggest that time spent in sedentary behaviors is associated with all-cause mortality including obesity, diabetes, and cardiovascular diseases, independent of time spent in exercise. Frequent interruptions to sedentary time are however beneficially associated with metabolic health outcomes, even in individuals who exercise regularly. The goal is to use integrative approach to understand the biological mechanisms that underlie these associations in a longitudinal intervention study in overweight sedentary adults. The investigators believe that the proposed study will provide an initial evidence base for the health benefits of breaking up prolonged sitting with short bursts of activity. This innovative strategy may be more effective at combating the adverse effects of sedentary behaviors than more traditional approaches.

Detailed Description
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To compare the effects of 4-weeks of microbursts of moderate-intensity activity to a calorically equivalent single bout of 45 minutes of moderate-intensity exercise training, both performed 5 days per week for a total of 45 minutes, in free-living sedentary overweight adults on: Aim 1: plasma inflammatory and cardiometabolic health biomarkers in association with total energy expenditure and time spent in sedentary behaviors. H1: Microbursts of activity will result in higher daily energy expenditure and lower time spent sedentary, as respectively measured with doubly labeled water and accelerometry, than traditional exercise training. This will be associated with healthier inflammatory Interleukin 1 alpha (IL1a), Interleukin 6 (IL6), Interleukin 10 (IL10), Tumour Necrosis Factor alpha (TNFa) and cardiometabolic (triglycerides, cholesterol, C-Reactive Protein (CRP), High-density lipoprotein (HDL), and Low-density lipoprotein (LDL) profiles compared to those obtained with traditional exercise training program. Aim 2: 24-hr total fat and carbohydrate oxidation, exogenous carbohydrate oxidation, dietary fat trafficking between oxidation and incorporation into muscle lipid fractions, and mitochondrial function. H2: Both one single continuous bout and microbouts of activity will increase 24-hr total (whole-room calorimetry) and dietary (D9-palmitate) fat oxidation due to greater mitochondrial lipid oxidation (high resolution respirometry) and lower incorporation of dietary fatty acid into muscle lipid fractions (D9-palmitate), as compared to baseline sedentary control condition. Microbouts of activity will further result in greater increases in 24-hr total (whole-room calorimetry) and exogenous (U-13C6 glucose) carbohydrate oxidation and in mitochondrial carbohydrate-linked oxidation, than traditional isocaloric exercise training. Aim 3: Whole-body insulin sensitivity. H3: Both one single continuous bout and microbouts of activity will improve whole-body insulin sensitivity Intravenous Glucose Tolerance Test (IVGTT) compared to the baseline sedentary condition, but the improvement will likely be higher with the microbouts of activity. Exploratory aim: Self-perceived appetite, hunger, and levels of mood, fatigue and vigor/energy. H3: Microbursts of activity will result in less appetite, hunger and fatigue but in greater feelings of vigor and overall well-being than traditional isocaloric exercise training. As a result adherence to microbursts will be better than adherence to single bouts of physical activity.

Official Title
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Effects of Microbouts of Activity on Metabolic Health

Conditions
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Health Behavior

Intervention / Treatment
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* Behavioral: Traditional Exercise Training
* Behavioral: Daily Microbursts of Activity


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Overweight but weight stable (+/- 3kg over previous 6 months) sedentary male and female adults (n=30) will be recruited. Ages between 18-45 years old BMI of 25-35 kg/m2 Sedentary (< 1hr/wk of moderate-to-vigorous activity, less than 6,500 steps per day as measured for 5 days in free-living conditions with a pedometer). Based on subjects self-report during the H&P visit The use of birth pill control will be accepted Exclusion criteria: Any history of renal (present or past kidney failure, kidney transplant, dialysis or kidney cysts), Uncontrolled hypertension Cardiovascular (present or past atherosclerosis, heart attack, ischemic stroke, heart failure) Hepatic diseases (past or present hepatitis B or C, fibrosis, cirrhosis, NAFLD/NASH) Type 1 or 2 diabetes Cancer Smoking Consumption of drugs (marijuana included) Consumption of alcohol (>40g/d) HIV positivity Psychiatric disorders Any medications known to interfere with lipid or energy metabolism Known physical activity contraindications Major illness/physical problems (acute or chronic) that may limit their ability to perform the walking activities The blood draw will be used to objectively exclude peri- or postmenopausal women (FSH>25 mlU/mL in early follicular phase) Hypertriglyceridemia (triglycerides > 400mg/dL).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Traditional Exercise Training<br>Participants will be asked to perform moderate-intensity exercise (brisk walking) for 45 minutes for 5 days/week for 4 weeks. This intervention corresponds to the current recommendations. | Behavioral: Traditional Exercise Training<br>* Participants will be asked to perform moderate-intensity exercise (brisk walking) for 45 minutes for 5 days/week for 4 weeks. This intervention corresponds to the current recommendations.<br>|
| Experimental: Daily Microbursts of Activity<br>Participants will be asked to break up their sedentary activities of daily living for 5-minutes every hour for 10 hours, 5 days/week, by brisk walking for 4 weeks. | Behavioral: Daily Microbursts of Activity<br>* Participants will be asked to break up their sedentary activities of daily living for 5-minutes every hour for 10 hours, 5 days/week, by brisk walking for 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in sedentary time as measured by ActiPAL | Over each 2 week period, participants will be instructed to wear an ActiPAL (PALTechnologies: Glasgow, Scotland) activity monitor on their right leg. Participants will be instructed to wear the monitors at all times except when sleeping or participating in water-based activities. The time-stamped event data file from the activPAL software will be used to determine time spent sitting/lying, standing and stepping per day. | weeks 1-2 and weeks 5-6 | 
| Changes in total substrate oxidation | Total fat oxidation during the test day will be determined using whole-room indirect calorimetry. O2 consumption and CO2 production will be determined from the flow rates and differences in gas concentrations between air entering and air exiting the calorimeter as previously described | week 2 and week 7 | 
| Changes in insulin sensitivity | Insulin sensitivity will be determined via an insulin modified frequently sampled intra-venous glucose tolerance test (IVGTT). After baseline samples, intravenous glucose (0.3 g/kg) will be infused over 1 minute, followed by insulin at 0.03 U/kg, 20 minutes after glucose administration. Blood samples will be frequently sampled over 5 hours, and insulin sensitivity will be calculated using the Bergman minimal model. | week 2 and week 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in total energy expenditure (TEE) | Total energy expenditure (TEE) will be measured before and at the end of the intervention using doubly labeled water (DLW) over a 10-day period, as previously described (31). Subjects will ingest premixed 2g/kg total body water (TBW), estimated as 73% of fat free mass) dose of DLW composed of 0.2 and 0.15 g/kg estimated TBW of H218O and 2H2O, respectively. Urine samples will be collected in duplicate on days 0, 6, 8 and 10. 2H and 18O enrichment will be determined in urine samples by isotope ratio mass spectrometry (Delta V Advantage IRMS) | week 1-2 and week 5-6 | 
| Changes in Moderate-to-vigorous physical activity as measured by ActiGraph | Over the same 10-day period, participants will be instructed to wear an Actigraph GT3X+ accelerometer (Actigraph, LLC, Fort Walton Beach, FL) on their hip. Participants will be instructed to wear the monitors at all times except when sleeping or participating in water-based activities. | weeks 1-6 | 
| Changes in plasma CRP concentration | Weekly fasting blood samples will be obtained for the measurements of CRP (mg/dL). | Once weekly for 5 weeks | 
| Changes in Dietary Carbohydrate Oxidation | After the investigators have shown the subjects the procedure, subjects will collect their own hourly breath sampling for CO2 by blowing through a straw into two 15ml Vacutainers. Breath CO2 will be sampled directly from the Vacutainer with a syringe, and 13CO2 /12CO2 measured with IRMS. | week 2 and week 7 | 
| Changes in Dietary Fat Oxidation | Hourly urine sampling will be collected by the subjects for 24 hours and stored in 5mL cryovials at -20C until further analysis. To measure 2 hour fat oxidation, 2 hour/1 hour ratios from urine samples will be analyzed, as above described for the doubly labeled water method. The oxidation rate of glucose/water will be calculated from the cumulative recovery of 2 hours in total body water (TBW) as detailed previously. | week 2 and week 7 | 
| Changes in Mitochondria function | Freshly isolated skeletal muscle biopsies will be cut into small samples, the fibre bundles separated mechanically and partially teased apart and permeabilised. Small samples (2-5mg) will be added to the 2ml chamber of an Oroboros high-resolution respirometer with a mitochondrial respiration buffer. With the addition of several substrates, different states will be reached to analyse mitochondrial function. Pyruvate, malate and glutamate will be added as substrates to examine respiration through Complex I, succinate will be used to examine respiration through Complex II and octanoylcarnitine will be used to examine respiration through the electron-transferring flavoprotein, ETF. | week 2 and week 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sedentary Behavior