Activating Brown Adipose Tissue Through Exercise

Study Overview
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Brief Summary
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The energy burning capacity of brown adipose tissue makes it an attractive target for anti-obesity therapies. Sympathetic nervous system (SNS) is the classical regulator of brown adipose tissue; however, recent findings show a pool of novel brown adipose tissue activators that sidestep the need for stimulating the SNS, including cardiac natriuretic peptides. Of interest is that both SNS and non-SNS brown adipose tissue activators are sensitive to physical exercise, which opens new horizons and opportunities to study the potential effect of exercise-based therapeutic interventions. Moreover, a new protein released by exercise-stimulated skeletal muscle, irisin, seems to play a key role in the browning program of white adipose tissue. Most of the available evidence comes from animal studies, which is sometimes difficult to infer to human physiology. The overall objective of the ACTIBATE randomized controlled trial is to study the effect of long-term exercise training (6 months) on brown adipose tissue activity and quantity (primary outcomes) in young overweight and obese adults. The clinical significance of activating and recruiting brown adipose tissue on resting metabolic rate and cardiometabolic profile in humans will be determined. The investigators will also study at the molecular level the benefits of exercise on the regulation pathways in two different tissues: white adipose tissue and skeletal muscle, as well as identifying possible cross-talk between the exercising muscle and heart, and fat. Information from exercise-induced signaling on brown adipose tissue, white adipose tissue and skeletal muscle will help on identifying potential molecular therapeutic candidates.

Detailed Description
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The energy burning capacity of brown adipose tissue (BAT) makes it an attractive target for antiobesity therapies. Sympathetic nervous system (SNS) is the classical regulator of BAT; however, recent findings show a pool of novel BAT activators that sidestep the need for stimulating the SNS. Of interest is that both SNS and non-SNS BAT activators are sensitive to physical exercise, which opens new horizons and opportunities to study the potential effect of exercise-based therapeutic interventions. Moreover, a new protein released by exercise-stimulated skeletal muscle, irisin, seems to play a key role in the browning program in white adipose tissue. Most of the available evidence comes from animal studies, which is sometimes difficult to infer to human physiology. To determine whether a controlled physical exercise program is able to facilitate BAT maintenance and function, stimulating pre-existing brown precursors and inducing the specific gene program to favor white-to-brown adipocyte transformation in humans is of clinical relevance. The primary objective of the ACTIBATE randomized controlled trial (RCT) is to quantify the dose-effect of different exercise intensities, i.e. no exercise, moderate-intensity and vigorous-intensity, on BAT activity and mass (primary outcome), and on energy expenditure, thermogenic response to a test meal, shivering threshold, and cardiovascular disease risk factors, in young adults. The investigators will also obtain biopsies from white adipose tissue and skeletal muscle to analyse the expression of genes encoding proteins involved in the thermogenic machinery. The intervention groups will train 4-5 days/week (60 min per session) for a 24-week period. With the final aim of making the exercise program transferable to society, the basis for the specific exercise dose in ACTIBATE is the physical activity recommendations for adults proposed by the World Health Organization. Since there is no information regarding the ideal exercise model to activate and recruit BAT, a major objective of ACTIBATE is to evaluate various exercise intensity levels that fall within the current public health recommendations to test whether higher intensity levels provides more benefit than the standard moderate-intensity level. ACTIBATE will combine both aerobic and resistance training.

Official Title
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Activating Brown Adipose Tissue Through Exercise: Randomized Controlled Trial

Conditions
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Obesity, Diabetes Mellitus, Metabolic Syndrome X

Intervention / Treatment
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* Other: Exercise training based on recommendations for adults (WHO)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI: 20-35 kg/m2. Not engaged in regular physical activity >20 min on >3 days/week. Not participating in a weight loss program. Stable weight over the last 3 months (body weight changes <3 kg). Normal electrocardiogram. Participants must be capable and willing to provide consent, understand exclusion criteria and accept the randomized group assignment. Exclusion Criteria: History of cardiovascular disease. Diabetes or hypertension. Pregnancy, or planning to get pregnant during the study period. Medication for hypertension, hyperlipidemia, hyperuricemia or other illness. Beta blockers or benzodiazepins use. Smoking. Frequent exposure to cold temperatures (Granada is surrounded by high mountains where people can sky or do trekking). Taking medication for thyroid. Other significant medical conditions that are life-threatening or that can interfere with or be aggravated by exercise. Unwillingness to either complete the study requirements or to be randomized into control or training group.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 25 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Usual care group (control)<br>Participants randomly assigned to the usual care (control) group will receive general advices from the exercise-training specialist about the positive effects of physical activity at the start of the study. The investigators will prepare informative pamphlets describing the benefits of physical activity that the investigators group has prepared for the Region of Andalucía (Southern Spain),http://www.juntadeandalucia.es/salud/servicios/contenidos/andaluciaessalud/docs/130/Guia_Recomendaciones_AF.pdf. | |
| Experimental: Moderate-intensity group<br>Exercise training based on recommendations for adults (WHO) | Other: Exercise training based on recommendations for adults (WHO)<br>* The length of the trial will be 6 months. the total time of aerobic exercise in both moderate-intensity and vigorous-intensity groups will be 150 minutes/week, whereas the time needed to complete the resistance training exercises will be ≈15-30 minutes for both groups.<br>|
| Experimental: Vigorous-intensity group<br>Exercise training based on recommendations for adults (WHO) | Other: Exercise training based on recommendations for adults (WHO)<br>* The length of the trial will be 6 months. the total time of aerobic exercise in both moderate-intensity and vigorous-intensity groups will be 150 minutes/week, whereas the time needed to complete the resistance training exercises will be ≈15-30 minutes for both groups.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in BAT mass and activity evaluated with Positron emission tomography/computed tomography (PET/CT) |  | Baseline and 6 month later (immediately after the interventions ends) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in gene expression of white adipose tissue, aliquots will be obtained by biopsies. |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in gene expression of muscle, aliquots will be obtained by biopsies. | Aliquots will be designated to gene expression, immunoblotting and morphologic studies. | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in resting energy expenditure measured through indirect calorimetry |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in meal Induced Thermogenesis measured through indirect calorimetry |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in Cold Induced Thermogenesis measured through indirect calorimetry |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in Body composition: fat mass. Using a Dual Energy X-ray Absorptiometry scan |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in Body composition: lean body mass Using a Dual Energy X-ray Absorptiometry scan |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in Shivering threshold: Temperature of water in a water perfuse vest connected to a chiller unit |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in Thermic response to cold exposure with both subjective (Visual Analog Scales) and objective measures (skin and sublingual temperature) |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in subjective Thermic response to cold exposure: Visual Analog Scale |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in Thermic response to a test meal with skin temperature |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in Appetite: ad-libitum meal |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in Appetite: Visual Analog Scale after a test meal |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in Lipid Profile: In a blood sample |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in biomolecular markers: energy metabolism during cold exposure: In a blood sample |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in Cardiorespiratory fitness measured on a maximum effort test |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in Thermic response to a maximum effort test record with skin thermal receptors |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in Muscular strength: 1 Repetition Maximum |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in Dietary habits: 24h questionaire |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in Physical activity levels: With an accelerometer |  | Baseline and 6 month later (immediately after the interventions ends) | 
| Change from Baseline in Basal Heart Rate Variability: with a heart rate monitor |  | Baseline and 6 month later (immediately after the interventions ends) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BRITE adipose tissue, physical activity, Thermogenesis, Body Temperature Regulation, Energy Metabolism