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Aim: Exercise training improves the risk of cardiometabolic diseases; yet the underlying mechanisms are unclear. Exercise induces release of IL-6 from skeletal muscle. Acute elevations in IL-6 improve lipid and glucose metabolism, the latter partly through a delayed gastric emptying. Physical inactivity causes accumulation of visceral fat (VAT). Visceral and epicardial adipose tissue (EAT) is more inflamed than subcutaneous adipose tissue. Thus, the investigators hypothesize that exercise-induced IL-6 mediates the exercise-induced reduction in EAT and VAT. Secondly, the investigators hypothesize that exercise-induced adaptations in glucose metabolism and gastric motility are dependent on IL-6. Finally the investigators hypothesise that both endurance and resistance exercise training reduce VAT and EAT.
Primary aim: To investigate the effects of exercise training on VAT and to determine to what extend IL-6 mediates this effect.
Secondary aims: 1) To determine whether 12 weeks of endurance and strength training can reduce the amount of EAT. 2) To study whether the effects of exercise on glucose metabolism and gastric emptying are dependent on IL-6.
Methods: Inclusion: 70 inactive men and women, >18 years, waist to height ratio > 0.5 and/or waist circumference ≥ 88 cm (women); waist circumference ≥ 102 cm (men) Design: A 12-week, double-blinded randomised, placebo-controlled exercise intervention study.
Intervention: Subjects will be randomised to one of five groups: i) Tocilizumab (IL-6 receptor antibody) and endurance training, ii) Placebo to Tocilizumab and endurance training, iii) Tocilizumab, no exercise iv) Placebo to Tocilizumab and no training, and v) Placebo to Tocilizumab, and resistance training. Tocilizumab/placebo dose will be administered (according to standard recommendations) before the first training session, and maintained during the 12-week training program. Training will be supervised to ensure intensity and compliance. Subjects will be instructed not to change eating habits and informed that this study does not aim for a weight loss.
Statistical considerations: Study investigators are blinded to treatment allocation. Dropouts will be replaced. A sample size of 70 subjects is needed to detect a 10% change in visceral adipose, with a power of 80% and a significance level of 0.05.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Endurance exercise + infusion of Tocilizumab | Experimental | Endurance exercise training + monthly infusion of Tocilizumab |
|
| Endurance exercise + infusion of placebo | Experimental | Endurance exercise training + monthly infusion of placebo |
|
| No exercise + infusion of Tocilizumab | Experimental | No exercise + monthly infusion of Tocilizumab |
|
| No exercise + infusion of placebo | Placebo Comparator | No exercise training + monthly infusion of placebo |
|
| Resistance exercise + infusion of placebo | Experimental | Resistance exercise training + monthly infusion of placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Endurance Exercise Training | Behavioral | Three months of supervised training. Interval training, 3 sessions weekly of 45 min. During intervals the intensity will be minimum 70 % of VO2 max |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in visceral fat mass | Visceral fat mass will be measured by MRI before and after the intervention. Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: Endurancetraining + tocilizumab and group: Endurancetraining + placebo. | 0, 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in visceral fat mass | Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: Endurancetraining + placebo and group: no training + placebo. | 0, 12 weeks |
| Changes in visceral fat mass |
| Measure | Description | Time Frame |
|---|---|---|
| Peri- and paracardial adipose tissue volume (measured by MRI) | 0, 12 weeks | |
| Body composition analysis (measured by Dual-energy X-ray absorptiometry) | 0, 4, 8 and 12 weeks | |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Bente K Pedersen, Professor | Rigshospitalet, Denmark | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Rigshospitalet, Centre of Inflammation and Metabolism (CIM) Centre for Physical Activity Research (CFAS) | Copenhagen | 2100 | Denmark |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30595477 | Result | Wedell-Neergaard AS, Lang Lehrskov L, Christensen RH, Legaard GE, Dorph E, Larsen MK, Launbo N, Fagerlind SR, Seide SK, Nymand S, Ball M, Vinum N, Dahl CN, Henneberg M, Ried-Larsen M, Nybing JD, Christensen R, Rosenmeier JB, Karstoft K, Pedersen BK, Ellingsgaard H, Krogh-Madsen R. Exercise-Induced Changes in Visceral Adipose Tissue Mass Are Regulated by IL-6 Signaling: A Randomized Controlled Trial. Cell Metab. 2019 Apr 2;29(4):844-855.e3. doi: 10.1016/j.cmet.2018.12.007. Epub 2018 Dec 27. | |
| 31268469 |
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| ID | Term |
|---|---|
| D009765 | Obesity |
| ID | Term |
|---|---|
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D055070 | Resistance Training |
| C502936 | tocilizumab |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D005081 | Exercise Therapy |
| D012046 | Rehabilitation |
| D000359 | Aftercare |
| D003266 | Continuity of Patient Care |
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|
| Resistance Exercise Training | Behavioral | Three months of supervised resistance training. Subjects will perform 3 weekly sessions of 45 min. The intensity will be kept at minimum 60% of 1RM. |
|
|
| No Exercise | Behavioral | Control to exercise |
|
| Tocilizumab | Drug | Tocilizumab infusion will be administered monthly (8 mg/kg body weight i.v., maximun 800 mg). Each subject will receive 3 infusions during the study period. |
|
|
| Placebo | Drug | Saline infusion will be administered monthly (same volume as Tocilizumab). Each subject will receive 3 infusions during the study period. |
|
|
2. Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: Endurancetraining + placebo and group: resistance training + placebo.
| 0, 12 weeks |
| Changes in visceral fat mass | 3. Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: Endurancetraining + tocilizumab and group: no training + tocilizumab. | 0, 12 weeks |
| Changes in visceral fat mass | 4. Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: resistance training + placebo and group: no training + placebo. | 0, 12 weeks |
| Changes in visceral fat mass | 5. Difference in change in visceral fat mass from baseline to 12 weeks follow up will be compared between group: no training + placebo and group: no training + tocilizumab. | 0, 12 weeks |
| Epicardial adipose tissue | Cardiac fat volume will be measured by a cardiac MRI scan before and after the interventions. All groups will be compared. | 0, 12 weeks |
| Gastric emptying | Gastric emptying will be measured by paracetamol blood levels (mmol/l) before and after the interventions. The paracetamol levels will be compared between groups as follows. Group: Endurancetraining + tocilizumab and group: Endurancetraining + placebo. Group: Endurancetraining + placebo and group: no training + placebo. Group: Endurancetraining + tocilizumab and group: no training + tocilizumab. Group: No training + placebo and group: no training + tocilizumab. | 0, 12 weeks |
| Waist circumference (measured in cm) |
| 0, 4, 8 and 12 weeks |
| BMI (kg/m^2, weight in kilograms, height in meters) | 0, 4, 8 and 12 weeks |
| Resting blood pressure as a measure of cardiovascular function | 0, 12 weeks |
| Maximal aerobic capacity (cardiovascular fitness) (VO2 peak) | 0, 12 weeks |
| Muscle strength measured by one repetition maximum (1RM) | 0, 12 weeks |
| Oral glucose tolerance test | 0, 12 weeks |
| Glycemic control during mixed meal tolerance test | 0, 12 weeks |
| Free-living glycemic control using continuous glucose monitoring | 0, 12 weeks |
| Pro- and anti-inflammatory cytokines(Interleukin-6, Interleukin-1ra, Interleukin-1, Interleukin-18, Interleukin-15, Interleukin-10) | 0,4, 8 and 12 weeks |
| soluble Interleukin-6 receptor (sIL-6R) | 0,4, 8 and 12 weeks |
| soluble gp130 | 0,4, 8 and 12 weeks |
| Adipose characteristic by blood markers | Blood sampling | 0,4, 8 and 12 weeks |
| Cortisol | Blood sampling | 0,4, 8 and 12 weeks |
| Catecholamines (Epinephrine and norepinephrine) | 0,4, 8 and 12 weeks |
| leukocytes | Blood sampling | 0,4, 8 and 12 weeks, (Timepoints: 0, 22, 45, 01:45, 02:45, at week 0 and 12) |
| Glucagon | blood sampling | 0,4, 8 and 12 weeks |
| Blood lipid | Blood sampling | 0,4, 8 and 12 weeks |
| Cardiovascular function assessed by blood markers | 0,4, 8 and 12 weeks |
| Inflammation status assessed by blood markers | 0,4, 8 and 12 weeks |
| Adipose biopsy to assess the adipokine expression signature | 0, 12 weeks |
| Photo of subjects | To asses if the visual appearance of the stomach is reflecting the amount of visceral fat mass and to see if there is a difference in the visual appearance before and after the intervention | 0, 12 weeks |
| Faecal and urine samples to asses changes in the microbiome | 0, 12 weeks |
| Change in sleepiness | Self-report using the Epworth questionnaire | 0, 12 weeks |
| Exercise factors during an acute exercise bout | cortisol, il-6, epinephrine and norepinephrine | Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks) |
| Glucose metabolism during an acute exercise bout | At each timepoint exercise factors: cortisol, il-6, epinephrine and norepinephrine will be measured. Furthermore pro anti-inflammatory cytokines, glucose, insulin, C-peptide, C-reactive protein will be reported. | Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks) |
| Whole blood stimulation with Lipopolysaccharide and phytohaemagglutinin | in vitro stimulation of whole blood. | During the acute exercise bout at Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks) |
| Fibroblast growth factor 21 | During the acute exercise bout at Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks) |
| oxidative burst in neutrophils | During the acute exercise bout at Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks) |
| gastrointestinal health | A questionnaire regarding gastrointestinal symptoms. A Visual Analog Score will be used. | 0,12 weeks |
| Physical activity | Self-report physical activity using The Minnesota Leisure Time Physical Activity Questionnaire | 0 weeks |
| Diet registration | Self-report diet registration for 3 days | 0,4,12 |
| Satiety | self-report using a satiety questionnaire during mixed meal tolerance test | 0,12 |
| Cardiac function measured by heart rate recovery | 0, 12 weeks |
| Muscle biopsy to assess expression of exercise induced cytokines | 0, 12 weeks |
| Coronary sinus flow reserve as a measure of global perfusion using MRI | 0, 12 weeks |
| Insulin during mixed meal tolerance test | Time Frame: 0, 12 weeks |
| C-peptide during mixed meal tolerance test | Time Frame: 0, 12 weeks |
| Glucagon during mixed meal tolerance test | Time Frame: 0, 12 weeks |
| GLP-1 during mixed meal tolerance test | Time Frame: 0, 12 weeks |
| Insulin sensitivity index (Matsuda) based on mixed meal tolerance test | Time Frame: 0, 12 weeks |
| Insulin secretion index based on mixed meal tolerance test | Time Frame: 0, 12 weeks |
| IL-6 released in respons to an exercise bout | IL-6 in plasma measured before and after an exercise bout | one of the first 3 and one of the last 3 exercise bouts |
| Derived |
| Christensen RH, Wedell-Neergaard AS, Lehrskov LL, Legaard GE, Dorph E, Larsen MK, Launbo N, Fagerlind SR, Seide SK, Nymand S, Ball M, Vinum NB, Dahl CN, Henneberg M, Ried-Larsen M, Boesen MP, Christensen R, Karstoft K, Krogh-Madsen R, Rosenmeier JB, Pedersen BK, Ellingsgaard H. Effect of Aerobic and Resistance Exercise on Cardiac Adipose Tissues: Secondary Analyses From a Randomized Clinical Trial. JAMA Cardiol. 2019 Aug 1;4(8):778-787. doi: 10.1001/jamacardio.2019.2074. |
| 29720225 | Derived | Christensen RH, Wedell-Neergaard AS, Lehrskov LL, Legard GE, Dorph EB, Nymand S, Ball MK, Zacho M, Christensen R, Ellingsgaard H, Rosenmeier JB, Krogh-Madsen R, Pedersen BK, Karstoft K. The role of exercise combined with tocilizumab in visceral and epicardial adipose tissue and gastric emptying rate in abdominally obese participants: protocol for a randomised controlled trial. Trials. 2018 May 2;19(1):266. doi: 10.1186/s13063-018-2637-0. |
| D001835 |
| Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D005791 |
| Patient Care |
| D013812 | Therapeutics |
| D026741 | Physical Therapy Modalities |
| D064797 | Physical Conditioning, Human |
| D015444 | Exercise |
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |