Adiposity
Conditions
Brief summary
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.
Interventions
BEHAVIORALEndurance Exercise Training
Three months of supervised training. Interval training, 3 sessions weekly of 45 min. During intervals the intensity will be minimum 70 % of VO2 max
BEHAVIORALResistance Exercise Training
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.
BEHAVIORALNo Exercise
Control to exercise
DRUGTocilizumab
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.
DRUGPlacebo
Saline infusion will be administered monthly (same volume as Tocilizumab). Each subject will receive 3 infusions during the study period.
Sponsors
Rigshospitalet, Denmark
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
Yes
Inclusion criteria
* Men and women * Sedentary * Waist to height ratio ≥ ½ and/or waist circumference ≥ 88 cm (women); waist circumference ≥ 102 cm (men) * Age ≥ 18 y
Exclusion criteria
* Pregnancy * Diagnosed with diabetes (HbA1c ≥ 48 mmol/mol or fasting glucose ≥ 7.0 mmol/l) * Diagnosed with ischemic heart disease * Atrial fibrillation * Treatment with biologic rheumatic drugs, systemic prednisolone or other immunosuppressive treatments * Health conditions that prevents individuals from participating in the exercise training intervention e.g. severe obesity * Patients who cannot undergo MRI scans (e.g. kidney disease, metallic implants or claustrophobia)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in visceral fat mass | 0, 12 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in visceral fat mass | 0, 12 weeks | 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. |
| Epicardial adipose tissue | 0, 12 weeks | Cardiac fat volume will be measured by a cardiac MRI scan before and after the interventions. All groups will be compared. |
| Gastric emptying | 0, 12 weeks | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Body composition analysis (measured by Dual-energy X-ray absorptiometry) | 0, 4, 8 and 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 | 0,4, 8 and 12 weeks | Blood sampling |
| Cortisol | 0,4, 8 and 12 weeks | Blood sampling |
| Catecholamines (Epinephrine and norepinephrine) | 0,4, 8 and 12 weeks | — |
| leukocytes | 0,4, 8 and 12 weeks, (Timepoints: 0, 22, 45, 01:45, 02:45, at week 0 and 12) | Blood sampling |
| Glucagon | 0,4, 8 and 12 weeks | blood sampling |
| Blood lipid | 0,4, 8 and 12 weeks | Blood sampling |
| GLP-1 during mixed meal tolerance test | Time Frame: 0, 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 | 0, 12 weeks | 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 |
| Faecal and urine samples to asses changes in the microbiome | 0, 12 weeks | — |
| Change in sleepiness | 0, 12 weeks | Self-report using the Epworth questionnaire |
| Exercise factors during an acute exercise bout | Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks) | cortisol, il-6, epinephrine and norepinephrine |
| Glucose metabolism during an acute exercise bout | Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks) | 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. |
| Whole blood stimulation with Lipopolysaccharide and phytohaemagglutinin | During the acute exercise bout at Timepoints: 0, 22, 45, 01:45, 02:45, before and after the intervention (0,12 weeks) | in vitro stimulation of whole blood. |
| 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 | 0,12 weeks | A questionnaire regarding gastrointestinal symptoms. A Visual Analog Score will be used. |
| Physical activity | 0 weeks | Self-report physical activity using The Minnesota Leisure Time Physical Activity Questionnaire |
| Diet registration | 0,4,12 | Self-report diet registration for 3 days |
| Satiety | 0,12 | self-report using a satiety questionnaire during mixed meal tolerance test |
| 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 sensitivity index (Matsuda) based on 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 | — |
| Insulin during 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 | one of the first 3 and one of the last 3 exercise bouts | IL-6 in plasma measured before and after an exercise bout |
| Peri- and paracardial adipose tissue volume (measured by MRI) | 0, 12 weeks | — |
Countries
Denmark
Outcome results
None listed