Obesity, Inflammation and Aging: Effects of Physical Exercise and Omega-3 Fatty Acids.

Study Overview
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Brief Summary
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Dysfunction of adipose tissue in obesity, inflammation and aging: mechanisms and effects of physical exercise and omega-3 fatty acids.

Detailed Description
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Obesity is associated with the development of metabolic diseases including type 2 diabetes and immune disorders. Obesity also leads to reduced lifespan and accelerated cellular processes similar to those of aging. On the other hand, aging is accompanied by the accumulation of visceral fat and the metabolic complications associated to obesity. Both obesity and aging have been identified as chronic, low-grade inflammation disorders. The inflammation in aging has been considered as a risk factor for the development of most of age-related diseases, and therefore for morbidity and mortality in the elderly. However, the specific mechanisms leading to inflammation in aging remain largely unknown. Resolution of inflammation is an active process which involves production of several series of specialized pro-resolving lipid mediators such lipoxins, resolvin, protectins and maresin. The hypothesis of this trial is that the chronic inflammation associated to obesity and aging could be the result of an impaired production of these specialized pro-resolutive lipid mediators, mainly in adipose tissue. On the other hand, the investigators also propose that altered transcriptional pattern might be responsible for the development of the inflammation associated with the pathophysiology of obesity and aging. Therefore the first general aim of the current project will be to characterize the mechanisms involved in the unresolved chronic inflammation that arises during obesity and aging. Because n-3 PUFAs (polyunsaturated fatty acids) serve as substrates for the synthesis of specialized pro-resolving lipid mediators and are important transcriptional regulators, the investigators propose that dietary supplementation with n-3 PUFAs, alone or in combination with regular physical exercise could promote the resolution of local and systemic inflammation and the subsequent metabolic disorders associated to obesity and aging. A trial in overweight/obese postmenopausal women will be carried out to characterize the potential beneficial effects of regular administration of a DHA-rich dietary supplement and/or a progressive resistance training (PRT) program on weight and fat mass loss, insulin sensitivity, inflammatory markers and gene/miRNA/lipidomic/metabolomic profile in serum and/or adipose tissue. Moreover, changes in gut microbiota will be also addressed.

Official Title
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Dysfunction of Adipose Tissue in Obesity, Inflammation and Aging: Mechanisms and Effects of Physical Exercise and Omega-3 Fatty Acids.

Conditions
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Obesity, Aging, Inflammation

Intervention / Treatment
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* Dietary Supplement: Omega-3 (DHA-rich dietary supplement)
* Dietary Supplement: Placebo (olive oil)
* Other: Resistance training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Post-menopausal women Age between 55 and 70 years Body Mass Index (BMI) between 27.5 and 35 kg/m² Weight unchanged (± 3 kg) for the last 3 months Overall physical and psychological condition that the investigator believes is in accordance with the overall aim of the study Exclusion Criteria: Use of regular prescription medication: specially statins, antidiabetic drugs, menopausal hormone replacement therapy To suffer from any chronic metabolic condition: severe dislipidemia, type 1 or 2 diabetes, hepatic (cirrhosis), renal disease, cardiovascular disease, neuromuscular disease, arthritic disease, pulmonary disease and/or other debilitating diseases Food allergies and/or food intolerance expected to come up during the study Following special diets (Atkins, vegetarian, etc.) prior three months the start of the study Eating disorders Surgically treated obesity Alcohol or drug abuse

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Dietary advice for a healthy diet supplemented with placebo (olive oil). | Dietary Supplement: Placebo (olive oil)<br>* Double-blind randomized placebo-controlled intervention with DHA-rich dietary supplement with or without resistance training program for 16 weeks.<br>|
| Experimental: Omega-3<br>Dietary advice for a healthy diet supplemented with DHA-rich dietary supplement (providing 1.650 mg/day of DHA). | Dietary Supplement: Omega-3 (DHA-rich dietary supplement)<br>* Double-blind randomized placebo-controlled intervention with DHA-rich dietary supplement with or without resistance training program for 16 weeks.<br>|
| Experimental: Resistance Training<br>Dietary advice for a healthy diet supplemented with placebo (olive oil) and moderate resistance training program. | Dietary Supplement: Placebo (olive oil)<br>* Double-blind randomized placebo-controlled intervention with DHA-rich dietary supplement with or without resistance training program for 16 weeks.<br>Other: Resistance training<br>* Double-blind randomized placebo-controlled intervention with DHA-rich dietary supplement with or without resistance training program for 16 weeks.<br>|
| Experimental: Omega-3 + Resistance Training<br>Dietary advice for a healthy diet supplemented with a DHA-rich dietary supplement (providing 1.650 mg/day of DHA) and moderate resistance training program. | Dietary Supplement: Omega-3 (DHA-rich dietary supplement)<br>* Double-blind randomized placebo-controlled intervention with DHA-rich dietary supplement with or without resistance training program for 16 weeks.<br>Other: Resistance training<br>* Double-blind randomized placebo-controlled intervention with DHA-rich dietary supplement with or without resistance training program for 16 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fat mass reduction | Evaluation of body fat mass changes induced by the different interventions, analyzed by Dual X-ray Absorptiometry (DXA). | Week 0 (baseline) | 
| Fat mass reduction | Evaluation of body fat mass changes induced by the different interventions, analyzed by Dual X-ray Absorptiometry (DXA). | Week 16 (end of intervention) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evolution of fat mass reduction | Evaluation of body fat mass changes induced by the different interventions analyzed by bioimpedance. | Week 0 (baseline) | 
| Evolution of fat mass reduction | Evaluation of body fat mass changes induced by the different interventions analyzed by bioimpedance. | Week 2 | 
| Evolution of fat mass reduction | Evaluation of body fat mass changes induced by the different interventions analyzed by bioimpedance. | Week 4 | 
| Evolution of fat mass reduction | Evaluation of body fat mass changes induced by the different interventions analyzed by bioimpedance. | Week 6 | 
| Evolution of fat mass reduction | Evaluation of body fat mass changes induced by the different interventions analyzed by bioimpedance. | Week 8 | 
| Evolution of fat mass reduction | Evaluation of body fat mass changes induced by the different interventions analyzed by bioimpedance. | Week 10 | 
| Evolution of fat mass reduction | Evaluation of body fat mass changes induced by the different interventions analyzed by bioimpedance. | Week 12 | 
| Evolution of fat mass reduction | Evaluation of body fat mass changes induced by the different interventions analyzed by bioimpedance. | Week 14 | 
| Evolution of fat mass reduction | Evaluation of body fat mass changes induced by the different interventions analyzed by bioimpedance. | Week 16 (end of intervention) | 
| Weight loss | Changes in body weight will be measured by a body weight scale to the nearest 0.1 kg | Week 0 (baseline) | 
| Weight loss | Changes in body weight will be measured by a body weight scale to the nearest 0.1 kg | Week 2 | 
| Weight loss | Changes in body weight will be measured by a body weight scale to the nearest 0.1 kg | Week 4 | 
| Weight loss | Changes in body weight will be measured by a body weight scale to the nearest 0.1 kg | Week 6 | 
| Weight loss | Changes in body weight will be measured by a body weight scale to the nearest 0.1 kg | Week 8 | 
| Weight loss | Changes in body weight will be measured by a body weight scale to the nearest 0.1 kg | Week 10 | 
| Weight loss | Changes in body weight will be measured by a body weight scale to the nearest 0.1 kg | Week 12 | 
| Weight loss | Changes in body weight will be measured by a body weight scale to the nearest 0.1 kg | Week 14 | 
| Weight loss | Changes in body weight will be measured by a body weight scale to the nearest 0.1 kg | Week 16 (end of intervention) | 
| Evolution of body composition | Evaluation of fat-free mass changes will be analyzed by bioimpedance. | Week 0 (baseline) | 
| Evolution of body composition | Evaluation of fat-free mass changes will be analyzed by bioimpedance. | Week 2 | 
| Evolution of body composition | Evaluation of fat-free mass changes will be analyzed by bioimpedance. | Week 4 | 
| Evolution of body composition | Evaluation of fat-free mass changes will be analyzed by bioimpedance. | Week 6 | 
| Evolution of body composition | Evaluation of fat-free mass changes will be analyzed by bioimpedance. | Week 8 | 
| Evolution of body composition | Evaluation of fat-free mass changes will be analyzed by bioimpedance. | Week 10 | 
| Evolution of body composition | Evaluation of fat-free mass changes will be analyzed by bioimpedance. | Week 12 | 
| Evolution of body composition | Evaluation of fat-free mass changes will be analyzed by bioimpedance. | Week 14 | 
| Evolution of body composition | Evaluation of fat-free mass changes will be analyzed by bioimpedance. | Week 16 (end of intervention) | 
| Hip circumference | Hip circumference will be measured with a measuring tape. | Week 0 (baseline) | 
| Hip circumference | Hip circumference will be measured with a measuring tape. | Week 8 | 
| Hip circumference | Hip circumference will be measured with a measuring tape. | Week 16 (end of intervention) | 
| Neck circumference | Neck circumference will be measured with a measuring tape. | Week 0 (baseline) | 
| Neck circumference | Neck circumference will be measured with a measuring tape. | Week 8 | 
| Neck circumference | Neck circumference will be measured with a measuring tape. | Week 16 (end of intervention) | 
| Waist circumference | Waist circumference will be measured with a measuring tape. | Week 0 (baseline) | 
| Waist circumference | Waist circumference will be measured with a measuring tape. | Week 8 | 
| Waist circumference | Waist circumference will be measured with a measuring tape. | Week 16 (end of intervention) | 
| Abdomen circumference | Abdomen circumference will be measured with a measuring tape. | Week 0 (baseline) | 
| Abdomen circumference | Abdomen circumference will be measured with a measuring tape. | Week 8 | 
| Abdomen circumference | Abdomen circumference will be measured with a measuring tape. | Week 16 (end of intervention) | 
| Arm circumference | Arm circumference will be measured with a measuring tape. | Week 0 (baseline) | 
| Arm circumference | Arm circumference will be measured with a measuring tape. | Week 8 | 
| Arm circumference | Arm circumference will be measured with a measuring tape. | Week 16 (end of intervention) | 
| Midthigh circumference | Midthigh circumference will be measured with a measuring tape. | Week 0 (baseline) | 
| Midthigh circumference | Midthigh circumference will be measured with a measuring tape. | Week 8 | 
| Midthigh circumference | Midthigh circumference will be measured with a measuring tape. | Week 16 (end of intervention) | 
| Midcalf circumference | Midcalf circumference will be measured with a measuring tape. | Week 0 (baseline) | 
| Midcalf circumference | Midcalf circumference will be measured with a measuring tape. | Week 8 | 
| Midcalf circumference | Midcalf circumference will be measured with a measuring tape. | Week 16 (end of intervention) | 
| Triceps skinfold | Triceps skinfold will be measured with a caliper. | Week 0 (baseline) | 
| Triceps skinfold | Triceps skinfold will be measured with a caliper. | Week 8 | 
| Triceps skinfold | Triceps skinfold will be measured with a caliper. | Week 16 (end of intervention) | 
| Thigh skinfold | Thigh skinfold will be measured with a caliper. | Week 0 (baseline) | 
| Thigh skinfold | Thigh skinfold will be measured with a caliper. | Week 8 | 
| Thigh skinfold | Thigh skinfold will be measured with a caliper. | Week 16 (end of intervention) | 
| Medial calf skinfold | Medial calf skinfold will be measured with a caliper. | Week 0 (baseline) | 
| Medial calf skinfold | Medial calf skinfold will be measured with a caliper. | Week 8 | 
| Medial calf skinfold | Medial calf skinfold will be measured with a caliper. | Week 16 (end of intervention) | 
| Blood pressure | Systolic and diastolic blood pressure will be measured with a tensiometer. | Week 0 (baseline) | 
| Blood pressure | Systolic and diastolic blood pressure will be measured with a tensiometer. | Week 8 | 
| Blood pressure | Systolic and diastolic blood pressure will be measured with a tensiometer. | Week 16 (end of intervention) | 
| Serum glucose | Fasting serum glucose will be measured after overnight fast. | Week 0 (baseline) | 
| Serum glucose | Fasting serum glucose will be measured after overnight fast. | Week 16 (end of intervention) | 
| Serum insulin | Fasting serum insulin will be measured after overnight fast. | Week 0 (baseline) | 
| Serum insulin | Fasting serum insulin will be measured after overnight fast. | Week 16 (end of intervention) | 
| Oral Glucose Tolerance Test | Oral Glucose Tolerance Test will be carried out after overnight fast. | Week 0 (baseline) | 
| Oral Glucose Tolerance Test | Oral Glucose Tolerance Test will be carried out after overnight fast. | Week 16 (end of intervention) | 
| Lipid metabolism biomarkers | Serum free fatty acids, triglycerides, total cholesterol, LDL-cholesterol and HDL-cholesterol concentrations will be measured after an overnight fast. | Week 0 (baseline) | 
| Lipid metabolism biomarkers | Serum free fatty acids, triglycerides, total cholesterol, LDL-cholesterol and HDL-cholesterol concentrations will be measured after an overnight fast. | Week 16 (end of intervention) | 
| Ketone bodies | Ketone bodies concentrations will be measured after an overnight fast. | Week 0 (baseline) | 
| Ketone bodies | Ketone bodies concentrations will be measured after an overnight fast. | Week 16 (end of intervention) | 
| Thyroid function (body metabolism) | TSH (thyroid-stimulating hormone), T3 and T4 hormones will be evaluated with ELISA kits | Week 0 (baseline) | 
| Thyroid function (body metabolism) | TSH (thyroid-stimulating hormone), T3 and T4 hormones will be evaluated with ELISA kits | Week 16 (end of intervention) | 
| Cardiovascular risk biomarkers | PAI-1 (plasminogen activator inhibitor-1), ADMA (asymmetric dimethylarginine) and VEGF (vascular endothelial growth factor) will be measured in plasma using ELISA kits | Week 0 (baseline) | 
| Cardiovascular risk biomarkers | PAI-1 (plasminogen activator inhibitor-1), ADMA (asymmetric dimethylarginine) and VEGF (vascular endothelial growth factor) will be measured in plasma using ELISA kits | Week 16 (end of intervention) | 
| Inflammation biomarkers | TNF-α (tumour necrosis factor-alpha), IL-6 (interleukin 6), C-reactive protein, serum A-amyloid, leptin, adiponectin, chemerin will be measured by ELISA kits | Week 0 (baseline) | 
| Inflammation biomarkers | TNF-α (tumour necrosis factor-alpha), IL-6 (interleukin 6), C-reactive protein, serum A-amyloid, leptin, adiponectin, chemerin will be measured in plasma by ELISA kits | Week 16 (end of intervention) | 
| Satiety and eating behavior traits | Satiety will be also estimated by using a VAS (visual analogue scale) questionnaire and eating behavior traits will be also evaluated with validated questionnaires | Week 0 (baseline) | 
| Satiety and eating behavior traits | Satiety will be also estimated by using a VAS (visual analogue scale) questionnaire and eating behavior traits will be also evaluated with validated questionnaires | Week 16 (end of intervention) | 
| Plasma adipokines and myo-kines | CT-1, irisin, FGF21 (fibroblast growth factor 21) and meteorin-like will be measured using ELISA kits | Week 0 (baseline) | 
| Plasma adipokines and myo-kines | CT-1, irisin, FGF21 (fibroblast growth factor 21) and meteorin-like will be measured using ELISA kits | Week 16 (end of intervention) | 
| Plasma lipids and bioactive lipid mediators | Lipidomic profile will be measured using targeted metabolomic-lipidomics by HPLC-MS (high pressure liquid chromatography-mass spectrometry). | Week 0 (baseline) | 
| Plasma lipids and bioactive lipid mediators | Lipidomic profile will be measured using targeted metabolomic-lipidomics by HPLC-MS (high pressure liquid chromatography-mass spectrometry). | Week 16 (end of intervention) | 
| Adipose tissue gene profiling | A biopsy (2 g) of subcutaneous abdominal periumbilical area adipose tissue will be obtained by liposuction under local anesthesia. RNA expression will be measured by RNA-seq or GeneChip Human Gene 2.1 ST Array (Affymetrix). | Week 0 (baseline) | 
| Adipose tissue gene profiling | A biopsy (2 g) of subcutaneous abdominal periumbilical area adipose tissue will be obtained by liposuction under local anesthesia. RNA expression will be measured by RNA-seq or GeneChip Human Gene 2.1 ST Array (Affymetrix). | Week 16 (end of intervention) | 
| Adipose tissue miRNA profiling | MiRNA expression will be measured by RNA-seq or GeneChip miRNA 4.0 Array (Affymetrix) in subcutaneous abdominal adipose tissue biopsies. | Week 0 (baseline) | 
| Adipose tissue miRNA profiling | MiRNA expression will be measured by RNA-seq or GeneChip miRNA 4.0 Array (Affymetrix) in subcutaneous abdominal adipose tissue biopsies. | Week 16 (end of intervention) | 
| Bioactive lipid mediators involved in inflammation in adipose tissue | Lipidomic profile will be measured using targeted metabolomic-lipidomics by HPLC-MS | Week 0 (baseline) | 
| Bioactive lipid mediators involved in inflammation in adipose tissue | Lipidomic profile will be measured using targeted metabolomic-lipidomics by HPLC-MS | Week 16 (end of intervention) | 
| Determination of telomeres length | Telomeres length will be measured in genomic DNA extracted from human peripheral blood and adipose tissue samples with a real-time quantitative PCR (polymerase chain reaction) approach. | Week 0 (baseline) | 
| Determination of telomeres length | Telomeres length will be measured in genomic DNA extracted from human peripheral blood and adipose tissue samples with a real-time quantitative PCR (polymerase chain reaction) approach. | Week 16 (end of intervention) | 
| Characterization of gut microbiota | Feces will collected and gut microbiota profiling will be carried out by high-throughput 16S (Svedberg units) rDNA (ribosomal deoxyribonucleic acid) amplicon sequencing approach. | Week 0 (baseline) | 
| Characterization of gut microbiota | Feces will collected and gut microbiota profiling will be carried out by high-throughput 16S (Svedberg units) rDNA (ribosomal deoxyribonucleic acid) amplicon sequencing approach. | Week 16 (end of intervention) | 
| Urine metabolomic profile | Urine will be collected and urinary metabolomic profile will be also evaluated by a HPLC-MS approach. | Week 0 (baseline) | 
| Urine metabolomic profile | Urine will be collected and urinary metabolomic profile will be also evaluated by a HPLC-MS approach. | Week 16 (end of intervention) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin resistance, Exercise, Omega-3 fatty acids, Adipose tissue