Clinical trial NCT03300388: Obesity, Inflammation and Aging: Effects of Physical Exercise and Omega-3 Fatty Acids.
Official title: Dysfunction of Adipose Tissue in Obesity, Inflammation and Aging: Mechanisms and Effects of Physical Exercise and Omega-3 Fatty Acids.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Obesity
Aging
Inflammation
Keywords: Insulin resistance
Exercise
Omega-3 fatty acids
Adipose tissue
Lead sponsor: Clinica Universidad de Navarra, Universidad de Navarra
Sponsor class: OTHER
Collaborators: name: Ministerio de Economía y Competitividad, Spain
name: Centro de Estudios, Investigación y Medicina del Deporte
name: Instituto de Investigación Sanitaria de Navarra (IdiSNA)
First posted: 2017-10-03
Enrollment: 85
Sex: FEMALE
Minimum age (years): 55
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Fat mass reduction
timeFrame: Week 0 (baseline)
measure: Fat mass reduction
timeFrame: Week 16 (end of intervention)
Secondary outcomes:
measure: Evolution of fat mass reduction
timeFrame: Week 0 (baseline)
measure: Evolution of fat mass reduction
timeFrame: Week 2
measure: Evolution of fat mass reduction
timeFrame: Week 4
measure: Evolution of fat mass reduction
timeFrame: Week 6
measure: Evolution of fat mass reduction
timeFrame: Week 8
measure: Evolution of fat mass reduction
timeFrame: Week 10
measure: Evolution of fat mass reduction
timeFrame: Week 12
measure: Evolution of fat mass reduction
timeFrame: Week 14
measure: Evolution of fat mass reduction
timeFrame: Week 16 (end of intervention)
measure: Weight loss
timeFrame: Week 0 (baseline)
measure: Weight loss
timeFrame: Week 2
measure: Weight loss
timeFrame: Week 4
measure: Weight loss
timeFrame: Week 6
measure: Weight loss
timeFrame: Week 8
measure: Weight loss
timeFrame: Week 10
measure: Weight loss
timeFrame: Week 12
measure: Weight loss
timeFrame: Week 14
measure: Weight loss
timeFrame: Week 16 (end of intervention)
measure: Evolution of body composition
timeFrame: Week 0 (baseline)
measure: Evolution of body composition
timeFrame: Week 2
measure: Evolution of body composition
timeFrame: Week 4
measure: Evolution of body composition
timeFrame: Week 6
measure: Evolution of body composition
timeFrame: Week 8
measure: Evolution of body composition
timeFrame: Week 10
measure: Evolution of body composition
timeFrame: Week 12
measure: Evolution of body composition
timeFrame: Week 14
measure: Evolution of body composition
timeFrame: Week 16 (end of intervention)
measure: Hip circumference
timeFrame: Week 0 (baseline)
measure: Hip circumference
timeFrame: Week 8
measure: Hip circumference
timeFrame: Week 16 (end of intervention)
measure: Neck circumference
timeFrame: Week 0 (baseline)
measure: Neck circumference
timeFrame: Week 8
measure: Neck circumference
timeFrame: Week 16 (end of intervention)
measure: Waist circumference
timeFrame: Week 0 (baseline)
measure: Waist circumference
timeFrame: Week 8
measure: Waist circumference
timeFrame: Week 16 (end of intervention)
measure: Abdomen circumference
timeFrame: Week 0 (baseline)
measure: Abdomen circumference
timeFrame: Week 8
measure: Abdomen circumference
timeFrame: Week 16 (end of intervention)
measure: Arm circumference
timeFrame: Week 0 (baseline)
measure: Arm circumference
timeFrame: Week 8
measure: Arm circumference
timeFrame: Week 16 (end of intervention)
measure: Midthigh circumference
timeFrame: Week 0 (baseline)
measure: Midthigh circumference
timeFrame: Week 8
measure: Midthigh circumference
timeFrame: Week 16 (end of intervention)
measure: Midcalf circumference
timeFrame: Week 0 (baseline)
measure: Midcalf circumference
timeFrame: Week 8
measure: Midcalf circumference
timeFrame: Week 16 (end of intervention)
measure: Triceps skinfold
timeFrame: Week 0 (baseline)
measure: Triceps skinfold
timeFrame: Week 8
measure: Triceps skinfold
timeFrame: Week 16 (end of intervention)
measure: Thigh skinfold
timeFrame: Week 0 (baseline)
measure: Thigh skinfold
timeFrame: Week 8
measure: Thigh skinfold
timeFrame: Week 16 (end of intervention)
measure: Medial calf skinfold
timeFrame: Week 0 (baseline)
measure: Medial calf skinfold
timeFrame: Week 8
measure: Medial calf skinfold
timeFrame: Week 16 (end of intervention)
measure: Blood pressure
timeFrame: Week 0 (baseline)
measure: Blood pressure
timeFrame: Week 8
measure: Blood pressure
timeFrame: Week 16 (end of intervention)
measure: Serum glucose
timeFrame: Week 0 (baseline)
measure: Serum glucose
timeFrame: Week 16 (end of intervention)
measure: Serum insulin
timeFrame: Week 0 (baseline)
measure: Serum insulin
timeFrame: Week 16 (end of intervention)
measure: Oral Glucose Tolerance Test
timeFrame: Week 0 (baseline)
measure: Oral Glucose Tolerance Test
timeFrame: Week 16 (end of intervention)
measure: Lipid metabolism biomarkers
timeFrame: Week 0 (baseline)
measure: Lipid metabolism biomarkers
timeFrame: Week 16 (end of intervention)
measure: Ketone bodies
timeFrame: Week 0 (baseline)
measure: Ketone bodies
timeFrame: Week 16 (end of intervention)
measure: Thyroid function (body metabolism)
timeFrame: Week 0 (baseline)
measure: Thyroid function (body metabolism)
timeFrame: Week 16 (end of intervention)
measure: Cardiovascular risk biomarkers
timeFrame: Week 0 (baseline)
measure: Cardiovascular risk biomarkers
timeFrame: Week 16 (end of intervention)
measure: Inflammation biomarkers
timeFrame: Week 0 (baseline)
measure: Inflammation biomarkers
timeFrame: Week 16 (end of intervention)
measure: Satiety and eating behavior traits
timeFrame: Week 0 (baseline)
measure: Satiety and eating behavior traits
timeFrame: Week 16 (end of intervention)
measure: Plasma adipokines and myo-kines
timeFrame: Week 0 (baseline)
measure: Plasma adipokines and myo-kines
timeFrame: Week 16 (end of intervention)
measure: Plasma lipids and bioactive lipid mediators
timeFrame: Week 0 (baseline)
measure: Plasma lipids and bioactive lipid mediators
timeFrame: Week 16 (end of intervention)
measure: Adipose tissue gene profiling
timeFrame: Week 0 (baseline)
measure: Adipose tissue gene profiling
timeFrame: Week 16 (end of intervention)
measure: Adipose tissue miRNA profiling
timeFrame: Week 0 (baseline)
measure: Adipose tissue miRNA profiling
timeFrame: Week 16 (end of intervention)
measure: Bioactive lipid mediators involved in inflammation in adipose tissue
timeFrame: Week 0 (baseline)
measure: Bioactive lipid mediators involved in inflammation in adipose tissue
timeFrame: Week 16 (end of intervention)
measure: Determination of telomeres length
timeFrame: Week 0 (baseline)
measure: Determination of telomeres length
timeFrame: Week 16 (end of intervention)
measure: Characterization of gut microbiota
timeFrame: Week 0 (baseline)
measure: Characterization of gut microbiota
timeFrame: Week 16 (end of intervention)
measure: Urine metabolomic profile
timeFrame: Week 0 (baseline)
measure: Urine metabolomic profile
timeFrame: Week 16 (end of intervention)
Other outcomes:
Locations:
city: Pamplona
country: Spain
facility: Department of Nutrition, Food Science and Physiology. Centre for Nutrition Research.
state: Navarra
Study officials:
affiliation: University of Navarra
name: María J Moreno-Aliaga, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Navarra
name: Silvia Lorente-Cebrián, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Martinez-Fernandez L, Gonzalez-Muniesa P, Laiglesia LM, Sainz N, Prieto-Hontoria PL, Escote X, Odriozola L, Corrales FJ, Arbones-Mainar JM, Martinez JA, Moreno-Aliaga MJ. Maresin 1 improves insulin sensitivity and attenuates adipose tissue inflammation in ob/ob and diet-induced obese mice. FASEB J. 2017 May;31(5):2135-2145. doi: 10.1096/fj.201600859R. Epub 2017 Feb 10.
citation: Lopez-Yoldi M, Stanhope KL, Garaulet M, Chen XG, Marcos-Gomez B, Carrasco-Benso MP, Santa Maria EM, Escote X, Lee V, Nunez MV, Medici V, Martinez-Anso E, Sainz N, Huerta AE, Laiglesia LM, Prieto J, Martinez JA, Bustos M, Havel PJ, Moreno-Aliaga MJ. Role of cardiotrophin-1 in the regulation of metabolic circadian rhythms and adipose core clock genes in mice and characterization of 24-h circulating CT-1 profiles in normal-weight and overweight/obese subjects. FASEB J. 2017 Apr;31(4):1639-1649. doi: 10.1096/fj.201600396RR. Epub 2017 Jan 17.
citation: Laiglesia LM, Lorente-Cebrian S, Prieto-Hontoria PL, Fernandez-Galilea M, Ribeiro SM, Sainz N, Martinez JA, Moreno-Aliaga MJ. Eicosapentaenoic acid promotes mitochondrial biogenesis and beige-like features in subcutaneous adipocytes from overweight subjects. J Nutr Biochem. 2016 Nov;37:76-82. doi: 10.1016/j.jnutbio.2016.07.019. Epub 2016 Aug 26.
citation: Huerta AE, Prieto-Hontoria PL, Fernandez-Galilea M, Escote X, Martinez JA, Moreno-Aliaga MJ. Effects of dietary supplementation with EPA and/or alpha-lipoic acid on adipose tissue transcriptomic profile of healthy overweight/obese women following a hypocaloric diet. Biofactors. 2017 Jan 2;43(1):117-131. doi: 10.1002/biof.1317. Epub 2016 Aug 10.
citation: Huerta AE, Prieto-Hontoria PL, Sainz N, Martinez JA, Moreno-Aliaga MJ. Supplementation with alpha-Lipoic Acid Alone or in Combination with Eicosapentaenoic Acid Modulates the Inflammatory Status of Healthy Overweight or Obese Women Consuming an Energy-Restricted Diet. J Nutr. 2015 Apr 1;146(4):889S-896S. doi: 10.3945/jn.115.224105.
citation: Milagro FI, Moreno-Aliaga MJ, Martinez JA. FTO Obesity Variant and Adipocyte Browning in Humans. N Engl J Med. 2016 Jan 14;374(2):190-1. doi: 10.1056/NEJMc1513316. No abstract available.
citation: Prieto-Hontoria PL, Perez-Matute P, Fernandez-Galilea M, Lopez-Yoldi M, Sinal CJ, Martinez JA, Moreno-Aliaga MJ. Effects of alpha-lipoic acid on chemerin secretion in 3T3-L1 and human adipocytes. Biochim Biophys Acta. 2016 Mar;1861(3):260-8. doi: 10.1016/j.bbalip.2015.12.011. Epub 2015 Dec 22.
citation: Martinez-Fernandez L, Laiglesia LM, Huerta AE, Martinez JA, Moreno-Aliaga MJ. Omega-3 fatty acids and adipose tissue function in obesity and metabolic syndrome. Prostaglandins Other Lipid Mediat. 2015 Sep;121(Pt A):24-41. doi: 10.1016/j.prostaglandins.2015.07.003. Epub 2015 Jul 26.
citation: Mansego ML, Milagro FI, Zulet MA, Moreno-Aliaga MJ, Martinez JA. Differential DNA Methylation in Relation to Age and Health Risks of Obesity. Int J Mol Sci. 2015 Jul 24;16(8):16816-32. doi: 10.3390/ijms160816816.
citation: Huerta AE, Prieto-Hontoria PL, Fernandez-Galilea M, Sainz N, Cuervo M, Martinez JA, Moreno-Aliaga MJ. Circulating irisin and glucose metabolism in overweight/obese women: effects of alpha-lipoic acid and eicosapentaenoic acid. J Physiol Biochem. 2015 Sep;71(3):547-58. doi: 10.1007/s13105-015-0400-5. Epub 2015 Mar 28.
citation: Lorente-Cebrian S, Costa AG, Navas-Carretero S, Zabala M, Laiglesia LM, Martinez JA, Moreno-Aliaga MJ. An update on the role of omega-3 fatty acids on inflammatory and degenerative diseases. J Physiol Biochem. 2015 Jun;71(2):341-9. doi: 10.1007/s13105-015-0395-y. Epub 2015 Mar 11.
citation: Huerta AE, Navas-Carretero S, Prieto-Hontoria PL, Martinez JA, Moreno-Aliaga MJ. Effects of alpha-lipoic acid and eicosapentaenoic acid in overweight and obese women during weight loss. Obesity (Silver Spring). 2015 Feb;23(2):313-21. doi: 10.1002/oby.20966. Epub 2014 Dec 31.
citation: Gonzalez-Muniesa P, Marrades MP, Martinez JA, Moreno-Aliaga MJ. Differential proinflammatory and oxidative stress response and vulnerability to metabolic syndrome in habitual high-fat young male consumers putatively predisposed by their genetic background. Int J Mol Sci. 2013 Aug 22;14(9):17238-55. doi: 10.3390/ijms140917238.
citation: Lorente-Cebrian S, Costa AG, Navas-Carretero S, Zabala M, Martinez JA, Moreno-Aliaga MJ. Role of omega-3 fatty acids in obesity, metabolic syndrome, and cardiovascular diseases: a review of the evidence. J Physiol Biochem. 2013 Sep;69(3):633-51. doi: 10.1007/s13105-013-0265-4. Epub 2013 Jun 22.
citation: Lorente-Cebrian S, Bustos M, Marti A, Fernandez-Galilea M, Martinez JA, Moreno-Aliaga MJ. Eicosapentaenoic acid inhibits tumour necrosis factor-alpha-induced lipolysis in murine cultured adipocytes. J Nutr Biochem. 2012 Mar;23(3):218-27. doi: 10.1016/j.jnutbio.2010.11.018. Epub 2011 Apr 14.
citation: Marrades MP, Gonzalez-Muniesa P, Martinez JA, Moreno-Aliaga MJ. A dysregulation in CES1, APOE and other lipid metabolism-related genes is associated to cardiovascular risk factors linked to obesity. Obes Facts. 2010 Oct;3(5):312-8. doi: 10.1159/000321451. Epub 2010 Oct 15.
citation: Marrades MP, Gonzalez-Muniesa P, Arteta D, Martinez JA, Moreno-Aliaga MJ. Orchestrated downregulation of genes involved in oxidative metabolic pathways in obese vs. lean high-fat young male consumers. J Physiol Biochem. 2011 Mar;67(1):15-26. doi: 10.1007/s13105-010-0044-4. Epub 2010 Sep 30.
citation: Moreno-Aliaga MJ, Lorente-Cebrian S, Martinez JA. Regulation of adipokine secretion by n-3 fatty acids. Proc Nutr Soc. 2010 Aug;69(3):324-32. doi: 10.1017/S0029665110001801. Epub 2010 Jun 14.
citation: Lorente-Cebrian S, Bustos M, Marti A, Martinez JA, Moreno-Aliaga MJ. Eicosapentaenoic acid up-regulates apelin secretion and gene expression in 3T3-L1 adipocytes. Mol Nutr Food Res. 2010 May;54 Suppl 1:S104-11. doi: 10.1002/mnfr.200900522.
citation: Lorente-Cebrian S, Bustos M, Marti A, Martinez JA, Moreno-Aliaga MJ. Eicosapentaenoic acid stimulates AMP-activated protein kinase and increases visfatin secretion in cultured murine adipocytes. Clin Sci (Lond). 2009 Aug 14;117(6):243-9. doi: 10.1042/CS20090020.
citation: Perez-Echarri N, Perez-Matute P, Marcos-Gomez B, Marti A, Martinez JA, Moreno-Aliaga MJ. Down-regulation in muscle and liver lipogenic genes: EPA ethyl ester treatment in lean and overweight (high-fat-fed) rats. J Nutr Biochem. 2009 Sep;20(9):705-14. doi: 10.1016/j.jnutbio.2008.06.013. Epub 2008 Sep 30.