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      Living at Higher Altitude and Incidence of Overweight/Obesity: Prospective Analysis of the SUN Cohort

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          Abstract

          Background

          Residence at high altitude has been associated with lower obesity rates probably due to hypoxia conditions. However, there is no evidence of this association in a free-living population.

          Objectives

          We assessed the association between the altitude where each participant of a Spanish cohort (the SUN Project) was living and the incidence of overweight/obesity.

          Methods

          The SUN Project is a dynamic, prospective, multipurpose cohort of Spanish university graduates with a retention rate of 89%. We included in the analysis 9 365 participants free of overweight/obesity at baseline. At the baseline questionnaire, participants reported their postal code and the time they had been living in their city/village. We imputed the altitude of each postal code according to the data of the Spanish National Cartographic Institute and categorized participants in tertiles. We used Cox regression models to adjust for potential confounding variables.

          Results

          During a median follow-up of 10 years, we identified 2 156 incident cases of overweight/obesity. After adjusting for sex, age, time of residence at current city, baseline body mass index, physical activity, sedentarism and years of education (≤ 3 years, ≥ 4 years, Master/PhD), those participants in the third tertile (>456 m) exhibited a statistically significant 14% reduction in the risk of developing overweight/obesity in comparison to those in the first tertile (<124 m) (adjusted HR = 0.86; 95% CI: 0.77, 0.96).

          Conclusions

          Living in cities of higher altitude was inversely associated with the risk of developing overweight/obesity in a cohort of Spanish university graduates.

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          Most cited references27

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          High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein.

          Hypoxic pulmonary vasoconstriction is associated with but may not be sufficient for the development of high-altitude pulmonary oedema (HAPO). Hypoxia is known to induce an inflammatory response in immune cells and endothelial cells. It has been speculated that hypoxia-induced inflammatory cytokines at high altitude may contribute to the development of HAPO by causing capillary leakage in the lung. We were interested if such an inflammatory response, possibly involved in a later development of HAPO, is detectable at high altitude in individuals without HAPO. We examined the plasma levels of interleukin 6 (IL-6), interleukin 1 receptor antagonist (IL-1ra) and C-reactive protein (CRP) in two independent studies: study A, Jungfraujoch, Switzerland, three overnight stays at 3458 m, n=12; study B: Capanna Regina Margherita, Italy, 3 overnight stays at 3647 m and one overnight stay at 4559 m, n=10. In both studies, probands showed symptoms of acute mountain sickness but no signs of HAPO. At the Jungfraujoch, IL-6 increased from 0.1+/-0.03 pg/ml to 2. 0+/-0.5 pg/ml (day 2, P=0.03), IL-1ra from 101+/-21 to 284+/-73 pg/ml (day 2, P=0.01), and CRP from 1.0+/-0.4 to 5.8+/-1.5 micrograms/ml (day 4, P=0.01). At the Capanna Margherita, IL-6 increased from 0. 5+/-0.2 pg/ml to 2.0+/-0.8 pg/ml (P=0.02), IL-1ra from 118+/-25 to 213+/-28 pg/ml (P=0.02), and CRP from 0.4+/-0.03 to 3.5+/-1.1 micrograms/ml (P=0.03). IL-8 was below the detection limit of the ELISA (<25 pg/ml) in both studies. The increase of IL-6 and IL-1ra in response to high altitude was delayed and preceded the increase of CRP. We conclude that: (1) circulating IL-6, IL-1ra and CRP are upregulated in response to hypobaric hypoxic conditions at high altitude, and (2) the moderate systemic increase of these inflammatory markers may reflect considerable local inflammation. The existence and the kinetics of high altitude-induced cytokines found in this study support the hypothesis that inflammation is involved in the development of HAPO. Copyright 2000 Academic Press.
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            Hypoxia and adipocyte physiology: implications for adipose tissue dysfunction in obesity.

            Hypoxia develops in white adipose tissue in obese mice, resulting in changes in adipocyte function that may underpin the dysregulation that leads to obesity-associated disorders. Whether hypoxia occurs in adipose tissue in human obesity is unclear, with recent studies contradicting earlier reports that this was the case. Adipocytes, both murine and human, exhibit extensive functional changes in culture in response to hypoxia, which alters the expression of up to 1,300 genes. These include genes encoding key adipokines such as leptin, interleukin (IL)-6, vascular endothelial growth factor (VEGF), and matrix metalloproteinase-2 (MMP-2), which are upregulated, and adiponectin, which is downregulated. Hypoxia also inhibits the expression of genes linked to oxidative metabolism while stimulating the expression of genes associated with glycolysis. Glucose uptake and lactate release by adipocytes are both stimulated by hypoxia, and insulin sensitivity falls. Preadipocytes and macrophages in adipose tissue also respond to hypoxia. The hypoxia-signaling pathway may provide a new target for the treatment of obesity-associated disorders.
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              Hypoxia, energy balance and obesity: from pathophysiological mechanisms to new treatment strategies.

              High altitude exposure is often accompanied by weight loss. Postulated mechanisms are a reduction of nutritional energy intake, a reduction of intestinal energy uptake from impaired intestinal function and increased energy expenditure. Beyond the field of altitude, there are good reasons for renewed interest in the relationship between hypoxia and energy balance. The increasing prevalence of obesity and associated comorbidities represent a major health concern. Obesity is frequently associated with sleep disorders leading to intermittent systemic hypoxia with deleterious cardiovascular and metabolic consequences. Hypoxic regions may be present within hypertrophic white adipose tissue leading to chronic systemic inflammation. Among the increasing number of people commuting to altitude for work or leisure, obesity is a risk factor for acute mountain sickness. Paradoxically, exposure to intermittent hypoxia might be considered as a means to lose body mass and to improve metabolic risk factors. Daytime exposure to intermittent hypoxia has been used to treat hypertension in former Soviet Union countries and is now being experimented elsewhere. Such intermittent hypoxic exposure at rest or during exercise may lead to improvement in body composition and health status with improved exercise tolerance, metabolism and systemic arterial pressure. Future research should confirm whether hypoxic training could be a new treatment strategy for weight loss and comorbidities in obese subjects and elucidate the underlying mechanisms and signalling pathways. © 2013 The Authors. obesity reviews © 2013 International Association for the Study of Obesity.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                3 November 2016
                2016
                : 11
                : 11
                : e0164483
                Affiliations
                [1 ]University of Navarra, Department of Preventive Medicine and Public Health, School of Medicine, Pamplona, Spain
                [2 ]IDISNA Navarra’s Health Research Institute, Pamplona, Spain
                [3 ]CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
                [4 ]Harvard TH Chan School of Public Health, Boston, United States of America
                [5 ]University of Navarra, Department of History, Art History, and Geography, School of Humanities and Social Sciences, Pamplona, Spain
                [6 ]University of Navarra, Department of Nutrition and Food Sciences and Physiology, School of Pharmacy, Pamplona, Spain
                Hunter College, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: MAMG PGM JAM MBR.

                • Formal analysis: JDG MBR.

                • Funding acquisition: MAMG MBR.

                • Methodology: MBR.

                • Project administration: MAMG MBR.

                • Software: JJPI.

                • Supervision: MAMG MBR.

                • Validation: MAMG MBR.

                • Writing – original draft: JDG MAMG MBR.

                • Writing – review & editing: JDG MAMG JJPI PGM JAM MBR.

                Author information
                http://orcid.org/0000-0003-0351-4018
                Article
                PONE-D-16-14860
                10.1371/journal.pone.0164483
                5094724
                27812092
                0be529f8-f339-430c-a4d1-0c720d4fa0e2
                © 2016 Díaz-Gutiérrez et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 12 April 2016
                : 25 September 2016
                Page count
                Figures: 2, Tables: 4, Pages: 13
                Funding
                The Seguimiento Universidad de Navarra (SUN) study has received funding from the Spanish Ministry of Health and European Regional Development Fund (FEDER) (Grants PI10/02993, PI10/02658, PI13/00615, PI14/01668, PI14/01798, PI14/1764, RD06/0045, G03/140), the Navarra Regional Government (45/2011, 122/2014), and the University of Navarra. Funding sources had no role in study design, data collection, analysis, interpretation of results, and in the writing of the manuscript. All authors were and are independent from funders.
                Categories
                Research Article
                Biology and Life Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Obesity
                Medicine and Health Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Obesity
                Medicine and Health Sciences
                Pulmonology
                Medical Hypoxia
                Medicine and Health Sciences
                Public and Occupational Health
                Physical Activity
                People and Places
                Population Groupings
                Educational Status
                Graduates
                Biology and Life Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Weight Gain
                Medicine and Health Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Weight Gain
                Biology and Life Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Medicine and Health Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Biology and Life Sciences
                Biochemistry
                Hormones
                Peptide Hormones
                Leptin
                Physical Sciences
                Chemistry
                Chemical Elements
                Oxygen
                Custom metadata
                Data from this manuscript can be located in Figshare at https://dx.doi.org/10.6084/m9.figshare.3984466.v1.

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