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Background: Exercise and diet are the cornerstones for the treatment of obesity in obese children and adolescents. However, compensatory changes in appetite and energy expenditure elicited by exercise and dieting make it hard to maintain a reduced weight over the longterm. The anorexic effect of hypoxia can be potentially utilized to counteract this compensatory increase, thereby enhancing the success of weight loss. The purpose of the study is to assess the effectiveness of four week intermittent hypoxia exposure added to a traditional exercise and diet intervention on inducing short- and longterm weight loss in obese adolescents., Methods/design: In this randomized parallel group controlled clinical trial, 40 obese adolescents (20 boys and 20 girls, 11 to 15-years-old), will be recruited from a summer weight loss camp at the Shanghai University of Sport, China. Participants will be stratified by gender and randomly assigned to either the control group or the hypoxia group. During the four-week intervention period, both groups will exercise and eat a balanced diet. Additionally, the control group will sleep in normal conditions, while the hypoxia group will sleep in a normobaric hypoxia chamber (sleep high and train low). The primary outcome will be body composition and the main secondary outcomes will be the circulating levels of appetite regulatory gastrointestinal hormones. All the outcome measures will be assessed at baseline, after the four-week intervention, and at two months follow-up., Discussion: Our study will be the first to evaluate the effectiveness of 'sleep high and train low' on short- and longterm weight loss among obese adolescents. A potential mechanism for the appetite regulatory effect of hypoxia will also be explored. The results of the study will provide an evidence-based recommendation for the use of hypoxia in a weight loss intervention among obese children and adolescents. Furthermore, the clarification of mechanisms leading to weight loss in 'sleep high and train low' might provide information for the development of new strategies in combating obesity., Trial Registration: This trial was registered on 10 January 2014 at the Chinese Clinical Trial Registry with the registration number: ChiCTR-TRC-14004106.

Tibetan natives have lived on the Tibetan plateau (altitude ∼ 4,000 m) for at least 25,000 years, and as such they are adapted to life and reproduction in a hypoxic environment. Recent studies have identified two genetic loci, EGLN1 and EPAS1, that have undergone natural selection in Tibetans, and further demonstrated an association of EGLN1/EPAS1 genotype with hemoglobin concentration. Both genes encode major components of the hypoxia-inducible factor (HIF) transcriptional pathway, which coordinates an organism's response to hypoxia. Patients living at sea level with genetic disease of the HIF pathway have characteristic phenotypes at both the integrative-physiology and cellular level. We sought to test the hypothesis that natural selection to hypoxia within Tibetans results in related phenotypic differences. We compared Tibetans living at sea level with Han Chinese, who are Tibetans' most closely related major ethnic group. We found that Tibetans had a lower hemoglobin concentration, a higher pulmonary ventilation relative to metabolism, and blunted pulmonary vascular responses to both acute (minutes) and sustained (8 h) hypoxia. At the cellular level, the relative expression and hypoxic induction of HIF-regulated genes were significantly lower in peripheral blood lymphocytes from Tibetans compared with Han Chinese. Within the Tibetans, we found a significant correlation between both EPAS1 and EGLN1 genotype and the induction of erythropoietin by hypoxia. In conclusion, this study provides further evidence that Tibetans respond less vigorously to hypoxic challenge. This is evident at sea level and, at least in part, appears to arise from a hyporesponsive HIF transcriptional system.