Introduction 1 3 5 6 9 10 11 13 14 The construction design of our facility with normobaric hypoxic climate rooms allows pretending hypoxic conditions without actually running the rooms in hypoxic climate (sham hypoxia) and to perform a single blind randomized controlled weight loss study in simulated altitude. 2 Materials and methods Site 2 2 1 Fig. 1 2  Subjects 2 3 Fig. 2 Mean age (SD), weight, and body mass index (BMI) of the subjects who finished the trial in the hypoxia group  Fig. 3 Mean Age, weight, and BMI of the subjects who finished the trial in the sham hypoxia group  2 −1 −1 2 −1 −1 Study parameters Training period 2 −1 −1 2 2 2 Statistical analysis t p Ethics and informed consent Results All 20 subjects who were included in the training sessions finished the study without problems. No adverse side effects were reported by the subjects, including no signs of acute mountain sickness in those who exercised in 15.2 vol.% oxygen level. 2 Because of the neutral smell of the air-conditioned air, subjects could not tell if they are in hypoxia or sham hypoxia. More than 50% of the subjects guessed wrongly as to which group they belong. p 4 5 p Fig. 4 Mean (SD) weight loss after 7 weeks in the hypoxia group vs the sham hypoxia group  Fig. 5 y x  p 6 7 Fig. 6 Mean (SD) reduction and increase in triglycerides values of the hypoxia vs sham hypoxia group  Fig. 7 HDL  The healthy subjects of both groups were not diabetics. They had HbA1C levels on the edge but still in normal values (mean 5.67 and 5.47%), and those levels did not change after the training period of 8 weeks. Discussion The here presented study on fat metabolism and weight loss in mild to moderate hypoxia is, to our knowledge, the first one with a sham hypoxia control protocol. 2 2 There are, due to the nature of the study and above that, several limitations, which have to be addressed. The number of subjects is not big enough to show a reduction in BMI, and power analysis shows that we would need about 32 subjects to have a significant BMI reduction. We wanted to get more subjects into the study, but the reduction of subjects to a limited number due to time restrictions and willingness is a common problem in weight loss protocols with obese people. The difference in weight loss in mean with 1.14 kg seems, for 8 weeks of training, not really a lot. However, several subjects did significantly lose more weight in the hypoxia group, and the mean bodyweight loss is not due to natural swings in weight change. This also happened although the hypoxia group trained at a slightly lower wattage due to a slightly increased heart frequency in hypoxia. We cannot fully exclude that the normoxia group decreased body fat and increased muscle mass due to the slightly higher level of muscle load, but it seems unlikely with this very low intense training. Because we did not put our subjects on a stringent diet, there might have been the chance that some individuals did eat more than normally and some less. Keeping the subjects on their routine food seemed to us the natural choice of being uninfluenced in the weight change by a special nutritional diet. The other point is that weight loss in hypoxia might be caused by reduced food intake, and that was a part of the study. To let the subjects reduce their food intake, you have to have them on a longer leash. This is especially true if leptin and hypothalamic signals come into play and might let subjects be less hungry, respectively, less hungry for fat. To achieve more accuracy, the only chance would be to exactly control the nutrition of all subjects already before the study and during the training period. To do this, subjects have to be under full supervision all the time. This is an almost impossible achievement in ambulatory care or with independent volunteers. 11 14 2 13 14 14 16 17 6 10 15 In conclusion, there is more and more evidence that even mild moderate hypoxia in comfortable simulated altitude, if combined with exercise, leads to weight loss. Weight loss regimes with exercise and diets or just exercise could be combined with normobaric hypoxia in the future. Future investigations should include whether the stay in moderate hypoxia alone without exercise increases the weight loss and if such a regimen would still be safe.