Combination of Intermittent Hypoxic Exposure and Exercise Improves Body Composition and Glucose Tolerance in High-Fat Diet-Induced Obese Mice.

purposeTo determine the independent effects of moderate-intensity exercise training and intermittent normobaric hypoxic exposure and whether their combination provides additional improvements in body composition, energy metabolism, and glucose homeostasis in high-fat diet (HFD)-induced obese mice.

methodsMale Institute of Cancer Research mice were fed an HFD for 7 wk to induce obesity, then assigned to sedentary normoxia (SED+NOR), sedentary hypoxia (SED+HYP), exercise normoxia (EXE+NOR), or combined exercise plus hypoxia (EXE+HYP) for 5 wk. Hypoxic exposure was applied under normobaric conditions by reducing inspired oxygen fraction (FiO 2 = 12%) for 12 h/d during the inactive phase, whereas exercise was performed during the active phase as speed-defined moderate-intensity treadmill running (5 d/wk) under normoxia. Body composition was assessed by dual-energy X-ray absorptiometry before and after the intervention. Glucose regulation was evaluated using fasting blood glucose, circulating insulin levels, oral glucose tolerance test, and HOMA-IR. Resting gas exchange and substrate oxidation were assessed to characterize energy metabolism. Skeletal muscle proteins related to substrate metabolism and glucose transport were measured by immunoblotting.

resultsExercise training and intermittent hypoxic exposure improved obesity-associated metabolic impairments via distinct mechanisms. Exercise primarily reduced fat mass and improved glucose tolerance, accompanied by increased skeletal muscle GLUT4 abundance. Hypoxic exposure improved insulin sensitivity and systemic glucose regulation (lower insulin and HOMA-IR), despite limited effects on body weight. Notably, the combined EXE+HYP intervention produced the most pronounced overall improvements, including greater benefits in body composition and resting carbohydrate utilization compared with either intervention alone. In skeletal muscle, EXE+HYP increased oxidative metabolism-related protein expression relative to sedentary HFD controls.

conclusionsIntermittent normobaric hypoxic exposure and moderate-intensity exercise training provide complementary metabolic benefits in HFD-induced obese mice, and their combination yields additional improvements in key markers of body composition and glucose homeostasis. These findings support integrating hypoxic exposure with exercise as a potential nonpharmacological strategy to optimize metabolic health and motivate further mechanistic and translational studies.