Hypoxic Training in Obese Mice Improves Metabolic Disorder

Abstract

Hypoxic training has been reported to lower obesity morbidity without clear underlying mechanisms. This study investigates the effect of hypoxic training on metabolic changes, particularly, on liver metabolism of high fat diet (HFD)-induced obese mice. We compared the hypoxic training group with normoxic sedentary, normoxic training, and hypoxic sedentary groups. Body weight, fat mass, glucose tolerance and liver physiology were determined after 4 weeks intervention. In both normoxic training and hypoxic training groups, body weight was lower than the normoxic sedentary group, with less fat mass. Insulin sensitivity was improved after hypoxic training. Moreover, liver metabolomics revealed insights into the protective effect of hypoxic training on HFD-induced fatty liver. Taken together, these findings provide a molecular metabolic mechanism for hypoxic training.

Keywords: hypoxic training; liver; metabolism; metabolomics; obesity.

Figure 1

Hypoxic training decreases body weight and fat mass. (A) Body weight curves of high-fat diet induced obese (DIO) mice on sedentary (S, n = 8), normoxia training (NT, n = 8), hypoxia (H, n = 10), and hypoxia + training (HT, n = 8) for 4 weeks. (B) Epididymal and perirenal fat mass in DIO mice after 4 weeks of sedentary (S, n = 8), normoxia training (NT, n = 7), hypoxia (H, n = 8), and hypoxia + training (HT, n = 8) treatment at 22 weeks of age. All data are presented as mean ± SEM. *p < 0.05, **p < 0.01, compared with sedentary (S) group mice.

Figure 2

Hypoxic training improves glucose hemostasis of HFD-fed mice. Plots for glucose tolerance tests (GTT, 2 g/kg BW, n = 7–8) in overnight fasted mice (A) and insulin tolerance tests (ITT, 1 U/kg BW, n = 7–8) in mice fasted for 6 h (B), respectively from mice in each group. (C,D) AUC values confirmed improvements of glucose tolerance in HT group mice and no difference of insulin tolerance in all the groups. All data are presented as Mean ± SEM, *p < 0.05, compared with sedentary (S) group mice, by two-way ANOVA.

Figure 3

Hypoxic training improves hepatocellular injury of HFD-fed mice. Serum ALT level was decreased in H and HT group (n = 7–8). All data are presented as Mean ± SEM, **p < 0.01, compared with sedentary (S) group mice; #p < 0.05, compared with normoxic training (NT) group mice, by two-way ANOVA.

Figure 4

Effect of hypoxic training on the level of lipid droplets in mice liver sections. Representative figures of liver Oil Red O Staining from respectively mice in each group (A–D). Representative figures of liver hematoxylin-eosin staining from respectively mice in each group (E–H). Scale bar: 50 um.

Figure 5

Effects of hypoxic training on glucose and lipid metabolism. Changes of metabolites in response to hypoxic training in mice (A). Data are shown as mean ± SEM, n = 8, *p < 0.05, **p < 0.01. (B) Summary of metabolic pathways associated with hypoxia training intervention. The italic metabolite represents the undetected metabolite, and the red font is the significantly increased metabolite of Group D vs. Group A. The pink box is glucose metabolism pathway, and the yellow box is lipid metabolism pathway.