Objective To explore the mechanism of the ghrelin-GHSR pathway to alleviate obesity in hypoxic- exercise mice by observing ghrelin level changes in the gastric tissue and GHSR levels in the hypothalamic tissue. Methods Male C57BL/ 6J mice were randomly divided into the control group ( C, n = 8) or high-fat diet group ( H, n = 52) to establish the obesity model. After 8 weeks, the H group was further divided into the obese control group (HC), obese exercise group (HE), obese hypoxic exposure group (HH) and obese hypoxic exercise group (HHE). The HE and HHE groups were intervened by mid-intensity treadmill training while under intermittent hypoxic exposure ( 11. 2% oxygen). Weight and food intake were recorded weekly. Total cholesterol (TC), triglycerides (TG) and glucose levels in the serum were tested as well as the total ghrelin levels; the expression of GHSR mRNA in the hypothalamic tissue and ghrelin mRNA in the gastric tissue were detected via RT-PCR. GHSR and NPY in the hypothalamic tissue and the ghrelin, Goat and HIF- 2α protein expressions in the gastric tissue were detected via western blot after 4 weeks of intervention. Results (1) The HE, HH and HHE group weights were significantly lower than those of the HC group after intervention. In the initial stage of hypoxic intervention, the food intake decreased in the HH and HHE groups, and the food intake in the obese groups gradually became nearly the same as the intervention time increased. ( 2) The serum levels of the HC group were significantly higher than those of the C group; the TC level in the HH group significantly decreased, and the glucose levels in the HE, HH and HHE groups significantly decreased. The serum total ghrelin levels in the HH and HHE groups were significantly lower than those of the HC group. (3) Compared with the C group, the GHSR mRNA level in the hypothalamic tissue and the ghrelin mRNA level in the gastric tissue of the HC group were significantly decreased. The GHSR mRNA levels in the HH and HHE groups were significantly higher than those in the HC group. (4) In the hypothalamic tissue, the GHSR protein levels in the HE, HH and HHE groups and the NPY protein levels in the HE and HHE groups were significantly higher than those of the HC group. (5) In the gastric tissue, the ghrelin protein levels in the HE, HH and HHE groups, the Goat protein levels in the HE and HHE groups and the HIF-2α protein levels in the HH and HHE groups were significantly higher than those in the HC group. Conclusions Hypoxic training affects glucose and lipid metabolism by regulating the ghrelin-GHSR signaling pathway in the gastric tissue to control weight in obese mice.