Infertility occurs more significantly in overweight and obese women with disruption of reproductive hormone profiles. Although the clinical impact of obesity on female infertility has been extensively studied with clearly demonstrated improvement by reducing weight, the effective medical treatment is still a distance away due to unclear pathological molecular mechanisms. MC4R KO mice are an obese model with reported hyperphagia, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and hepatic steatosis. This mouse line was an overeating obese model with remarkable female reproductive hormone disturbance, dysregulated estrous cycle, and significantly reduced formation of corpus luteum (CL)1. Dapagliflozin is an SGLT2 inhibitor used clinically in the treatment of diabetes with the demonstrated improvement of obesity in this mouse model2. In this experiment, dapagliflozin treatment (1 mg/kg/day for 14 weeks from 14-week-old) of MC4R KO female mice improved glucose tolerance, restored partially the pulsatile profiles of growth hormone (GH) and luteinizing hormone (LH), including the amount of pulsatile secretion, mean pulse mass, and pulsatile secretion, and changed approximate entropy and secretion mode. The estrous cycle was partially and significantly normalized, and the number of CL was markedly increased in female MC4R KO mice by the dapagliflozin treatment. The expression of genes related to reproductive regulatory factors and hormones in the hypothalamic and pituitary was significantly elevated by the dapagliflozin treatment. Based on the above data, it may be concluded that dapagliflozin recovers reproductive function in an obese mouse model through recovering reproductive endocrine profiles. Dapagliflozin treatment may potentially be useful in the treatment of infertility in clinic obese patients.