Infertility occurs more frequently in overweight and obese women with disruption of regular menstrual cycles and reproductive hormone profiles. Although the clinical impact of obesity on female reproduction has been investigated with improvement by reducing weight, the pathological molecular mechanism of such infertility is still not clear. A simple overeating obese mouse line (MC4R KO) is characterized by hyperphagia, obesity, hyperinsulinemia, progressive insulin resistance, NAFLD, and development of infertility. We demonstrated a remarkable development of female reproductive hormone disturbance, with dysregulated rodent oestrous cycles, and significantly reduced formation of corpus luteum (CL). At the same time, hyperinsulinemia occurred before any significant difference in fasting blood glucose levels. Dapagliflozin is an SGLT2 inhibitor used clinically in the treatment of obese 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 oestrous cycle was partially but 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.
This work was supported by NHMRC, CSC of China and The University of Queensland.