Semaglutide ameliorates metabolic disorders in offspring via regulation of oocyte ROS of pre-pregnancy obesity mice

Pre-pregnancy obesity (PPO) seriously threatens the health of both mother and offspring. Pre-pregnancy weight management is particularly important for the prevention of metabolic diseases in offspring. Semaglutide is one of the most effective glucagon-like peptide-1 agonizts for the management of obesity and metabolic diseases, but little is known about its effect on the long-term health of offspring. In this study we investigated the effects of semaglutide administered before pregnancy on the offspring health from PPO mice. PPO mice model was established by feeding with high-fat diet for 16 weeks, and then injected with semaglutide (30 nmol/kg^-1·d^-1, sc.) for 22 days before pregnancy. After the treatment, the mice were mated with normal males or underwent in vitro fertilization (IVF) for offspring reproduction. We showed that the semaglutide treatment not only improved the lipid and glucose metabolic disorders and fertility of PPO mice, but also significantly reversed the overweight, impaired energy balance, adipose inflammatory state, lipid and glucose metabolic disorders and insulin resistance of their IVF offspring. By conducting RNA-seq analysis, SOD activity and malondialdehyde assays in ovaries, as well as ROS staining in oocytes, we revealed that the semaglutide treatment reduced the elevated oxidative stress in ovaries and high ROS levels in oocytes from PPO mice, possibly through activating the PI3K/AKT pathway and improving the state of SOD. Interestingly, incubation of oocytes from semaglutide-treated dams with H₂O₂ (100 μM) in vitro during IVF blocked the protective effects of semaglultide against the metabolic disorders in the offspring. In conclusion, semaglutide treatment before pregnancy effectively alleviates obesity-related metabolic disorders in offspring. The regulation of ROS in oocytes plays a crucial role in the protective effects of semaglutide.