Melatonin protects against maternal obesity‐associated oxidative stress and meiotic defects in oocytes via the SIRT3‐SOD2‐dependent pathway

Abstract

Maternal obesity in humans is associated with poor outcomes across the reproductive spectrum. Emerging evidence indicates that these defects are likely attributed to factors within the oocyte. Although various molecules and pathways may contribute to impaired oocyte quality, prevention of fertility issues associated with maternal obesity is a challenge. Using mice fed a high-fat diet (HFD) as an obesity model, we document spindle disorganization, chromosome misalignment, and elevated reactive oxygen species (ROS) levels in oocytes from obese mice. Oral administration of melatonin to HFD mice not only reduces ROS generation, but also prevents spindle/chromosome anomalies in oocytes, consequently promoting the developmental potential of early embryos. Consistent with this finding, we find that melatonin supplement during in vitro maturation also markedly attenuates oxidative stress and meiotic defects in HFD oocytes. Finally, by performing morpholino knockdown and acetylation-mimetic mutant overexpression assays, we reveal that melatonin ameliorates maternal obesity-induced defective phenotypes in oocytes through the SIRT3-SOD2-dependent mechanism. In sum, our data uncover the marked beneficial effects of melatonin on oocyte quality from obese females; this opens a new area for optimizing culture system as well as fertility management.

Role of melatonin in sleep deprivation‐induced intestinal barrier dysfunction in mice

“…For example, previous studies reported in the rat that intraperitoneal injection of 15 mg/kg MT reduced gastrointestinal motility disorder caused by noise stress, while intraperitoneal injection of 40 mg/kg MT attenuated effectively methotrexate‐induced oxidative stress and small intestinal damage . Oral administration of 30 mg/kg MT to mice fed a high‐fat diet for three consecutive weeks can resist obesity . In addition, rats were given to intraperitoneal injection of MT at a dose of 15 mg/kg/day (body weight) between 7:00 and 8:00 to explore the role of MT in ameliorating cognitive impairment induced by SD .…”

Melatonin Mitigates Mitochondrial Meltdown: Interactions with SIRT3

“…Because of the worldwide increase in obesity, female fertility has shown a marked decline. Since mitochondrial SIRT3 is suppressed in obese rodents, which leads to reduced SOD2 and unrestrained ROS formation, Han et al [210] fed melatonin to obese rats. As anticipated, melatonin greatly improved oocyte quality and fertilizability; this was accompanied by an activation (deacetylation) of SIRT3, which induced SOD2 ultimately reducing oxidative stress in the oocytes.…”

“…This suggests that the antioxidant action of melatonin in oocytes depends on stimulation (deacetylation) of SIRT3 which enhances the activity of the antioxidant enzyme, superoxide dismutase. Figure drawn from the data of Han et al [210]. * p > 0.001.…”

SETD2 reduction adversely affects the development of mouse early embryos

“…20 In brief, female ICR mice were primed with pregnant mare serum gonadotropin. 20 In brief, female ICR mice were primed with pregnant mare serum gonadotropin.…”