Diet-Induced Obesity Model: Abnormal Oocytes and Persistent Growth Abnormalities in the Offspring

Abstract

Associations between maternal obesity and adverse fetal outcomes are well documented, but the mechanisms involved are largely unknown. Most previous work has focused on postconceptional events, however, our laboratory has shown pre- and periconceptional aberrations in maternal glucose metabolism have adverse effects on oocytes and embryos that carry on to the fetus. To demonstrate effects of maternal obesity in the pre- and periconceptional periods, we compared reproductive tissues from diet-induced obese female mice to those of control mice. Ovaries were either stained for follicular apoptosis or dissected and evaluated for oocyte size and meiotic maturation. Mice were also mated and followed for reproductive outcomes including preimplantation embryonic IGF-I receptor (IGF-IR) immunostaining, midgestation fetal growth, and midgestational placental IGF receptor 2 (Igf2r) mRNA. Delivered pups were followed for growth and development of markers of metabolic syndrome. Compared with controls, obese mice had significantly more apoptotic ovarian follicles, smaller and fewer mature oocytes, decreased embryonic IGF-IR staining, smaller fetuses, increased placental Igf2r mRNA, and smaller pups. All weaned pups were fed a regular diet. At 13 wk pups delivered from obese mice were significantly larger, and these pups demonstrated glucose intolerance and increased cholesterol and body fat suggesting early development of a metabolic-type syndrome. Together, our findings suggest maternal obesity has adverse effects as early as the oocyte and preimplantation embryo stage and that these effects may contribute to lasting morbidity in offspring, underscoring the importance of optimal maternal weight and nutrition before conception.

Adolescence and the next generation

“…Both animal and human studies have shown that the preconception environment may alter oocyte maturation 69 with maternal obesity affecting the metabolism of the developing ova and early offspring growth 70,71 . Because mitochondrial DNA is only passed on through the maternal line, oocyte mitochondrial DNA may provide a further sex-specific intergenerational mechanism.…”

Increased body mass index negatively impacts blastocyst formation rate in normal responders undergoing in vitro fertilization

“…In a recent study, oocytes of obese mice at the meiosis II stage displayed significant spindle defects and chromosome misalignment leading to early embryonic loss [25]. Others have found that obese mice exhibit significantly more apoptotic ovarian follicles, smaller oocyte size, and fewer mature oocytes when compared to control mice [24]. Furthermore, studies have reported mitochondrial dysfunction [25] as well as lipotoxicity, increased oxidative stress, and increased apoptosis in the cumulus-oocyte complexes of mice fed an HFD [26].…”

“…Animal studies have indicated that obesity significantly impacts oocyte quality [22][23][24][25]. Researchers have used a murine model of mice fed a high-fat diet (HFD) to mimic the effects of obesity and metabolic dysfunction in humans.…”

The impact of obesity on egg quality

“…Mice fed a high fat diet for 16 weeks led to an increase in weight and elevated glucose, but not to the point of being considered diabetic. Even without severe hyperglycemia, this diet resulted in delayed oocyte maturation, increased apoptosis in ovarian follicles, and smaller oocyte size [40]. Studies from human ART clinics have shown an impairment in oocyte maturation is associated with increasing BMI [41][42][43]; however, others found no difference in oocyte maturation between different BMI scores [44].…”