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

TLDR

Maternal obesity is linked to adverse fetal outcomes, yet the underlying mechanisms remain unclear; our laboratory has shown that pre‑ and periconceptional glucose metabolism disturbances affect oocytes and embryos, influencing fetal development. To demonstrate the effects of maternal obesity during the pre‑ and periconceptional periods, we compared reproductive tissues from diet‑induced obese female mice to those of control mice. We examined ovaries for follicular apoptosis and oocyte size/maturation, mated mice to assess preimplantation IGF‑IR staining, midgestation fetal growth, and placental Igf2r mRNA, and tracked offspring growth and metabolic markers, feeding all weaned pups a standard diet. Obese mice exhibited increased ovarian follicle apoptosis, reduced mature oocyte numbers, lower embryonic IGF‑IR staining, smaller fetuses, higher placental Igf2r mRNA, and smaller pups; by 13 weeks, their offspring were larger yet glucose‑intolerant with elevated cholesterol and adiposity, indicating that maternal obesity induces early embryonic defects that persist as metabolic syndrome in the offspring, highlighting the need for optimal maternal weight before conception.

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.