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.

Figure 1

IGF-I receptor expression is decreased in blastocysts recovered from female mice on a HFD (n = 10 mice) vs. a regular-fat diet (n = 8 mice) (P < 0.001). A, Relative IGF-I receptor expression was determined by two independent and blinded observers. B, Confocal image of IGF-I receptor protein. Blue channel, Nuclear staining; green channel, IGF-I receptor labeling.

Figure 2

Smaller fetuses in mice fed a HFD. A, Crown-rump length at embryonic day 14.5 (e14.5) is significantly lower in the fetuses collected from the mice on a HFD (n = 65 pups) vs. the regular diet (n = 75 pups) (P < 0.0001). B, Representative fetuses from each group.

Figure 3

Adverse metabolic parameters in pups from high-fat fed mice. A, Average weight of pups from embryonic day 14.5 (e14.5) to 13 wk of age (p91) (weight at e14.5 time point n = 9 pups from 3 control dams, n = 7 from 3 HFD dams; weight at p18–p91 time points n = 7 pups from 3 control dams; n = 6 pups from 3 HFD dams). *, P < 0.01; **, P < 0.001. B, GTT at 13 wk of age [Control diet n = 3 experiments with different mice (n = 4 pups from 2 control dams, n = 4 pups from 2 HFD dams); HFD n = 3 experiments with different mice (n = 4 pups from 2 control dams, n = 4 pups from 2 HFD dams); *, P < 0.01]. C, Percent body fat by DXA in 6.5-wk and 10-wk-old offspring from mice fed a HFD (n = 6 females; n = 3 males from 3 HFD dams) vs. control diet (n = 4 females and n = 4 males from 3 control dams). *, P < 0.05; **, P < 0.001; ^, P < 0.0001. D, Total serum cholesterol (mg/dl) in 10-wk-old offspring of age from mice fed a HFD (n = 6 females; n = 3 males from 3 HFD dams) vs. control diet (n = 4 females and n = 4 males from 3 control dams). *, P < 0.0001.