High Fat Diet Induced Developmental Defects in the Mouse: Oocyte Meiotic Aneuploidy and Fetal Growth Retardation/Brain Defects

Abstract

BackgroundMaternal obesity is associated with poor outcomes across the reproductive spectrum including infertility, increased time to pregnancy, early pregnancy loss, fetal loss, congenital abnormalities and neonatal conditions. Furthermore, the proportion of reproductive-aged woman that are obese in the population is increasing sharply. From current studies it is not clear if the origin of the reproductive complications is attributable to problems that arise in the oocyte or the uterine environment.Methodology/Principal FindingsWe examined the developmental basis of the reproductive phenotypes in obese animals by employing a high fat diet mouse model of obesity. We analyzed very early embryonic and fetal phenotypes, which can be parsed into three abnormal developmental processes that occur in obese mothers. The first is oocyte meiotic aneuploidy that then leads to early embryonic loss. The second is an abnormal process distinct from meiotic aneuploidy that also leads to early embryonic loss. The third is fetal growth retardation and brain developmental abnormalities, which based on embryo transfer experiments are not due to the obese uterine environment but instead must be from a defect that arises prior to the blastocyst stage.Conclusions/SignificanceOur results suggest that reproductive complications in obese females are, at least in part, from oocyte maternal effects. This conclusion is consistent with IVF studies where the increased pregnancy failure rate in obese women returns to the normal rate if donor oocytes are used instead of autologous oocytes. We postulate that preconceptional weight gain adversely affects pregnancy outcomes and fetal development. In light of our findings, preconceptional counseling may be indicated as the preferable, earlier target for intervention in obese women desiring pregnancy and healthy outcomes.

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

“…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. 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].…”

“…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.…”

“…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].…”

Diet Induced Inflammation and Potential Consequences on Fetal Development

“…Induction of adipogenic transcription factor peroxisome proliferator-activated receptor (PPAR) γ activity is enhanced under limited or excess nutrient availability. Nonetheless, this occurs via different mechanisms involving PPARγ coregulators: in undernutrition, it is upregulation of coactivators, whereas in excess nutriton, it is downregulation of corepressors [58][59][60].…”

Biotin-deficient diet induces chromosome misalignment and spindle defects in mouse oocytes

“…1) Recent studies have shown that macronutrients affect the oocyte maturation 2,3) and that high-fat diets in mice induce the formation of abnormal oocytes that has chromosome misalignment and spindle defects. 2) Caloric restriction without malnutrition, depressed the aging-related increase in the oocyte aneuploidy and chromosomal misalignment. 4) Biotin deficiency affects fetal development and growth.…”