Exposure to high glucose and lipid impairs oocyte developmental competence in association with ER stress and O-GlcNAcylation — ASN Events
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  3. Exposure to high glucose and lipid impairs oocyte developmental competence in association with ER stress and O-GlcNAcylation

Exposure to high glucose and lipid impairs oocyte developmental competence in association with ER stress and O-GlcNAcylation (#236)

Siew L Wong 1 , Linda L Wu 1 , Rebecca L Robker 1 , Jeremy G Thompson 1 , Melanie L Sutton-McDowall 1
  1. Obstetrics and Gynaecology, Robinson Research Institute, Adelaide, South Australia, Australia

Maternal diabetes and conditions such as obesity, in which blood glucose, insulin and lipids are elevated, have long been associated with reduced fertility and poor pregnancy outcomes. In order to begin to understand how these metabolic disruptions influence oocyte developmental competence, this study exposed cumulus-oocyte complexes (COCs) to hyperglycaemia and lipid individually and in combination and examined the effect on embryo development. Firstly, a new maturation system for investigating lipid inclusion was established and there was a dose dependent increase in lipid accumulation in mouse COCs with increasing lipid doses. Glucosamine (GlcN), a hyperglycaemic mimetic, was used as a positive control, throughout the study. The presence of GlcN or lipid during in vitro maturation (IVM) severely perturbed blastocyst development (48% and 50% respectively; P<0.05). We next investigated the ability of these metabolites to induce endoplasmic reticulum (ER) stress and hexosamine biosynthesis, which are key regulatory pathways in COCs. High glucose, GlcN and the combination of high glucose and lipid treatment significantly increased in total O-GlcNAcylation (P<0.0001), demonstrated by immunohistochemistry and an increased trend following Western blot. Of these treatments, GlcN and combination of high glucose and lipid also activated the downstream pathways, inducing the mRNA expression of the ER-stress gene Xbp1. Other ER stress genes including Atf4 (P<0.05) and Grp78 (P<0.0001) were also up-regulated following GlcN treatment. Presence of high glucose in the culture also resulted in increased Atf4 (P<0.05) expression. Most surprising was the repression of hexosamine biosynthetic pathway (HBP) enzymes Gfpt2 (P<0.0001) and Ogt (P=0.0001) by the lipid treatment. These results support the hypothesis that the HBP is a “nutrient sensor” that can lead to regulation of metabolism based on fuel availability. These findings partially implicate the mechanism of O-GlcNAcylation and ER stress as likely contributors to the reduced pregnancy rates observed in obese women.

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