Hyperglycaemia and lipid differentially impair mouse oocyte developmental competence

Area of Science:

• Reproductive Biology
• Metabolic Endocrinology
• Developmental Biology

Background:

• Maternal diabetes and obesity involve elevated blood glucose, insulin, and lipids, activating fuel-sensing and stress pathways.
• Previous studies showed hyperglycaemia-induced hexosamine biosynthetic pathway (HBP) activation and hyperlipidaemia-induced endoplasmic reticulum (ER) stress independently impair oocyte and embryo development.

Purpose of the Study:

• To investigate the combined effects of glucose and lipid metabolic disruptions on oocyte developmental competence.
• To elucidate the roles of HBP activity and ER stress in compromised fertility associated with maternal metabolic conditions.

Main Methods:

• Mouse cumulus-oocyte complexes were exposed to hyperglycaemia (30mM) and/or lipid (40μM) during in vitro maturation.
• Effects on blastocyst development, HBP activity, protein O-linked glycosylation (O-GlcNAcylation), and ER stress gene expression were examined.

Main Results:

• Hyperglycaemia, glucosamine (GlcN), and combined hyperglycaemia + lipid treatments significantly impaired blastocyst development.
• All tested conditions increased HBP activity and protein O-GlcNAcylation.
• ER stress pathways were induced by all treatments.
• Lipid treatment repressed the expression of HBP enzymes Gfpt2 and Ogt.

Conclusions:

• Both hyperglycaemia and hyperlipidaemia negatively impact oocyte developmental competence.
• Increased HBP activity and ER stress are key mechanisms contributing to compromised fertility in metabolically challenged pregnancies.
• These findings highlight the role of O-GlcNAcylation and ER stress in the reduced fertility of obese women.