title: Hyperglycaemia and lipid differentially impair mouse oocyte developmental competence.
abstract: Maternal diabetes and obesity are characterised by elevated blood glucose, insulin and lipids, resulting in upregulation of specific fuel-sensing and stress signalling pathways. Previously, we demonstrated that, separately, upregulation of the hexosamine biosynthetic pathway (HBP; under hyperglycaemic conditions) and endoplasmic reticulum (ER) stress (due to hyperlipidaemia) pathways reduce blastocyst development and alter oocyte metabolism. In order to begin to understand how both glucose and lipid metabolic disruptions influence oocyte developmental competence, in the present study we exposed mouse cumulus-oocyte complexes to hyperglycaemia (30mM) and/or lipid (40μM) and examined the effects on embryo development. The presence of glucosamine (GlcN; a hyperglycaemic mimetic) or increased lipid during in vitro maturation severely perturbed blastocyst development (P<0.05). Hyperglycaemia, GlcN and hyperglycaemia + lipid treatments significantly increased HBP activity, increasing total O-linked glycosylation (O-GlcNAcylation) of proteins (P<0.0001). All treatments also induced ER stress pathways, indicated by the expression of specific ER stress genes. The expression of genes encoding the HBP enzymes glutamine:fructose-6-phosphate amidotransferase 2 (Gfpt2) and O-linked β-N-acetylglucosaminyltransferase (Ogt) was repressed following lipid treatment (P<0.001). These findings partially implicate the mechanism of O-GlcNAcylation and ER stress as likely contributors to compromised fertility of obese women.
authors.affiliation: Robinson Research Institute, School of Paediatrics and Reproductive Health, The University of Adelaide, Medical School, Frome Road, Adelaide, SA 5005, Australia.
authors.forename: Siew L
authors.initials: SL
authors.lastname: Wong
authors.affiliation: Robinson Research Institute, School of Paediatrics and Reproductive Health, The University of Adelaide, Medical School, Frome Road, Adelaide, SA 5005, Australia.
authors.forename: Linda L
authors.initials: LL
authors.lastname: Wu
authors.affiliation: Robinson Research Institute, School of Paediatrics and Reproductive Health, The University of Adelaide, Medical School, Frome Road, Adelaide, SA 5005, Australia.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Robker
authors.affiliation: Robinson Research Institute, School of Paediatrics and Reproductive Health, The University of Adelaide, Medical School, Frome Road, Adelaide, SA 5005, Australia.
authors.forename: Jeremy G
authors.initials: JG
authors.lastname: Thompson
authors.affiliation: Robinson Research Institute, School of Paediatrics and Reproductive Health, The University of Adelaide, Medical School, Frome Road, Adelaide, SA 5005, Australia.
authors.forename: Melanie L Sutton
authors.initials: ML
authors.lastname: McDowall
mesh_terms: D000818:Animals; D054885:Cumulus Cells / Q000187:drug effects* / Q000378:metabolism; D047108:Embryonic Development / Q000187:drug effects* / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D005944:Glucosamine / Q000494:pharmacology*; D006943:Hyperglycemia / Q000378:metabolism*; D008055:Lipids / Q000494:pharmacology*; D051379:Mice; D009865:Oocytes / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D009866:Oogenesis / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D008055:Lipids; D005944:Glucosamine