Oral Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

Obesity, oocyte quality and the legacy of the egg (#114)

Rebecca L Robker 1
  1. Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide, SA, Australia

All of the mitochondria in an individual’s tissues are derived from those of the oocyte from which it was conceived; and mitochondrial replication during pre-implantation embryogenesis is tightly controlled. We have found that obesity in mothers imparts a legacy of mitochondrial loss in offspring, that is due to cellular stress during oocyte maturation but that is preventable prior to conception. These studies in mice showed that insulin resistance and hyperlipidemia in female mice led to endoplasmic reticulum stress in the oocyte complex and altered mitochondrial activity in oocytes. In vitro fertilization of oocytes from obese mice demonstrates their impaired developmental potential and marked mtDNA loss by the blastocyst stage. Subsequently, fetuses from obese oocytes were heavier than controls and had reduced liver, heart and kidney mtDNA content. These results offer a mechanism by which maternal obesity ‘programs’ metabolism in offspring. Importantly, treatment of the obese female mice with ER stress inhibitors prior to IVF normalized oocyte mitochondrial activity as well as subsequent blastocyst development, fetal weight and fetal tissue mtDNA content. Similar to obesity in women, reduced conception rates and fetal loss occurs in dairy cows with profound hyperlipidemia (resulting from negative energy balance). Our in vitro studies using cow cumulus-oocyte complexes show that direct exposure to high levels of non-esterified fatty acids (NEFA) increases lipid accumulation within the oocyte, and impairs metabolism. Following fertilization, the oocytes that were exposed to NEFA gave rise to embryos with altered developmental kinetics and the blastocysts had reduced mtDNA content. Similar to our findings in mice, treatment of the cow oocytes with ER stress inhibitor prior to fertilization prevented the NEFA-induced loss of mtDNA in embryos. Overall these results, in two distinct species and contexts, demonstrate that excess lipid impacts mitochondrial activity in oocytes and subsequent inheritance to embryos.