Abstract
Fatty acid oxidation is an important energy source for the oocyte; however, little is known about how this metabolic pathway is regulated in cumulus-oocyte complexes. Analysis of genes involved in fatty acid oxidation showed that many are regulated by the luteinizing hormone surge during in vivo maturation, including acyl-CoA synthetases, carnitine transporters, acyl-CoA dehydrogenases and acetyl-CoA transferase, but that many are dysregulated when cumulus-oocyte complexes are matured under in vitro maturation conditions using follicle stimulating hormone and epidermal growth factor. Fatty acid oxidation, measured as production of 3H2O from [3H]palmitic acid, occurs in mouse cumulus-oocyte complexes in response to the luteinizing hormone surge but is significantly reduced in cumulus-oocyte complexes matured in vitro. Thus we sought to determine whether fatty acid oxidation in cumulus-oocyte complexes could be modulated during in vitro maturation by lipid metabolism regulators, namely peroxisome proliferator activated receptor (PPAR) agonists bezafibrate and rosiglitazone. Bezafibrate showed no effect with increasing dose, while rosiglitazone dose dependently inhibited fatty acid oxidation in cumulus-oocyte complexes during in vitro maturation. To determine the impact of rosiglitazone on oocyte developmental competence, cumulus-oocyte complexes were treated with rosiglitazone during in vitro maturation and gene expression, oocyte mitochondrial activity and embryo development following in vitro fertilization were assessed. Rosiglitazone restored Acsl1, Cpt1b and Acaa2 levels in cumulus-oocyte complexes and increased oocyte mitochondrial membrane potential yet resulted in significantly fewer embryos reaching the morula and hatching blastocyst stages. Thus fatty acid oxidation is increased in cumulus-oocyte complexes matured in vivo and deficient during in vitro maturation, a known model of poor oocyte quality. That rosiglitazone further decreased fatty acid oxidation during in vitro maturation and resulted in poor embryo development points to the developmental importance of fatty acid oxidation and the need for it to be optimized during in vitro maturation to improve this reproductive technology.
Highlights
Oocytes acquire their developmental competence, the ability to undergo successful fertilization and development into an embryo, during ovarian folliculogenesis
We first determined whether genes involved in the fatty acid oxidation (FAO) metabolic pathway (Fig. 1) are regulated in the cumulus oocyte complex (COC) following an ovulatory dose of Human chorionic gonadotropin (hCG) to induce oocyte maturation in vivo
These results show that a number of FAO genes are dynamically regulated in COCs in vivo in response to ovulatory hCG and that even distinct isoforms of similar enzymes exhibit differential expression patterns
Summary
Oocytes acquire their developmental competence, the ability to undergo successful fertilization and development into an embryo, during ovarian folliculogenesis. Ovarian follicle growth begins from the primordial stage where a small oocyte is surrounded by a single layer of somatic cells known as granulosa cells. The final stages of oocyte developmental competence are acquired following a surge of luteinizing hormone (LH) from the pituitary which signals to the preovulatory follicle, via the granulosa cells, to ovulate. During this time maturation of the oocyte resumes and includes meiotic progression to metaphase II in preparation for fertilization in the oviduct. The mechanisms underlying the poor quality following IVM are not evident; it is understood that cellular metabolism and metabolic rate of the oocyte and cumulus cells are a determinant of oocyte quality [9,10,11,12,13] with ATP levels within the oocyte positively correlated with developmental potential [14]
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