Regulation of Fatty Acid Oxidation in Mouse Cumulus-Oocyte Complexes during Maturation and Modulation by PPAR Agonists

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.

Fatty acid metabolism during maturation affects glucose uptake and is essential to oocyte competence

“…This hypothesis is supported by recent reports in mouse COC where expression of genes involved in FAO were altered after FAO inhibition (Brisard et al 2014). Abundance of genes involved in FAO is also increased in COC after treatment with rosiglitazone, an agent known to inhibit FAO (Dunning et al 2014). Similar to the observed increase in Cpt2 transcripts in cumulus cells after maturation with low levels of palmitic acid, with or without carnitine, an increase in Cpt1 has been documented in pancreatic cell lines when palmitate, oleate, and linoleate are supplied (AssimacopoulosJeannet et al 1997).…”

Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health

“…During ovulation, the maturing oocyte increases energy use through mitochondrial oxidation of free fatty acids (FFAs) as a more efficient source of ATP than glycolysis (67)(68)(69). FFAs within the COC, either taken up from follicular fluid or broken down from cellular lipid, enter mitochondria to undergo conversion into acetyl CoA, which enters the TCA to produce ATP through beta-oxidation ( Fig.…”

Lipids and oocyte developmental competence: the role of fatty acids and β-oxidation

“…In porcine oocytes, levels of ACSL3 and ACADL, which activate long-chain fatty acids before their entry into mitochondria and catalyse the first step in the b-oxidation spiral respectively, were found to be dysregulated in another model of poor oocyte developmental competence (Yuan et al 2011). Recently we have found that mouse COCs matured in vitro metabolise fatty acid at less than half the rate of COCs matured in vivo, in association with dysregulated expression of at least 15 genes involved in fatty acid activation, transport and oxidation (Dunning et al 2014).…”