135. FATTY ACID OXIDATION IS ESSENTIAL FOR OOCYTE DEVELOPMENTAL COMPETENCE

Abstract

Oocyte lipid composition and developmental competence are influenced by dietary fat yet whether lipids are metabolised by the oocyte or essential for subsequent embryo development is largely unexplored. Fatty acid oxidation (FAO) is largely overlooked as an energy source for the oocyte, despite generating several-fold more energy than glucose oxidation. FAO requires the rate-limiting enzyme carnitine palmitoyltransferase-1 (Cpt1) and the metabolite Carnitine to shuttle fatty acids into mitochondria for energy production. Analysis of Cpt1 mRNA during oocyte maturation showed that Cpt1 expression was hormonally induced (p<0.05) in the cumulus oocyte complex (COC), peaking at 10h following ovulatory hCG treatment. In contrast, Cpt1 was not hormonally regulated in granulosa cells (p>0.05). To investigate the role of Cpt1-mediated FAO during oocyte maturation we measured FAO in oocytes in the presence and absence of Carnitine and inhibited FAO to determine its importance for oocyte developmental competence. Levels of FAO in COCs were assessed as metabolism of the fatty acid ³H-palmitate. During oocyte maturation there was a 2.1-fold increase (p<0.0001) in FAO compared to immature COCs. Carnitine supplementation led to a further 3.7-fold increase (p<0.001), while inhibition of Cpt1 with Etomoxir resulted in a 6.5-fold decrease (p<0.0002) in FAO during oocyte maturation. FAO inhibition had no effect on cumulus expansion. However inhibition of FAO during oocyte maturation followed by IVF and embryo culture in the absence of inhibitor, resulted in significantly decreased numbers of embryos developing ‘on time' (p<0.002). This is the first identification of hormonal induction of Cpt1 and Cpt1 mediated FAO in the COC during oocyte maturation. Further, the results demonstrate that oxidation of fatty acids by the oocyte is essential for oocyte developmental competence and can be modulated by Carnitine. These findings provide a potential mechanism by which dietary fat, obesity or metabolic disorders including CPT deficiency lead to infertility.