Fatty acid oxidation and meiotic resumption in mouse oocytes.
We have examined the potential role of fatty acid oxidation (FAO) in AMP-activated protein kinase (AMPK)-induced meiotic maturation. Etomoxir and malonyl CoA, two inhibitors of carnitine palmitoyl transferase-1 (CPT1), and thus FAO, blocked meiotic induction in dbcAMP-arrested cumulus cell-enclosed oocytes (CEO) and denuded oocytes (DO) by the AMPK activator, AICAR. C75, an activator of CPT1 and FAO, stimulated meiotic resumption in CEO and DO. This effect was insensitive to the AMPK inhibitor, compound C, indicating an action downstream of AMPK. Palmitic acid or carnitine also promoted meiotic resumption in DO in the presence of AICAR. Since C75 also suppresses the activity of fatty acid synthase (FAS), we tested another FAS inhibitor, cerulenin. Cerulenin stimulated maturation in arrested oocytes, but to a lesser extent, exhibited significantly slower kinetics and was effective in CEO but not DO. Moreover, etomoxir completely blocked C75-induced maturation but was ineffective in cerulenin-treated oocytes, suggesting that the meiosis-inducing action of C75 is through activation of FAO within the oocyte, while that of cerulenin is independent of FAO and acts within the cumulus cells. Finally, we determined that long chain, but not short chain, fatty acyl carnitine derivatives were stimulatory to oocyte maturation. Palmitoyl carnitine stimulated maturation in both CEO and DO, with rapid kinetics in DO; this effect was blocked by mercaptoacetate, a downstream inhibitor of FAO. These results indicate that activation of AMPK stimulates meiotic resumption in mouse oocytes by eliminating a block to FAO.
Downs
Stephen M
SM
Department of Biological Sciences, Marquette University, Milwaukee, Wisconsin 53233, USA. stephen.downs@marquette.edu
Mosey
Jessica L
JL
Klinger
Jonathan
J
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D002569:Cerulenin / Q000494:pharmacology; D054885:Cumulus Cells / Q000187:drug effects; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D008316:Malonyl Coenzyme A / Q000494:pharmacology; D008540:Meiosis / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology
C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D004852:Epoxy Compounds; D005227:Fatty Acids; D012265:Ribonucleotides; D002569:Cerulenin; D019308:Palmitic Acid; D000620:Aminoimidazole Carboxamide; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; C054207:etomoxir; D015107:4-Butyrolactone; D002331:Carnitine