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Peroxisome Proliferator-Activated Receptor- Agonist Rosiglitazone Reverses the Adverse Effects of Diet-Induced Obesity on Oocyte Quality

School of Paediatrics and Reproductive Health, Discipline of Obstetrics & Gynaecology, The University of Adelaide, Adelaide, South Australia 5005, Australia

Address all correspondence and requests for reprints to: Dr. R. Robker, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Adelaide, South Australia 5005, Australia. E-mail: rebecca.robker{at}adelaide.edu.au.

Obesity and its physiological consequences are increasingly prevalent among women of reproductive age and are associated with infertility. To investigate, female mice were fed a high-fat diet until the onset of insulin resistance, followed by assessments of ovarian gene expression, ovulation, fertilization, and oocyte developmental competence. We report defects to ovarian function associated with diet-induced obesity (DIO) that result in poor oocyte quality, subsequently reduced blastocyst survival rates, and abnormal embryonic cellular differentiation. To identify critical cellular mediators of ovarian responses to obesity induced insulin resistance, DIO females were treated for 4 d before mating with an insulin-sensitizing pharmaceutical: glucose and lipid-lowering AMP kinase activator, 5-aminoimidazole 4-carboxamide-riboside, 30 mg/kg·d; sodium salicylate, IK inhibitor that reverses insulin resistance, 50 mg/kg·d; or peroxisome proliferator activated receptor- agonist rosiglitazone, 10 mg/kg·d. 5-aminoimidazole 4-carboxamide-riboside or sodium salicylate treatment did not have significant effects on the reproductive parameters examined. However, embryonic development to the blastocyst stage was significantly improved when DIO mice were treated with rosiglitazone, effectively repairing development rates. Rosiglitazone also normalized DIO-associated abnormal blastomere allocation to the inner cell mass. Such improvements to oocyte quality were coupled with weight loss, improved glucose metabolism, and changes in ovarian mRNA expression of peroxisome proliferator activated receptor-regulated genes, Cd36, Scarb1, and Fabp4 cholesterol transporters. These studies demonstrate that peri-conception treatment with select insulin-sensitizing pharmaceuticals can directly influence ovarian functions and ultimately exert positive effects on oocyte developmental competence. Improved blastocyst quality in obese females treated with rosiglitazone before mating indicates that peroxisome proliferator activated receptor- is a key target for metabolic regulation of ovarian function and oocyte quality.