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, IkappaK inhibitor that reverses
insulin resistance, 50 mg/kg.d; or
peroxisome proliferator activated receptor-gamma 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-gamma is a key target for metabolic regulation of ovarian function and oocyte quality.