Pioglitazone administration alters ovarian gene expression in aging obese lethal yellow mice.
BACKGROUND
Women with polycystic ovary syndrome (PCOS) are often treated with insulin-sensitizing agents, e.g. thiazolidinediones (TZD), which have been shown to reduce androgen levels and improved ovulatory function. Acting via peroxisome proliferator-activated receptor (PPAR) gamma, TZD alter the expression of a large variety of genes. Lethal yellow (LY; C57BL/6J Ay/a) mice, possessing a mutation (Ay) in the agouti gene locus, exhibit progressive obesity, reproductive dysfunction, and altered metabolic regulation similar to women with PCOS. The current study was designed to test the hypothesis that prolonged treatment of aging LY mice with the TZD, pioglitazone, alters the ovarian expression of genes that may impact reproduction.


METHODS
Female LY mice received daily oral doses of either 0.01 mg pioglitazone (n = 4) or an equal volume of vehicle (DMSO; n = 4) for 8 weeks. At the end of treatment, ovaries were removed and DNA microarrays were used to analyze differential gene expression.


RESULTS
Twenty-seven genes showed at least a two-fold difference in ovarian expression with pioglitazone treatment. These included leptin, angiopoietin, angiopoietin-like 4, Foxa3, PGE1 receptor, resistin-like molecule-alpha (RELM), and actin-related protein 6 homolog (ARP6). For most altered genes, pioglitazone changed levels of expression to those seen in untreated C57BL/6J(a/a) non-mutant lean mice.


CONCLUSIONS
TZD administration may influence ovarian function via numerous diverse mechanisms that may or may not be directly related to insulin/IGF signaling.
Brannian
John D
JD
Department of Obstetrics and Gynecology and Division of Basic Biomedical Sciences Sanford School of Medicine of The University of South Dakota, Sioux Falls and Vermillion, SD, USA. jbrannia@usd.edu
Eyster
Kathleen M
KM
Weber
Mitch
M
Diggins
Maureen
M
D000284:Administration, Oral; D000375:Aging / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D020932:Nerve Growth Factor / Q000235:genetics; D009765:Obesity / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism; D000077205:Pioglitazone; D011506:Proteins / Q000235:genetics; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*
D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; C413576:Retnla protein, mouse; D045162:Thiazolidinediones; D020932:Nerve Growth Factor; D000077205:Pioglitazone