Progressive obesity leads to altered ovarian gene expression in the Lethal Yellow mouse: a microarray study

<p>Abstract</p> <p>Background</p> <p>Lethal yellow (LY; C57BL/6J <it>A</it>^<it>y</it>/<it>a</it>) mice exhibit adult-onset obesity, altered metabolic regulation, and early reproductive senescence. The present study was designed to test the hypothesis that obese LY mice possess differences in expression of ovarian genes relative to age-matched lean mice.</p> <p>Methods</p> <p>90- and 180-day-old LY and lean black (C57BL/6J <it>a/a</it>) mice were suppressed with GnRH antagonist (Antide^®), then stimulated with 5 IU eCG. cRNA derived from RNA extracts of whole ovarian homogenates collected 36 h post-eCG were run individually on Codelink Mouse Whole Genome Bioarrays (GE Healthcare Life Sciences).</p> <p>Results</p> <p>Fifty-two genes showed ≥ 2-fold differential (p < 0.05) expression between 180-day-old obese LY and lean black mice. LY mice exhibited elevated ovarian expression of agouti (350×), leptin (6.5×), and numerous genes involved in cholesterol/lipid transport and metabolism, e.g. lanosterol synthase, <it>Cyp51</it>, and steroidogenic acute regulatory protein (<it>Star</it>). Fewer genes showed lower expression in LY mice, e.g. angiotensinogen. In contrast, none of these genes showed differential expression in 90-day-old LY and black mice, which are of similar body weight. Interestingly, 180-day-old LY mice had a 2-fold greater expression of 11beta-hydroxysteroid dehydrogenase type 1 (<it>Hsd11b1</it>) and a 2-fold lesser expression of 11beta-hydroxysteroid dehydrogenase type 2 (<it>Hsd11b2</it>), differences not seen in 90-day-old mice. Consistent with altered <it>Hsd11b </it>gene expression, ovarian concentrations of corticosterone (C) were elevated in aging LY mice relative to black mice, but C levels were similar in young LY and black mice.</p> <p>Conclusion</p> <p>The data suggest that reproductive dysfunction in aging obese mice is related to modified intraovarian gene expression that is directly related to acquired obesity.</p

Pioglitazone administration alters ovarian gene expression in aging obese lethal yellow mice

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>TZD administration may influence ovarian function via numerous diverse mechanisms that may or may not be directly related to insulin/IGF signaling.</p

Declining fertility in the lethal yellow mouse is related to progressive hyperleptinemia and leptin resistance

Mice possessing the lethal yellow mutation (C57BL/6J Ay/a) become obese and develop hyperleptinemia and leptin resistance as they age. To determine the relationship between altered leptin physiology and reproductive function in these mice, we compared body weight (BW), serum leptin concentration, ovulation rate, and in vitro blastocyst development among 120- and 180-d-old lethal yellow and black non-mutant (a/a) mice. Estrous female yellow and black mice were mated with fertile black males. Oviducts were flushed ~ 36 h after mating and the recovered embryos were cultured for 96 h. BW, serum leptin levels, and the leptin:BW ratio differed among groups as follows: 180-d yellow > 120-d yellow > 180-d black = 120-d black. Ovulation rate was similar among 120-d yellow and black, and 180-d black mice. Among 180-d yellow mice, five of twelve mice failed to ovulate, but the other seven mice ovulated a similar number of oocytes as their black counterparts (8.4 ± 0.9 versus 8.0 ± 1.3). Non-ovulators had higher (P < 0.05) leptin levels (56.6 ± 1.8 ng·mL–1) than ovulators (46.2 ± 3.5), but BW did not differ significantly. Fewer embryos from 180-d yellow mice reached the blastocyst stage in culture than did the embryos from black mice (55% versus 83%, P < 0.05). Moreover, blastocyst development in 180-d old yellow mice negatively correlated with leptin levels (r = –0.797, P = 0.032) and leptin:BW ratio (r = –0.847, P = 0.016), but not with BW. Declining reproductive function in lethal yellow mice appears to be related to increasing levels of leptin and progression of leptin resistance