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

Lethal yellow (LY; C57BL/6J Ay/a) 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.

90- and 180-day-old LY and lean black (C57BL/6J a/a) mice were suppressed with GnRH antagonist (Antide(R)), 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).

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 (350x), leptin (6.5x), and numerous genes involved in cholesterol/lipid transport and metabolism, e.g. lanosterol synthase, Cyp51, and steroidogenic acute regulatory protein (Star). 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 (Hsd11b1) and a 2-fold lesser expression of 11beta-hydroxysteroid dehydrogenase type 2 (Hsd11b2), differences not seen in 90-day-old mice. Consistent with altered Hsd11b 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.

The data suggest that reproductive dysfunction in aging obese mice is related to modified intraovarian gene expression that is directly related to acquired obesity.