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Developmental Programming: Prenatal Testosterone Excess and Insulin Signaling Disruptions in Female Sheep.

ABSTRACT: Women with polycystic ovary syndrome often manifest insulin resistance. Using a sheep model of polycystic ovary syndrome-like phenotype, we explored the contribution of androgen and insulin in programming and maintaining disruptions in insulin signaling in metabolic tissues. Phosphorylation of AKT, ERK, GSK3beta, mTOR, and p70S6K was examined in the liver, muscle, and adipose tissue of control and prenatal testosterone (T)-, prenatal T plus androgen antagonist (flutamide)-, and prenatal T plus insulin sensitizer (rosiglitazone)-treated fetuses as well as 2-yr-old females. Insulin-stimulated phospho (p)-AKT was evaluated in control and prenatal T-, prenatal T plus postnatal flutamide-, and prenatal T plus postnatal rosiglitazone-treated females at 3 yr of age. GLUT4 expression was evaluated in the muscle at all time points. Prenatal T treatment increased mTOR, p-p70S6K, and p-GSK3beta levels in the fetal liver with both androgen antagonist and insulin sensitizer preventing the mTOR increase. Both interventions had partial effect in preventing the increase in p-GSK3beta. In the fetal muscle, prenatal T excess decreased p-GSK3beta and GLUT4. The decrease in muscle p-GSK3beta was partially prevented by insulin sensitizer cotreatment. Both interventions partially prevented the decrease in GLUT4. Prenatal T treatment had no effect on basal expression of any of the markers in 2-yr-old females. At 3 yr of age, prenatal T treatment prevented the insulin-stimulated increase in p-AKT in liver and muscle, but not in adipose tissue, and neither postnatal intervention restored p-AKT response to insulin stimulation. Our findings provide evidence that prenatal T excess changes insulin sensitivity in a tissue- and development-specific manner and that both androgens and insulin may be involved in the programming of these metabolic disruptions.

SUBMITTER: Lu C

PROVIDER: S-EPMC4939741 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Developmental Programming: Prenatal Testosterone Excess and Insulin Signaling Disruptions in Female Sheep.

Lu Chunxia C Cardoso Rodolfo C RC Puttabyatappa Muraly M Padmanabhan Vasantha V

Biology of reproduction 20160406 5

Women with polycystic ovary syndrome often manifest insulin resistance. Using a sheep model of polycystic ovary syndrome-like phenotype, we explored the contribution of androgen and insulin in programming and maintaining disruptions in insulin signaling in metabolic tissues. Phosphorylation of AKT, ERK, GSK3beta, mTOR, and p70S6K was examined in the liver, muscle, and adipose tissue of control and prenatal testosterone (T)-, prenatal T plus androgen antagonist (flutamide)-, and prenatal T plus i ...[more]

PMID: 27053365

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Project description:Prenatal testosterone (T)-treated sheep, similar to polycystic ovarian syndrome women, manifest reduced cyclicity, functional hyperandrogenism, and polycystic ovary (PCO) morphology. The PCO morphology results from increased follicular recruitment and persistence of antral follicles, a consequence of reduced follicular growth and atresia, and is driven by cell-specific gene expression changes that are poorly understood. Therefore, using RNA sequencing, cell-specific transcriptional changes were assessed in laser capture microdissection isolated antral follicular granulosa and theca cells from age 21 months control and prenatal T-treated (100 mg intramuscular twice weekly from gestational day 30 to 90; term: 147 days) sheep. In controls, 3494 genes were differentially expressed between cell types with cell signaling, proliferation, extracellular matrix, immune, and tissue development genes enriched in theca; and mitochondrial, chromosomal, RNA, fatty acid, and cell cycle process genes enriched in granulosa cells. Prenatal T treatment 1) increased gene expression of transforming growth factor β receptor 1 and exosome component 9, and decreased BCL6 corepressor like 1, BCL9 like, and MAPK interacting serine/threonine kinase 2 in both cells, 2) induced differential expression of 92 genes that included increased mitochondrial, ribosome biogenesis, ribonucleoprotein, and ubiquitin, and decreased cell development and extracellular matrix-related pathways in granulosa cells, and 3) induced differential expression of 56 genes that included increased noncoding RNA processing, ribosome biogenesis, and mitochondrial matrix, and decreased transcription factor pathways in theca cells. These data indicate that follicular function is affected by genes involved in transforming growth factor signaling, extracellular matrix, mitochondria, epigenetics, and apoptosis both in a common as well as a cell-specific manner and suggest possible mechanistic pathways for prenatal T treatment-induced PCO morphology in sheep.

Dataset Information

Developmental Programming: Prenatal Testosterone Excess and Insulin Signaling Disruptions in Female Sheep.

Publications

Developmental Programming: Prenatal Testosterone Excess and Insulin Signaling Disruptions in Female Sheep.

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