OR44-6 Down-regulation of Human Placental Growth Hormone Genes, Known Modulators of Maternal Metabolism, in Pregnancies Complicated by Obesity - A Possible Role for C/EBPβ

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR44-Female Reproductive Endocrinology
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 10:30 AM
Room 256 (Moscone Center)
Hana Vakili*, Yan Jin, Margaret E Bock, Savas M Menticoglou and Peter A Cattini
University of Manitoba, Winnipeg, MB, Canada
Human chorionic somatomammotropin (CS) and growth hormone variant (GH-V) act as metabolic adaptors in response to maternal insulin resistance, which occurs as part of "normal" pregnancy. Maternal obesity can exacerbate this "resistance", suggesting that CS/GH-V production and/or function might be affected. To test this we assessed CS/GH-V genes expression in term placental samples from women that are either lean (BMI<25 kg/m2) or obese (BMI≥35 kg/m2). Significant decreases in CS/GH-V expression were identified in obese versus lean women (p<0.01, n=5) by quantitative PCR. Further study of mechanism is limited by difficulties associated with sampling during pregnancy. Thus, we pursued “humanized” transgenic mice containing the human CS/GH-V genes together with upstream sequences that confer placenta-specific expression, to investigate regulation of CS/GH-V genes in a model of maternal obesity. Mice were fed a high fat diet prior to and during pregnancy, and this was associated with a 1.2-fold increase in gestational weight (p<0.01, n=9) and impaired glucose tolerance (p<0.05, n=6). This correlated with significant 40 and 60% decreases in CS and GH-V RNA levels (p<0.01, n=9) at gestational day 18.5 (pre-term). Binding of the transcription factor C/EBPβ to the "enhancer" regions of the CS/GH-V genes is linked to efficient expression. Thus, we assessed binding of C/EBPβ by chromatin immunoprecipitation (ChIP) assay, as a target for maternal obesity. Recruitment of RNA polymerase II to the promoter regions of the CS/GH-V genes was also assessed by ChIP as an indicator of transcriptional status of target genes. A 40% reduction in C/EBPβ binding to the enhancer regions (p<0.01, n=3) and association of RNA polymerase II with the CS/GH-V promoter regions (p<0.01, n=3) were observed. These data provide evidence for CS/GH-V dysregulation in pregnancies complicated by increased insulin resistance through obesity, and implicate changes at the transcriptional level. These data also support the use of “humanized” mice to study CS/GH-V gene control during pregnancy at the molecular level. This may provide the opportunity to assess interventions to manage or prevent negative maternal and fetal outcomes in pregnancies complicated by obesity and associated health risks.

Nothing to Disclose: HV, YJ, MEB, SMM, PAC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Funded by the CIHR and a studentship to HV from the MICH-MHRC.
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