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4: Antenatal origins of metabolic syndrome in fetuses of obese women

      Objective

      Molecular mechanisms that predispose offspring of obese pregnant women to insulin resistance, appetite dysregulation, and fatty liver disease are poorly understood. We sought to understand the effects of maternal obesity on fetal gene expression by analyzing cell-free fetal RNA (cffRNA) in amniotic fluid supernatant (AFS).

      Study Design

      We prospectively studied cffRNA in AFS of women with singleton fetuses undergoing clinically indicated 2nd trimester genetic amniocenteses. Eight obese gravidas (Ob, BMI ≥30) and 8 lean controls (L, BMI <25) were matched for gestational age and fetal sex. Exclusion criteria included abnormal karyotype and structural anomalies. CffRNA was extracted, amplified, and hybridized to whole genome expression arrays. Genes significantly differentially regulated in 8/8 pairs were identified using paired t-test with the Benjamini-Hochberg (BH) correction. Functional analyses were performed using Ingenuity Pathways Analysis™ software. Genes and transcription factors associated with bias-corrected absolute Z-scores ≥2.0 or BH p < .05 were called significant.

      Results

      Demographic characteristics are shown in Table 1. There were 205 differentially regulated genes in fetuses of obese gravidas. The most up-regulated gene (9-fold) in Ob was APOD, which encodes a lipoprotein integral to lipid regulation, glucose metabolism, and inflammatory response. Upstream regulator analyses demonstrated significant activation of the estrogen receptor and the transcription factors STAT3 and FOS in fetuses of obese women.
      Tabled 1Subject demographics and array hybridization characteristics
      Table thumbnail grr3

      Conclusion

      Expression of APOD, STAT3, and FOS is implicated in insulin resistance, hyperleptinemia, hepatic steatosis, atherosclerosis, toll-like receptor signaling, and inflammatory response. Analysis of cffRNA in AFS demonstrates a pro-estrogenic, pro-inflammatory milieu for fetuses of obese women. Molecular mechanisms predisposing offspring of obese women to metabolic complications may be initiated as early as the second trimester.