Identification of early transcriptome signatures in placenta exposed to insulin and obesity

Abstract

OBJECTIVE The purpose of this study was to investigate the effects of insulin on human placental transcriptome and biological processes in first-trimester pregnancy. STUDY DESIGN Maternal plasma and placenta villous tissue were obtained at the time of voluntary termination of pregnancy (7–12 weeks) from 17 lean (body mass index, 20.9 ± 1.5 kg/m2) and 18 obese (body mass index, 33.5 ± 2.6 kg/m2) women. Trophoblast cells were immediately isolated for in vitro treatment with insulin or vehicle. Patterns of global gene expression were analyzed using genome microarray profiling after hybridization to Human Gene 1.1 ST and real time reverse transcription–polymerase chain reaction. RESULTS The global trophoblast transcriptome was qualitatively separated in insulin-treated vs untreated trophoblasts of lean women. The number of insulin-sensitive genes detected in the trophoblasts of lean women was 2875 (P < .001). Maternal obesity reduced the number of insulin-sensitive genes recovered by 30-fold. Insulin significantly impaired several gene networks regulating cell cycle and cholesterol homeostasis but did not modify pathways related to glucose transport. Obesity associated with high insulin and insulin resistance, but not maternal hyperinsulinemia alone, impaired the global gene profiling of early gestation placenta, highlighting mitochondrial dysfunction and decreased energy metabolism. CONCLUSION We report for the first time that human trophoblast cells are highly sensitive to insulin regulation in early gestation. Maternal obesity associated with insulin resistance programs the placental transcriptome toward refractoriness to insulin with potential adverse consequences for placental structure and function.

Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child

“…30 The maternal metabolic environment affects early placental growth and gene expression, as well as later placental function, which become clinically manifest in late pregnancy. 31 A potential mechanism is that insulin receptors are more abundant on the maternal trophoblast surface in early gestation than in later gestation. 32 The hyperinsulinemia associated with obesity related insulin resistance results in differential responses in placental trophoblasts.…”

Review: Placental transport and metabolism of energy substrates in maternal obesity and diabetes

“…In humans, maternal obesity, in concert with insulin resistance, was associated with 210 altered placental expression of genes related to cholesterol uptake and metabolism [68]. In 211 women with high cholesterol, placental fatty acid synthase (FAS) and sterol regulatory 212 element-binding protein (SREBP)-2 expression were increased, with no alteration to SREBP-213 1 or HMG-CoA reductase (HMGR) [69].…”

When two obese parents are worse than one! Impacts on embryo and fetal development

“…As both in vivo-and in vitro-derived fetuses and placentas were reduced in size with combined paternal and maternal obesity, and since both pater-nal and maternity obesity alone alter placental gene expression (5,8,46,75), we established whether key imprinting, growth, nutrition, and mitochondrial specific gene regulation were further impaired when both parents were obese. We observed sex-specific effects on placental gene expression that were expected given the numerous reports of sex-specific phenotypes in offspring in models of maternal and paternal obesity (18,19,22,23,63,66,67).…”

“…Either maternal or paternal HFD in isolation has been shown to change the transcriptome of the developing placenta (5,8,46,75). Thus, we determined whether there were additive effects of combined paternal and maternal HFD on placental gene expression during gestation.…”