27: Maternal insulin resistance modifies placental transcriptome early in pregnancy

Abstract

ObjectiveIncreased insulin resistance (IR) alters maternal metabolic adaptations to pregnancy and modifies feto-placental growth. We hypothesized that the placenta senses and responds to changes in maternal insulin homeostasis. We investigated the effects of maternal IR on placental transcriptome in first trimester pregnancies.Study DesignPlasma and placenta villous tissue were obtained at time of pregnancy termination (7-11 weeks) in 67 healthy women. Maternal IR was estimated using the homeostatic model assessment (HOMA-IR) and ranged from 0.33 to 5.20. For in vitro studies, trophoblast cells were isolated from placentas of 17 women with low IR (LIR, HOMA <2.0, BMI: 20.9 ± 1.5) and 21 with high IR (HIR, HOMA>2.0, BMI: 33.5 ± 2.6). In vitro insulin treated vs. untreated trophoblasts were used for global gene expression analysis using microarray technology. Data were analyzed using principle component analysis (PCA), ClueGO and David software. Changes in gene expression were validated by quantitative real time PCR.ResultsThe global trophoblast transcriptome was qualitatively (PCA mapping) and quantitatively different in women with HIR vs. LIR. The primary effect of insulin resistance was to decrease (315) rather than increase (40) gene expression (Fig.1). Decreased pathways were related to steroid biosynthesis, cholesterol metabolism and fatty acid transport. Adding insulin to cultured trophoblast changed the expression of 2885 genes (67% decreased) in LIR and 87 (57% decreased) in HIR women (Fig.1). For example, the acetylcoA acyl transferases ACAT1 and ACAT2, responsible for formation of cholesterol esters, was downregulated 2.5 fold by insulin in trophoblast cells of HIR but not LIR women.Conclusion ObjectiveIncreased insulin resistance (IR) alters maternal metabolic adaptations to pregnancy and modifies feto-placental growth. We hypothesized that the placenta senses and responds to changes in maternal insulin homeostasis. We investigated the effects of maternal IR on placental transcriptome in first trimester pregnancies. Increased insulin resistance (IR) alters maternal metabolic adaptations to pregnancy and modifies feto-placental growth. We hypothesized that the placenta senses and responds to changes in maternal insulin homeostasis. We investigated the effects of maternal IR on placental transcriptome in first trimester pregnancies. Study DesignPlasma and placenta villous tissue were obtained at time of pregnancy termination (7-11 weeks) in 67 healthy women. Maternal IR was estimated using the homeostatic model assessment (HOMA-IR) and ranged from 0.33 to 5.20. For in vitro studies, trophoblast cells were isolated from placentas of 17 women with low IR (LIR, HOMA <2.0, BMI: 20.9 ± 1.5) and 21 with high IR (HIR, HOMA>2.0, BMI: 33.5 ± 2.6). In vitro insulin treated vs. untreated trophoblasts were used for global gene expression analysis using microarray technology. Data were analyzed using principle component analysis (PCA), ClueGO and David software. Changes in gene expression were validated by quantitative real time PCR. Plasma and placenta villous tissue were obtained at time of pregnancy termination (7-11 weeks) in 67 healthy women. Maternal IR was estimated using the homeostatic model assessment (HOMA-IR) and ranged from 0.33 to 5.20. For in vitro studies, trophoblast cells were isolated from placentas of 17 women with low IR (LIR, HOMA <2.0, BMI: 20.9 ± 1.5) and 21 with high IR (HIR, HOMA>2.0, BMI: 33.5 ± 2.6). In vitro insulin treated vs. untreated trophoblasts were used for global gene expression analysis using microarray technology. Data were analyzed using principle component analysis (PCA), ClueGO and David software. Changes in gene expression were validated by quantitative real time PCR. ResultsThe global trophoblast transcriptome was qualitatively (PCA mapping) and quantitatively different in women with HIR vs. LIR. The primary effect of insulin resistance was to decrease (315) rather than increase (40) gene expression (Fig.1). Decreased pathways were related to steroid biosynthesis, cholesterol metabolism and fatty acid transport. Adding insulin to cultured trophoblast changed the expression of 2885 genes (67% decreased) in LIR and 87 (57% decreased) in HIR women (Fig.1). For example, the acetylcoA acyl transferases ACAT1 and ACAT2, responsible for formation of cholesterol esters, was downregulated 2.5 fold by insulin in trophoblast cells of HIR but not LIR women. The global trophoblast transcriptome was qualitatively (PCA mapping) and quantitatively different in women with HIR vs. LIR. The primary effect of insulin resistance was to decrease (315) rather than increase (40) gene expression (Fig.1). Decreased pathways were related to steroid biosynthesis, cholesterol metabolism and fatty acid transport. Adding insulin to cultured trophoblast changed the expression of 2885 genes (67% decreased) in LIR and 87 (57% decreased) in HIR women (Fig.1). For example, the acetylcoA acyl transferases ACAT1 and ACAT2, responsible for formation of cholesterol esters, was downregulated 2.5 fold by insulin in trophoblast cells of HIR but not LIR women. Conclusion