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

doi:10.1016/j.ajog.2015.02.026

American Journal of Obstetrics and Gynecology

Volume 212, Issue 5, May 2015, Pages 647.e1-647.e11

Presented in oral format at the 35th annual meeting of the Society for Maternal-Fetal Medicine, San Diego, CA, Feb. 2-7, 2015.

https://doi.org/10.1016/j.ajog.2015.02.026 Get rights and content

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.

Section snippets

Study subjects

In this study we define lean as subjects whose pregravid weight for height (body mass index [BMI] kg/m²) was less than 25 kg/m² and obese as subjects whose BMI was greater than 30 kg/m².

This study was approved by the Institutional Review Boards of MetroHealth Medical Center. Volunteers provided written informed consent in accordance with institution guidelines for the protection of human subjects prior to sample collection. Women without medical complications or laboratory signs of infection or

Placental transciptome in early pregnancy

Microarray analysis is an effective way to explore possible mechanisms and give an overall perspective of how the total transcriptome is changed or affected by a determined condition. In this study we used microarray to investigate the effects of in vitro insulin treatment and maternal obesity on global gene expression of primary isolated trophoblasts from first-trimester placentas.

The first approach was to run a PCA in the different data sets used for each comparison. PCA of in vitro response

Comment

The primary finding of this study is the detection of several classic insulin-sensitive pathways in the placenta of first-trimester pregnancy. In vitro treatment of isolated placental cells with insulin induced a number of genes known as downstream mediators of insulin signal transduction such as Ras and protein kinase teta.26, 27 Insulin treatment increased the expression of several sodium-potassium adenosine triphosphatases, ion channels, and transporters as described in muscle and pancreatic

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: This work was supported by National Institutes of Health grant R01-HD22965 (P.M.C. and S.H.-d.M.).

: The authors report no conflict of interest.

: The racing flag logo above indicates that this article was rushed to press for the benefit of the scientific community.

: Cite this article as: Lassance L, Haghiac M, Leahy P, et al. Identification of early transcriptome signatures in placenta exposed to insulin and obesity. Am J Obstet Gynecol 2015;212:647.e1-11.

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

Objective

Study Design

Results

Conclusion

Section snippets

Study subjects

Placental transciptome in early pregnancy

Comment

Life Sci

Am J Obstet Gynecol

Am J Obstet Gynecol

Placenta

J Biol Chem

J Biol Chem

J Mol Cell Cardiol

Peptides

Am J Obstet Gynecol

Biochem Biophys Res Commun

Trends Endocrinol Metab

Placenta

Metabolic adaptations in pregnancy and their implications for the availability of substrates to the fetus

Eur J Clin Nutr

Two phases of adipose tissue metabolism in pregnancy: maternal adaptations for fetal growth

Endocrinology

Metabolic adjustments in normal and diabetic pregnancy

Clin Obstet Gynecol

Impact of maternal fuels and nutritional state on fetal growth

Diabetes

Role of gestational hormones in the induction of insulin resistance

J Clin Endocrinol Metab

Effects of pregnancy and progesterone and/or oestradiol on the insulin secretion and pancreatic insulin content in the perfused rat pancreas

Diabetes Metab

TNF-alpha is a predictor of insulin resistance in human pregnancy

Diabetes

Tumor necrosis factor alpha inhibits signaling from the insulin receptor

Proc Nat Acad Sci USA

Reversal of insulin resistance postpartum is linked to enhanced skeletal muscle insulin signaling

J Clin Endocrinol Metab

Human placental lactogen: studies of its acute metabolic effects and disposition in normal man

J Clin Invest

Human growth hormone and placental lactogen levels in midpregnancy and late postpartum

Obstet Gynecol

Characteristics of the microvillus brush border of human placenta: insulin receptor localization in brush border membranes

Endocrinology

Nonuniform distribution and grouping of insulin receptors on the surface of human placental syncytial trophoblast

Diabetes

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