Abstract
Objective:
The aim of this study was to determine gene expression and splicing changes associated with parturition and regions (visceral vs. subcutaneous) of the adipose tissue of pregnant women.
Study design:
The transcriptome of visceral and abdominal subcutaneous adipose tissue from pregnant women at term with (n=15) and without (n=25) spontaneous labor was profiled with the Affymetrix GeneChip Human Exon 1.0 ST array. Overall gene expression changes and the differential exon usage rate were compared between patient groups (unpaired analyses) and adipose tissue regions (paired analyses). Selected genes were tested by quantitative reverse transcription-polymerase chain reaction.
Results:
Four hundred and eighty-two genes were differentially expressed between visceral and subcutaneous fat of pregnant women with spontaneous labor at term (q-value <0.1; fold change >1.5). Biological processes enriched in this comparison included tissue and vasculature development as well as inflammatory and metabolic pathways. Differential splicing was found for 42 genes [q-value <0.1; differences in Finding Isoforms using Robust Multichip Analysis scores >2] between adipose tissue regions of women not in labor. Differential exon usage associated with parturition was found for three genes (LIMS1, HSPA5, and GSTK1) in subcutaneous tissues.
Conclusion:
We show for the first time evidence of implication of mRNA splicing and processing machinery in the subcutaneous adipose tissue of women in labor compared to those without labor.
Introduction
Parturition imposes an increased energy demand on the laboring woman. Labor is characterized by increased concentrations of nutrients including glucose [1–5], free fatty acids [3, 6], ketone bodies [7], and lactic acid [8]. There is an approximate three-fold increase in whole body glucose utilization during labor and delivery and, as expected, energy expenditure of the parturient women in the second stage of labor is 40% higher compared to the first stage [9]. Additional support for the metabolic burden of labor can also be found in the examination of myometrial glycogen storage, which is significantly increased at term [10], but almost completely depleted during labor [11]. Consistent with these findings, examination of the human myometrial transcriptome revealed that biological processes related to metabolism were among the molecular functions enriched in the differentially expressed genes between pregnant women with and without spontaneous term labor [12].
The conventional view is that the energy expenditure of labor and delivery is equivalent to that of moderate exercise [1, 9] and that similar mechanisms (e.g. insulin and non-insulin dependent glucose uptake, enhanced hepatic gluconeogenesis, and direct sympathetic nervous system stimulation) govern the metabolic adaptation to parturition [9, 13, 14]. However, whether or not adipose tissue, the major energy reservoir, is affected by labor and delivery is still unknown. Assessment of the putative role of adipose tissue in human parturition may be of special importance considering the large body of evidence indicating that this endocrinal organ is powerful [15] and exerts autocrine, paracrine and endocrine effects by the production and secretion of highly active peptides and proteins collectively termed adipokines [16]. Importantly, adipokines have been implicated in physiological adaptations of normal gestation [17–28] as well as in the pathophysiology of preeclampsia [21, 29–50], gestational diabetes mellitus [51–65], preterm birth [66–68], delivery of large-for-gestational-age (LGA) newborns [69], small-for-gestational-age (SGA) neonates [70–76], pyelonephritis [77–79], and intrauterine infection and inflammation [80–83]. Of note is the well-established association between obesity and these complications of pregnancy [84–113].
It has been suggested that the implication of adipose tissue in physiological or pathological processes should take into account the region-specific differences between fat depots. Particularly, differences in function [114–116], gene expression [115, 117–144], and metabolic effect [145–150] between the visceral and subcutaneous adipose tissue are to be considered. Indeed, regional variations of adipose tissue in specific genes were reported in non-pregnant individuals using both high throughput techniques [131–133, 136, 151] and targeted approaches [115, 116, 131, 133, 152–166]. Overall gene expression in the adipose tissue of pregnant women has been previously reported [32, 117–123, 167–178]; however, adipose tissue gene expression, biological processes, molecular functions, and pathways associated with spontaneous term parturition have not been described. Furthermore, to our knowledge, exon-level changes that can inform on alternative promoter usage, alternative splicing, and alternative transcript termination [179] between the visceral and subcutaneous regions have not been reported in either fat or other tissue of parturient women.
We undertook this study in order to characterize the transcriptome of human visceral and subcutaneous adipose tissue during normal labor at term to gain understanding of the global changes in gene expression and splicing associated with adiposity using an unbiased approach. The aims of this study were: 1) to determine differences in visceral and subcutaneous gene expression between pregnant women with and without spontaneous labor at term; 2) to determine regional variations in the transcriptome of adipose tissue of patients with spontaneous labor at term; and 3) to identify depot-specific alternative splicing alterations in the adipose tissue of women with spontaneous labor at term.
Materials and methods
Study groups
A prospective study was performed in which visceral and subcutaneous adipose tissue samples were obtained from women undergoing cesarean section at term (≥37 weeks) in the following groups: 1) not in labor (n=25) and 2) spontaneous labor (n=15).
The inclusion criteria for both groups were as follows: 1) absence of medical complications; 2) no antibiotic administration prior to the sample collection; 3) normal post-operative course; 4) absence of meconium staining of the amniotic fluid; 5) neonatal Apgar scores >7 at 1 and 5 min; 6) absence of histologic chorioamnionitis; 7) absence of obstetric complications of pregnancy; and 8) normal pregnancy outcome, including an infant who was of appropriate-weight-for-gestational-age (AGA) without congenital anomalies.
Eligible patients were enrolled at Hutzel Women’s Hospital (Detroit, MI, USA). All women provided written informed consent prior to the collection of adipose tissue samples. The collection and utilization of the samples for research purposes was approved by the Institutional Review Boards of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD/NIH/DHHS, Bethesda, MD, USA), and the Human Investigation Committee of Wayne State University (Detroit, MI, USA). Samples obtained from pregnant women not in labor have been previously used to study the differences in transcriptome between pregnant and non-pregnant women.
Clinical definitions
Patients not in labor underwent a cesarean section secondary to a fetus in the non-cephalic presentation, previous uterine surgery, or classical cesarean section, or an elective cesarean section with no more than one previous cesarean section. Women in spontaneous labor underwent cesarean section due to a fetal malpresentation or for non-reassuring fetal status as determined by the clinical staff. Patients with clinical or histological chorioamnionitis and those undergoing induction of labor were excluded.
Labor was diagnosed in the presence of spontaneous regular uterine contractions occurring at a minimum frequency of two every 10 min with cervical changes that required hospital admission. Histologic chorioamnionitis was diagnosed using previously described criteria [180, 181]. An AGA neonate was defined by a birth weight between the 10th and 90th percentiles for the gestational age at birth [182]. Body mass index (BMI) was calculated according to the formula: weight (kg)/height2 (m2).
Sample collection
Paired visceral and subcutaneous adipose tissue samples were obtained from each participant. Subcutaneous adipose tissue samples were collected at the site of a transverse lower abdominal incision, in the middle of the Pfannenstiel incision, from the deeper strata of subcutaneous fat. Visceral samples were obtained from the most distal portion of the greater omentum [116, 183–186]. Visceral and subcutaneous adipose tissues were collected using Metzenbaum scissors and measured approximately 1.0 cm3. Tissues were snap-frozen in liquid nitrogen and stored at –80°C until use.
RNA isolation
Total RNA was isolated from snap-frozen adipose tissue using TRI Reagent® combined with the Qiagen RNeasy Lipid Tissue kit protocol (Qiagen, Valencia, CA, USA), according to the manufacturers’ recommendations. The RNA concentrations and the A260 nm/A280 nm ratio were assessed using a NanoDrop 1000 spectrophotometer (Thermo Scientific, Wilmington, DE, USA). RNA integrity numbers were determined using the Bioanalyzer 2100 (Agilent Technologies, Wilmington, DE, USA).
Microarray analysis and quantitative real-time polymerase chain reaction
The Affymetrix GeneChip Human Exon 1.0 ST array (Affymetrix Inc., Santa Clara, CA, USA) platform was used to measure the expression levels in each unpooled specimen, per manufacturer’s instructions (http://www.affymetrix.com). The array contains approximately 5.4 million 5-μm features (probes) grouped into 1.4 million probesets interrogating more than one million exon clusters [187–189]. To verify the results from microarray-based analysis, 24 genes were selected for quantitative real-time polymerase chain reaction (qRT-PCR) assays in the same set of samples used for microarrays.
Statistical analyses
Differential expression:
The raw microarray probe intensity data were background corrected, quantile normalized [190] and summarized into one expression value for each transcript using a robust multi-array average implemented in the aroma.affymetrix package [191]. A paired moderated t-test [192] was used to test for differential expression with a false discovery rate (FDR) [193] correction of P-values to obtain q-values. Gene significance was inferred using q<0.1 and fold-change in expression >1.5 [194]. Gene ontology analysis was performed with algorithms previously described [195]. Pathway analysis was performed on the Kyoto Encyclopedia of Genes and Genomes (KEGG) [196] pathway database (96 pathways with three or more genes on our microarray platform) with an overrepresentation analysis [197]. Alternatively, the Pathway Analysis with Down-weighting of Overlaping Genes (PADOG) [198] was applied on the canonical pathways collection from the MSigDB database [199] (831 pathways with at least 20 genes represented on our microarray platform). Differential expression between adipose tissue regions of the same subjects based on qRT-PCR data was performed with a paired t-test on –ΔCt values.
Differential exon usage (splicing):
To identify differential exon usage between the groups of samples, we used the method Finding Isoforms using Robust Multichip Analysis (FIRMA) [200] to quantify how far (above or below) a given exon’s expression level was compared to the expected (average) transcript level in a given sample. Criteria for inclusion of transcripts and exons are described in the supplementary material. We applied a t-test for each probeset (typically one per exon) in each transcript based on the FIRMA scores, and inferred significance when the difference in mean FIRMA scores between groups was 2.0 or more combined with a threshold of 0.1 on the FDR-adjusted P-values (q-values). This was a more stringent approach than described in another study [200] in which positive results were identified based only on the difference in mean FIRMA scores above 1.5 units. Plotting of the probe-level expression data at exon levels vs. genomic coordinates was performed using functionality provided by the GenomeGraphs package with known isoforms in the ENSEMBL database retrieved with biomaRt [200]. All microarray analyses were performed using the R language and environment and Bioconductor [200, 201].
Demographic data analysis:
The Student’s t, Mann-Whitney U, and χ2 tests were used to identify significant differences in patient demographics between women in the microarray and qRT-PCR groups. SPSS software (version 14.0; SPSS Inc, Chicago, IL, USA) was used for statistical analysis of demographic data. A probability value of <0.05 was considered statistically significant.
Results
Demographics
Table 1 displays the demographic characteristics of patients who were included in the microarray and qRT-PCR analyses.
Demographic and clinical characteristics of the study population.
| Term labor (n=15) | Term not in labor (n=25) | P-value | |
|---|---|---|---|
| Maternal age (years) | 26 (24–38) | 27 (25–39) | 0.2 |
| Gestational age at delivery (weeks) | 39.7 (39–40.6) | 39.1 (38.9–39.4) | 0.2 |
| Pre-gestational BMI (kg/m2) | 35.3 (30.9–38.5) | 37.5 (26.2–40.2) | 0.5 |
| BMI at sampling (kg/m2) | 36.9 ( 32.5–39.7) | 37.2 (27.8–45.4) | 0.8 |
| Gravidity | 3 (2–3) | 3 (2–4) | 0.5 |
| Parity | 2 (1–3) | 2 (2–3) | 0.2 |
| Ethnic origin (%) | 1.0 | ||
| African American | 91.7 | 83.3 | |
| Caucasian | 8.3 | 16.7 | |
| Systolic blood pressure (mm Hg) | 124 (117–127) | 121 (115–126) | 0.4 |
| Diastolic blood pressure (mm Hg) | 75 (67–79) | 66 (62–77) | 0.3 |
| Cervical dilatation at sampling | 5 (4–7) | 1 (1–2) | <0.001 |
| Fasting glucose (mg/dL) | 93 (87–98) | 94 (88–97) | 0.7 |
| Birth weight (g) | 3320 (3155–3825) | 3275 (3105–3500) | 0.7 |
Data are presented as median and interquartile range (IQR). BMI=Body mass index.
Regional differences in the transcriptome of adipose tissue of women with and without labor
Differential expression
Microarray analysis demonstrated 485 transcripts corresponding to 482 unique genes differentially expressed between the visceral and subcutaneous adipose tissue of pregnant women in spontaneous labor at term (q-value <0.1; fold change >1.5). A total of 329 genes had decreased expression, and 153 genes had increased expression in the subcutaneous, compared to visceral, adipose tissue. A “volcano plot” shows the differential expression of all annotated probesets on the Affymetrix GeneChip Human Exon 1.0 ST array with the log (base 10) of q-values (y-axis) plotted against the log (base 2) fold changes (x-axis) between the visceral and subcutaneous adipose tissue (Figure 1). The heatmap in Figure 2 uses a color scale to show the consistency of the expression levels within each group of samples as well as the differences between the groups that led to positive test results. A list of the top 100 genes differentially expressed between visceral and subcutaneous adipose tissue of patients with and without spontaneous labor at term is presented in Table 2; the complete list of differentially expressed probes is available as supplementary material (Supplementary Table 1).
Differential expression of visceral versus subcutaneous adipose tissue transcripts in pregnant women in labor.
Volcano plot showing differential expression evidence between subcutaneous and visceral adipose tissue of women in labor. The x-axis represents the log2 fold changes in expression with positive values representing over-expression in the subcutaneous region compared to visceral. Transcripts outside the vertical red bars have fold change >1.5. The y-axis represents the q-values (–log10 of), with values above 1.0 corresponding to q<0.1.
Heat map representing fat depot-specific differences in gene expression of pregnant women in labor.
Heatmap showing the consistency of gene expression levels between subcutaneous and visceral regions of the adipose tissue of women in labor. Log2 transformed transcript expression values are centered and scaled row-wise.
A list of the top 100 differentially expressed genes between visceral and subcutaneous adipose tissue of patients with and without spontaneous labor at term.
| ENTREZ | Symbol | Name | Fold change | q-Value |
|---|---|---|---|---|
| 364 | AQP7 | Aquaporin 7 | 1.6 | 0.007 |
| 355 | FAS | Fas (TNF receptor superfamily, member 6) | –1.9 | 0.007 |
| 100293763 | AQP7P1 | Aquaporin 7 pseudogene 1 | 1.8 | 0.007 |
| 9871* | SEC24D | SEC24 family, member D (Saccharomyces cerevisiae) | –1.7 | 0.007 |
| 83666* | PARP9 | Poly(ADP-ribose) polymerase family, member 9 | –1.6 | 0.008 |
| 729085* | CCBP2 | Chemokine binding protein 2 | –1.6 | 0.008 |
| 6285 | S100B | S100 calcium binding protein B | 1.6 | 0.008 |
| 10555 | AGPAT2 | 1-Acylglycerol-3-phosphate O-acyltransferase 2 (lysophosphatidic acid acyltransferase, beta) | 1.6 | 0.008 |
| 6574 | SLC20A1 | Solute carrier family 20 (phosphate transporter), member 1 | –1.9 | 0.008 |
| 54566 | EPB41L4B | Erythrocyte membrane protein band 4.1 like 4B | 1.6 | 0.008 |
| 58477* | SRPRB | Signal recognition particle receptor, B subunit | –1.8 | 0.008 |
| 54988* | ACSM5 | Acyl-CoA synthetase medium-chain family member 5 | 1.6 | 0.008 |
| 9180 | OSMR | Oncostatin M receptor | –1.9 | 0.008 |
| 284221 | FAM38B2 | Family with sequence similarity 38, member B2 | –2.0 | 0.008 |
| 2819 | GPD1 | Glycerol-3-phosphate dehydrogenase 1 (soluble) | 1.7 | 0.008 |
| 9052 | GPRC5A | G protein-coupled receptor, family C, group 5, member A | –1.7 | 0.008 |
| 10973* | ASCC3 | Activating signal cointegrator 1 complex subunit 3 | –1.5 | 0.008 |
| 6517 | SLC2A4 | Solute carrier family 2 (facilitated glucose transporter), member 4 | 1.6 | 0.008 |
| 6713 | SQLE | Squalene epoxidase | –1.6 | 0.008 |
| 83716 | CRISPLD2 | Cysteine-rich secretory protein LCCL domain containing 2 | –1.9 | 0.008 |
| 10249 | GLYAT | Glycine-N-acyltransferase | 2.4 | 0.008 |
| 23555 | TSPAN15 | Tetraspanin 15 | 1.6 | 0.008 |
| 8908 | GYG2 | Glycogenin 2 | 1.5 | 0.008 |
| 5578 | PRKCA | Protein kinase C, alpha | –1.5 | 0.008 |
| 54884 | RETSAT | Retinol saturase (all-trans-retinol 13,14-reductase) | 1.6 | 0.008 |
| 5055 | SERPINB2 | Serpin peptidase inhibitor, clade B (ovalbumin), member 2 | –4.9 | 0.008 |
| 57568* | SIPA1L2 | Signal-induced proliferation-associated 1 like 2 | –1.5 | 0.008 |
| 5207 | PFKFB1 | 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 | 1.9 | 0.008 |
| 60559* | SPCS3 | Signal peptidase complex subunit 3 homolog (S. cerevisiae) | –1.6 | 0.008 |
| 9197* | SLC33A1 | Solute carrier family 33 (acetyl-CoA transporter), member 1 | –1.5 | 0.008 |
| 3991 | LIPE | Lipase, hormone-sensitive | 1.6 | 0.008 |
| 26064* | RAI14 | Retinoic acid induced 14 | –1.6 | 0.008 |
| 8542* | APOL1 | Apolipoprotein L, 1 | –1.6 | 0.008 |
| 374969 | CCDC23 | Coiled-coil domain containing 23 | 1.5 | 0.008 |
| 8639 | AOC3 | Amine oxidase, copper containing 3 (vascular adhesion protein 1) | 1.6 | 0.008 |
| 11098 | PRSS23 | Protease, serine, 23 | –1.7 | 0.008 |
| 2822 | GPLD1 | Glycosylphosphatidylinositol specific phospholipase D1 | 1.7 | 0.008 |
| 8659 | ALDH4A1 | Aldehyde dehydrogenase 4 family, member A1 | 1.8 | 0.008 |
| 4718 | THRSP | Thyroid hormone responsive (SPOT14 homolog, rat) | 1.8 | 0.008 |
| 55024* | BANK1 | B-cell scaffold protein with ankyrin repeats 1 | 1.6 | 0.008 |
| 6782* | HSPA13 | Heat shock protein 70 kDa family, member 13 | –1.8 | 0.008 |
| 65983 | GRAMD3 | GRAM domain containing 3 | –1.8 | 0.008 |
| 4137 | MAPT | Microtubule-associated protein tau | 1.6 | 0.008 |
| 1009 | CDH11 | Cadherin 11, type 2, OB-cadherin (osteoblast) | –2.0 | 0.008 |
| 10130* | PDIA6 | Protein disulfide isomerase family A, member 6 | –1.5 | 0.008 |
| 51602* | NOP58 | NOP58 ribonucleoprotein homolog (yeast) | –1.6 | 0.008 |
| 81539 | SLC38A1 | Solute carrier family 38, member 1 | –2.4 | 0.008 |
| 51716 | CES1 | Carboxylesterase 1 (monocyte/macrophage serine esterase 1) | 2.2 | 0.008 |
| 9643* | MORF4L2 | Mortality factor 4 like 2 | –1.5 | 0.008 |
| 666 | BOK | BCL2-related ovarian killer | 1.6 | 0.008 |
| 9945 | GFPT2 | Glutamine-fructose-6-phosphate transaminase 2 | –2.4 | 0.008 |
| 55254* | TMEM39A | Transmembrane protein 39A | –1.5 | 0.008 |
| 22915 | MMRN1 | Multimerin 1 | –3.8 | 0.008 |
| 84293 | C10orf58 | Chromosome 10 open reading frame 58 | 1.6 | 0.008 |
| 64757 | MOSC1 | MOCO sulphurase C-terminal domain containing 1 | 1.6 | 0.008 |
| 64805* | P2RY12 | Purinergic receptor P2Y, G-protein coupled, 12 | 1.6 | 0.008 |
| 91607 | SLFN13 | Schlafen family member 13 | –1.5 | 0.009 |
| 220 | ALDH1A3 | Aldehyde dehydrogenase 1 family, member A3 | –2.3 | 0.009 |
| 212* | ALAS2 | Aminolevulinate, delta-, synthase 2 | 1.7 | 0.009 |
| 10962 | MLLT11 | Myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 11 | –2.2 | 0.009 |
| 358* | AQP1 | Aquaporin 1 (Colton blood group) | –1.5 | 0.009 |
| 23612* | PHLDA3 | Pleckstrin homology-like domain, family A, member 3 | 1.5 | 0.009 |
| 6578 | SLCO2A1 | Solute carrier organic anion transporter family, member 2A1 | –1.7 | 0.009 |
| 286753* | TUSC5 | Tumor suppressor candidate 5 | 1.5 | 0.009 |
| 5271* | SERPINB8 | Serpin peptidase inhibitor, clade B (ovalbumin), member 8 | –1.7 | 0.009 |
| 63924 | CIDEC | Cell death-inducing DFFA-like effector c | 1.8 | 0.009 |
| 4189* | DNAJB9 | DnaJ (Hsp40) homolog, subfamily B, member 9 | –1.7 | 0.009 |
| 56265 | CPXM1 | Carboxypeptidase X (M14 family), member 1 | –1.7 | 0.009 |
| 58528* | RRAGD | Ras-related GTP binding D | 1.5 | 0.009 |
| 262* | AMD1 | Adenosylmethionine decarboxylase 1 | –1.5 | 0.009 |
| 222166 | C7orf41 | Chromosome 7 open reading frame 41 | 1.6 | 0.009 |
| 338 | APOB | Apolipoprotein B [including Ag(x) antigen] | 2.4 | 0.009 |
| 158295 | MGC24103 | Hypothetical MGC24103 | –1.5 | 0.009 |
| 1805* | DPT | Dermatopontin | 1.5 | 0.009 |
| 10237* | SLC35B1 | Solute carrier family 35, member B1 | –1.5 | 0.009 |
| 623 | BDKRB1 | Bradykinin receptor B1 | –3.0 | 0.009 |
| 5740 | PTGIS | Prostaglandin I2 (prostacyclin) synthase | –2.0 | 0.009 |
| 6272 | SORT1 | Sortilin 1 | 1.7 | 0.009 |
| 1645 | AKR1C2 | Aldo-keto reductase family 1, member C2 (dihydrodiol dehydrogenase 2; bile acid binding protein; 3-a hydroxysteroid dehydrogenase, type III) | 2.1 | 0.009 |
| 5649 | RELN | Reelin | –1.6 | 0.009 |
| 6446 | SGK1 | Serum/glucocorticoid regulated kinase 1 | –1.9 | 0.009 |
| 51330 | TNFRSF12A | Tumor necrosis factor receptor superfamily, member 12A | –1.8 | 0.009 |
| 388403* | YPEL2 | Yippee-like 2 (Drosophila) | 1.7 | 0.009 |
| 80704 | SLC19A3 | Solute carrier family 19, member 3 | 1.5 | 0.009 |
| 5140 | PDE3B | Phosphodiesterase 3B, cGMP-inhibited | 1.7 | 0.009 |
| 3036 | HAS1 | Hyaluronan synthase 1 | –1.7 | 0.009 |
| 1646 | AKR1C1 | Aldo-keto reductase family 1, member C1 (dihydrodiol dehydrogenase 1; 20-a (3-a)-hydroxysteroid dehydrogenase) | 2.3 | 0.009 |
| 1962 | EHHADH | Enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A dehydrogenase | 1.5 | 0.009 |
| 90355* | C5orf30 | Chromosome 5 open reading frame 30 | 1.6 | 0.009 |
| 283383 | GPR133 | G protein-coupled receptor 133 | –2.1 | 0.009 |
| 4199 | ME1 | Malic enzyme 1, NADP(+)-dependent, cytosolic | 1.7 | 0.009 |
| 6366 | CCL21 | Chemokine (C-C motif) ligand 21 | –3.5 | 0.009 |
| 4023 | LPL | Lipoprotein lipase | 1.6 | 0.009 |
| 6385 | SDC4 | Syndecan 4 | –2.5 | 0.009 |
| 84649 | DGAT2 | Diacylglycerol O-acyltransferase homolog 2 (mouse) | 1.6 | 0.009 |
| 80339* | PNPLA3 | Patatin-like phospholipase domain containing 3 | 1.6 | 0.009 |
| 783 | CACNB2 | Calcium channel, voltage-dependent, beta 2 subunit | –1.7 | 0.009 |
| 7086 | TKT | Transketolase | 1.5 | 0.009 |
| 63895* | FAM38B | Family with sequence similarity 38, member B | –1.6 | 0.009 |
| 4883 | NPR3 | Natriuretic peptide receptor C/guanylate cyclase C (atrionatriuretic peptide receptor C) | 1.8 | 0.009 |
Among the 482 genes differentially expressed between visceral and subcutaneous adipose tissue in patients with spontaneous labor at term, 91 were not part of the 632 genes differentially expressed in the not in labor group (ENTREZ IDs suffixed by a * in Table 2 and Supplementary Table 1).
In order to gain further insight into the biology of the differential gene expression, Gene Ontology enrichment analysis was employed. A total of 94 biological processes were associated with regional differences in the spontaneous term labor group (q<0.05) (Table 3). Pathway analysis performed using an over-representation on the KEGG database resulted in seven significant pathways in this comparison (q<0.05): complement and coagulation cascades, cytokine-cytokine receptor interaction, focal adhesion, steroid hormone biosynthesis, ECM-receptor interaction, African trypanosomiasis, and protein digestion and absorption.
Bological processes associated with regional differences in the spontaneous term labor group.
| Biological process | Term size | DE genes | Odds ratio | q-Value |
|---|---|---|---|---|
| Response to external stimulus | 951 | 74 | 2.7 | <0.001 |
| Retinal metabolic process | 9 | 8 | 216.8 | <0.001 |
| Circulatory system development | 739 | 61 | 2.6 | <0.001 |
| Regulation of complement activation | 18 | 9 | 27.1 | <0.001 |
| Blood vessel morphogenesis | 347 | 35 | 3.2 | <0.001 |
| Multicellular organismal process | 4870 | 232 | 1.7 | <0.001 |
| Positive regulation of cellular component movement | 283 | 30 | 3.3 | <0.001 |
| Anatomical structure formation involved in morphogenesis | 846 | 61 | 2.2 | <0.001 |
| Regulation of cell motility | 498 | 42 | 2.6 | <0.001 |
| Terpenoid metabolic process | 63 | 13 | 7.2 | <0.001 |
| Retinol metabolic process | 17 | 7 | 18.9 | <0.001 |
| Phototransduction, visible light | 70 | 13 | 6.2 | <0.001 |
| Vasculature development | 393 | 34 | 2.7 | 0.001 |
| Triglyceride catabolic process | 25 | 8 | 12.7 | 0.001 |
| Positive regulation of signal transduction | 905 | 60 | 2.1 | 0.001 |
| Glomerular filtration | 19 | 7 | 15.8 | 0.001 |
| Neutral lipid catabolic process | 29 | 8 | 10.3 | 0.002 |
| Regulation of inflammatory response | 123 | 16 | 4.2 | 0.002 |
| Cell motility | 461 | 35 | 2.5 | 0.002 |
| Positive regulation of cell-substrate adhesion | 60 | 11 | 6.1 | 0.002 |
| Detection of light stimulus | 86 | 13 | 4.9 | 0.003 |
| Acute inflammatory response | 75 | 12 | 5.2 | 0.003 |
| Reproductive system development | 321 | 28 | 2.6 | 0.004 |
| Striated muscle cell differentiation | 164 | 18 | 3.4 | 0.005 |
| Regulation of hormone levels | 122 | 15 | 3.9 | 0.005 |
| Tissue morphogenesis | 498 | 37 | 2.2 | 0.005 |
| Death | 1510 | 84 | 1.7 | 0.006 |
| Glycerolipid catabolic process | 36 | 8 | 7.7 | 0.007 |
| Cellular response to jasmonic acid stimulus | 3 | 3 | Inf | 0.008 |
| Positive regulation of phosphate metabolic process | 776 | 50 | 1.9 | 0.008 |
| Receptor-mediated endocytosis | 173 | 18 | 3.2 | 0.008 |
| Cellular developmental process | 2884 | 140 | 1.5 | 0.008 |
| Protein activation cascade | 49 | 9 | 6.1 | 0.009 |
| Tube development | 407 | 31 | 2.3 | 0.010 |
| Urogenital system development | 211 | 20 | 2.9 | 0.011 |
| Positive regulation vascular endothelial growth factor production | 21 | 6 | 10.8 | 0.011 |
| Cell junction assembly | 177 | 18 | 3.1 | 0.011 |
| Positive regulation of angiogenesis | 102 | 13 | 4.0 | 0.011 |
| Response to lipid | 607 | 41 | 2.0 | 0.012 |
| Positive regulation of macrophage derived foam cell differentiation | 14 | 5 | 14.9 | 0.012 |
| Cell chemotaxis | 181 | 18 | 3.0 | 0.013 |
| Single-organism process | 634 | 29 | 2.7 | 0.013 |
| Response to oxygen-containing compound | 948 | 56 | 1.8 | 0.013 |
| Terpenoid biosynthetic process | 8 | 4 | 26.8 | 0.013 |
| Embryonic limb morphogenesis | 106 | 13 | 3.8 | 0.014 |
| Regulation of response to stress | 847 | 52 | 1.8 | 0.014 |
| Negative regulation of protein processing | 234 | 21 | 2.7 | 0.014 |
| Positive regulation of epithelial cell proliferation | 123 | 14 | 3.5 | 0.016 |
| Regulation of behavior | 155 | 16 | 3.1 | 0.017 |
| Regulation of multicellular organismal development | 1167 | 66 | 1.7 | 0.017 |
| Response to wounding | 168 | 16 | 3.1 | 0.017 |
| Regulation of phosphorylation | 1016 | 59 | 1.7 | 0.019 |
| Complement activation, alternative pathway | 9 | 4 | 21.5 | 0.019 |
| Negative regulation of cardiac muscle tissue development | 16 | 5 | 12.2 | 0.019 |
| Epithelium development | 624 | 40 | 2.0 | 0.020 |
| Muscle cell migration | 46 | 8 | 5.7 | 0.021 |
| Oxoacid metabolic process | 849 | 51 | 1.8 | 0.022 |
| Regulation of transport | 1300 | 71 | 1.6 | 0.023 |
| Regulation of leukocyte chemotaxis | 72 | 10 | 4.4 | 0.023 |
| Positive regulation of focal adhesion assembly | 17 | 5 | 11.2 | 0.023 |
| Regulation of protein metabolic process | 152 | 15 | 3.1 | 0.024 |
| Small molecule metabolic process | 1919 | 97 | 1.5 | 0.024 |
| Endothelial cell morphogenesis | 10 | 4 | 17.9 | 0.025 |
| Negative regulation of heart growth | 10 | 4 | 17.9 | 0.025 |
| Response to acid chemical | 233 | 20 | 2.6 | 0.026 |
| Negative regulation of endopeptidase activity | 150 | 15 | 3.0 | 0.028 |
| Establishment of localization | 3464 | 158 | 1.4 | 0.028 |
| Cellular response to tumor necrosis factor | 90 | 11 | 3.8 | 0.031 |
| Endodermal cell differentiation | 39 | 7 | 5.9 | 0.034 |
| Retinoic acid biosynthetic process | 5 | 3 | 40.3 | 0.034 |
| Protein secretion | 352 | 26 | 2.2 | 0.035 |
| Cellular lipid metabolic process | 480 | 32 | 2.0 | 0.035 |
| Cellular response to endogenous stimulus | 836 | 49 | 1.7 | 0.035 |
| Regulation of cell adhesion | 418 | 29 | 2.1 | 0.035 |
| Positive regulation of locomotion | 193 | 17 | 2.7 | 0.035 |
| Appendage morphogenesis | 123 | 13 | 3.2 | 0.035 |
| Negative regulation of muscle tissue development | 29 | 6 | 7.0 | 0.035 |
| Positive regulation of cell proliferation | 487 | 32 | 2.0 | 0.036 |
| Regulation of striated muscle tissue development | 79 | 10 | 3.9 | 0.036 |
| Lung development | 110 | 12 | 3.4 | 0.038 |
| Triglyceride biosynthetic process | 53 | 8 | 4.8 | 0.039 |
| Positive regulation of mesenchymal cell proliferation | 30 | 6 | 6.7 | 0.040 |
| Negative regulation of muscle organ development | 30 | 6 | 6.7 | 0.040 |
| Positive regulation of leukocyte migration | 81 | 10 | 3.8 | 0.042 |
| Neutral lipid biosynthetic process | 54 | 8 | 4.7 | 0.042 |
| Peptide transport | 248 | 20 | 2.4 | 0.043 |
| Peptide hormone secretion | 195 | 17 | 2.6 | 0.045 |
| Inflammatory response | 227 | 18 | 2.5 | 0.047 |
| Cell adhesion | 493 | 31 | 2.0 | 0.047 |
| Response to toxic substance | 129 | 13 | 3.0 | 0.047 |
| Positive regulation of MAPK cascade | 236 | 19 | 2.4 | 0.047 |
| Regulation of cell-matrix adhesion | 69 | 9 | 4.1 | 0.047 |
| Daunorubicin metabolic process | 6 | 3 | 26.8 | 0.049 |
| Doxorubicin metabolic process | 6 | 3 | 26.8 | 0.049 |
qRT-PCR analysis
The results of qRT-PCR confirmed the differential expression of nine of 29 genes found to be significant on the microarray analysis: lipoprotein lipase (LPL), retinol binding protein 4 (RBP4), leptin (LEP), complement component 4B (Chido blood group) (C4B), insulin-like growth factor binding protein 2 (IGFBP2), monoglyceride lipase (MGLL), annexin A8 (ANXA8), klotho beta (KLB), and prolactin (PRL).
Differential splicing
Using the Affymetrix GeneChip Human Exon 1.0 ST array that probes individual exons of known genes, we compared the exon usage (inclusion) rates between adipose tissue regions. Significant differences in exon usage were found for 42 genes between visceral and subcutaneous adipose tissue of pregnant women not in labor (Table 4) but not in the labor group.
A list of the alternative splicing events associated with the regional differences of the adipose tissue of pregnant women not in labor.
| ENTREZ | SYMBOL | Name | Exon IDa | Diff. FIRMAb | P-value | q-Value |
|---|---|---|---|---|---|---|
| 5376 | PMP22 | Peripheral myelin protein 22 | 887424 | 5.2 | <0.001 | <0.001 |
| 6711 | SPTBN | Spectrin, beta, non-erythrocytic 1 | 103031 | –5.1 | <0.001 | <0.001 |
| 25818 | KLK5 | Kallikrein-related peptidase 5 | 960481 | –4.6 | <0.001 | <0.001 |
| 85442 | KNDC1 | Kinase non-catalytic C-lobe domain (KIND) containing 1 | 596822 | –3.5 | <0.001 | <0.001 |
| 388610 | TRNP1 | TMF1-regulated nuclear protein 1 | 7232 | –3.1 | <0.001 | <0.001 |
| 1612 | DAPK1 | Death-associated protein kinase 1 | 538110 | 3.1 | <0.001 | <0.001 |
| 9201 | DCLK1 | Doublecortin-like kinase 1 | 742860 | –3.0 | <0.001 | <0.001 |
| 9214 | FAIM3 | Fas apoptotic inhibitory molecule 3 | 84252 | –2.9 | <0.001 | <0.001 |
| 25891 | PAMR1 | Peptidase domain containing associated with muscle regeneration 1 | 656516 | 2.9 | <0.001 | <0.001 |
| 3983 | ABLIM1 | Actin binding LIM protein 1 | 619043 | 2.9 | <0.001 | <0.001 |
| 286204 | CRB2 | Crumbs homolog 2 (Drosophila) | 544486 | –2.8 | <0.001 | <0.001 |
| 11343 | MGLL | Monoglyceride lipase | 236116 | –2.7 | <0.001 | 0.0017 |
| 25891 | PAMR1 | Peptidase domain containing associated with muscle regeneration 1 | 656516 | 2.7 | <0.001 | <0.001 |
| 1674 | DES | Desmin | 131889 | –2.7 | <0.001 | 0.0068 |
| 10231 | RCAN2 | Regulator of calcineurin 2 | 399076 | 2.6 | <0.001 | <0.001 |
| 23524 | SRRM2 | Serine/arginine repetitive matrix 2 | 826444 | –2.6 | <0.001 | <0.001 |
| 23524 | SRRM2 | Serine/arginine repetitive matrix 2 | 826444 | –2.5 | <0.001 | <0.001 |
| 157506 | RDH10 | Retinol dehydrogenase 10 (all-trans) | 491273 | 2.5 | <0.001 | 0.0017 |
| 85442 | KNDC1 | Kinase non-catalytic C-lobe domain (KIND) containing 1 | 596819 | –2.5 | <0.001 | <0.001 |
| 79804 | HAND2 | Heart and neural crest derivatives expressed 2 | 298919 | –2.4 | <0.001 | <0.001 |
| 65108 | MARCKSL1 | 55081 | –2.4 | <0.001 | <0.001 | |
| 4071 | TM4SF1 | Transmembrane 4 L six family member 1 | 240134 | –2.4 | <0.001 | 0.006 |
| 4837 | NNMT | Nicotinamide N-methyltransferase | 644508 | –2.3 | <0.001 | 0.0099 |
| 51090 | PLLP | Plasma membrane proteolipid (plasmolipin) | 855189 | 2.3 | <0.001 | <0.001 |
| 1674 | DES | Desmin | 131895 | –2.3 | <0.001 | 0.0028 |
| 152 | ADRA2C | Adrenergic, a-2C-, receptor | 249900 | –2.3 | <0.001 | 0.0037 |
| 81539 | SLC38A1 | Solute carrier family 38, member 1 | 707206 | 2.3 | <0.001 | <0.001 |
| 57121 | LPAR5 | Lysophosphatidic acid receptor 5 | 701054 | –2.3 | <0.001 | 0.001 |
| 56920 | SEMA3G | Sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3G | 224606 | –2.3 | <0.001 | <0.001 |
| 9945 | GFPT2 | Glutamine-fructose-6-phosphate transaminase 2 | 359171 | 2.2 | <0.001 | <0.001 |
| 2627 | GATA6 | GATA binding protein 6 | 908232 | –2.2 | <0.001 | <0.001 |
| 4824 | NKX3-1 | NK3 homeobox 1 | 506935 | –2.1 | <0.001 | <0.001 |
| 3036 | HAS1 | Hyaluronan synthase 1 | 960742 | –2.1 | <0.001 | <0.001 |
| 5420 | PODXL | Podocalyxin-like | 472183 | –2.1 | <0.001 | <0.001 |
| 5420 | PODXL | Podocalyxin-like | 472213 | 2.1 | <0.001 | <0.001 |
| 3339 | HSPG2 | Heparan sulfate proteoglycan 2 | 52523 | –2.1 | <0.001 | 0.0746 |
| 23555 | TSPAN15 | Tetraspanin 15 | 582734 | –2.1 | <0.001 | <0.001 |
| 23428 | SLC7A8 | Solute carrier family 7 (cationic amino acid transporter, y+ system), member 8 | 772193 | –2.1 | <0.001 | <0.001 |
| 3913 | LAMB2 | Laminin, beta 2 (laminin S) | 223487 | –2.0 | <0.001 | <0.001 |
| 23428 | SLC7A8 | Solute carrier family 7 (cationic amino acid transporter, y+ system), member 8 | 772200 | –2.0 | <0.001 | <0.001 |
| 89932 | PAPLN | Papilin, proteoglycan-like sulfated glycoprotein | 763903 | –2.0 | <0.001 | <0.001 |
| 255743 | NPNT | Nephronectin | 263882 | 2.0 | <0.001 | <0.001 |
aExon Identifier based on annotation provided HuEx-1_0-st-v2.na30.hg19.probeset.csv file from www.affymetrix.com. bFIRMA scores are a measure of the exon abundance relative to the overall gene level in a given sample. Positive differences in FIRMA scores represent a higher exon usage rate in subcutaneous compared to visceral adipose tissue of women not in labor.
Patients with spontaneous term labor versus pregnant women not in labor
Differential expression
We did not find significant differences in gene expression in either visceral or subcutaneous adipose tissue of pregnant women with and without spontaneous labor using our predefined gene selection criteria. However, when applying PADOG pathway analysis, four KEGG pathways (spliceosome, snare interactions in vesicular transport, pathogenic Escherichia coli infection, DNA replication) and three Reactome database [202] pathways (processing of capped intron containing pre-mRNA, mRNA processing, mRNA splicing) were found to be significantly perturbed in the presence of labor in the subcutaneous region of the adipose tissue (see enrichment plots for two of these pathways in Figure 3). Unlike the over-representation approach requiring gene selection as a first step, PADOG determines whether the differential expression t-scores of a given pathway are higher (in absolute value) than those of all genes profiled on the array and, hence, detects potentially smaller but systematic differential expression in a given pathway compared to all genes on the array (Figure 3). When comparing the visceral region of the women in labor to those without labor, the PADOG identified the Reactome asparagine N-linked glycosylation pathway to be associated with parturition (see Figure S1).
Pathway perturbation associated with parturition in subcutaneous tissue.
PADOG pathway enrichment plots showing evidence of pathway perturbation associated with parturition in subcutaneous tissue. The distribution of moderated t-scores of genes in KEGG spliceosome and reactome mRNA splicing is superimposed on the distribution of all genes on the array, and shows more differential expression in these pathways than in the pool of all genes.
Differential splicing
Significant differences in exon usage were found between subcutaneous adipose tissue of pregnant women with and without spontaneous labor at term for three genes: Glutathione S-transferase kappa 1 (GSTK1), heat shock 70 kDa protein 5 (glucose-regulated protein, 78 kDa) (HSPA5), and LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1). None of the three genes were differentially expressed between visceral and subcutaneous adipose tissue of parturient women as the change in mRNA abundance was present only for one exon of each gene (Figures 4 and 5 illustrate the differential exon usage for LIMS1 and GSTK1). For all three genes, the exon showing differential usage had lower expression in the group of women in labor compared to the not-in-labor group. These three genes were not among the 42 genes with differential exon usage between visceral and subcutaneous adipose tissue of pregnant women not in labor (Table 4).
Differential exon usage for LIMS1 gene in subcutaneous adipose tissue of women with and without labor.
The top panel shows the log2 expression of probes targeting 12 exonic regions of the LIMS1 gene (separated by vertical gray lines). There are 1–4 probes per probeset. Each line corresponds to a sample, with colors blue and gray denoting one patient with and without labor, respectively. The second exon from the 5′ end targeted by Affymetrix probeset ID 2499062 (see red rectangles), shows systematically lower expression in women in labor, while the expression level for all other exons is very similar between groups, hence resulting in significantly lower FIRMA scores for this probeset between groups. The middle panel shows the genomic region and the gene model with each exon represented by one olive-colored rectangle. ENSEMBL transcripts that do or do not include the exon with differential usage are represented in blue with their corresponding identifiers.
Differential exon usage for the GSTK1 gene in subcutaneous adipose tissue of women with and without labor.
See Figure 3 legend for layout details. Affymetrix probeset ID 3028993 (see red rectangles), shows systematically lower expression in women in labor, while the expression level for all other exons is very similar between groups, hence resulting in significantly lower FIRMA scores for this probeset between groups. The only ENSEMBL transcript that includes the exonic region with differential usage between groups is ENST00000479303, and an imbalance of this isoform with respect to the other isoforms can explain the observed differences.
Discussion
The principal findings of this study include the following: 1) Visceral and subcutaneous adipose tissue transcriptome of pregnant women with spontaneous labor at term were different: i) 482 genes were differentially expressed between the two fat depots; ii) Gene Ontology analysis indicated specific biological processes (e.g. cell adhesion, vasculature development, and circulatory system development); iii) the KEGG pathways enriched in differentially expressed genes were: complement and coagulation cascades, cytokine-cytokine receptor interaction, focal adhesion, steroid hormone biosynthesis, ECM-receptor interaction, African trypanosomiasis, and protein digestion and absorption. 2) Significant differences in alternative spliced genes were found between the subcutaneous adipose tissue of pregnant women with and without spontaneous labor at term; three genes affected by alternative splicing were LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1), heat shock 70 kDa protein 5 (glucose-regulated protein, 78 kDa) (HSPA5), and Glutathione S-transferase kappa 1 (GSTK1); and 3) visceral and subcutaneous adipose tissue transcriptome of pregnant women with and without spontaneous labor at term did not differ significantly.
Visceral versus subcutaneous adipose tissue in pregnant women with spontaneous labor at term
This study describes, for the first time, the transcriptome of visceral and subcutaneous adipose tissue of pregnant women with spontaneous labor at term. High throughput technology has been employed in obstetrics [203–208]. Specifically, the transcriptome of the uterine cervix [209–217], myometrium [12, 218–224], chorioamniotic membranes [225, 226], amniotic fluid [227–236], maternal blood [237], and umbilical cord blood [238] have been reported. Region-specific differences were extensively investigated in non-pregnant individuals using both targeted and high-dimensional biology techniques [124–142, 145, 148–151, 153, 239–242]. In contrast, previous reports concerning gene expression in adipose tissue of pregnant women have used only the targeted approach [32, 117–123, 167–176] with two exceptions [178]. Resi et al. investigated the transcriptome of subcutaneous adipose tissue obtained from the gluteal depot. Participants in that study included healthy non-obese women and healthy women not in labor [178]. This is the first report to use either a high-dimensional biological technique or a targeted approach in the investigation of fat depots during normal human labor.
Bashiri et al. [243] have determined alterations in genome-wide transcription expression in visceral and abdominal subcutaneous fat depots in obese and lean pregnant women (four in each group) using the Affymetrix Human Exon 1.0 ST platform. The authors reported that global alteration in gene expression was identified in pregnancy complicated by obesity and the identification of indolethylamine N-methyltransferase, tissue factor pathway inhibitor-2, and ephrin type-B receptor 6 that were not previously associated with fat metabolism during pregnancy. In addition, subcutaneous fat of obese pregnant women demonstrated increased coding protein transcripts associated with apoptosis as compared to lean pregnant women. Of note, all participants in Bashiri et al. [243] were not in labor.
Comparison between the transcriptome of visceral and subcutaneous adipose tissue in pregnant women with and without spontaneous labor at term: evidence for an active role of adipose tissue response in the metabolic adaptation to parturition
An additional novel finding reported herein is the implication of alternative splicing in subcutaneous adipose tissue of pregnant women in spontaneous labor at term. Alternative splicing is a major biological process by which a relatively limited number of genes can be expended into elaborate proteomes [244]. It has been estimated that approximately two-thirds to three-quarters of all human genes undergo alternative splicing [201, 244–246]. This process allows cells to include or exclude different selective sections of pre-mRNA during RNA processing [247]. The altered transcripts result in closely related proteins expressed from a single locus [247]. The splicing process may affect function, localization, binding properties, and stability of the encoded proteins [244, 248] as well as degradation of the transcript [244, 249, 250]. It is an important regulatory mechanism that has been shown to be involved in several molecular pathways including angiogenesis and differentiation [247, 251]. To our knowledge, this is the first report implicating alternative splicing in parturition-related differences of subcutaneous adipose tissue or any other tissue.
While we did not find significant differences in gene expression between either visceral or subcutaneous adipose tissue of pregnant women with and without spontaneous labor at term, we identified three genes affected by alternative splicing: Glutathione S-transferase kappa 1 (GSTK1), heat shock 70 kDa protein 5 (glucose-regulated protein, 78 kDa) (HSPA5), and LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1). The Kappa class of glutathione S-transferases (GSTK) was first identified in the mitochondrial matrix from rat liver [252]. The human glutathione S-transferase kappa 1 (GSTK1) gene and protein were first characterized less than a decade ago [253]. Further studies of human GSTK1-1 have confirmed its presence in mitochondria and peroxisomes [253–255]. GSTK1-1 is highly expressed in adipose tissue, and its expression level was negatively correlated with obesity in humans and mice [256]. Importantly, GSTK1-1 plays a critical and selective role in regulating adiponectin biosynthesis. Specifically, suppression of GSTK1-1 inhibits adiponectin multimerization, probably by functioning as protein disulfide isomerase that regulates adiponectin disulfide bond formation, which is essential for multimerization.
Adiponectin, identified independently by four groups [257–260], is the most abundant gene (AMP1) product of adipose tissue; it circulates at a relatively high concentration [261]. Adiponectin has an important role in the pathophysiology of insulin resistance and diabetes [262], atherosclerosis [263], hypertension [264], dyslipidemia [265], and angiogenesis [266]. A solid body of evidence supports the role of adiponectin in normal gestation and pregnancy complications: 1) circulating maternal adiponectin correlates with insulin resistance indices during pregnancy [267]; 2) patients with gestational diabetes mellitus (GDM) have a lower concentration of adiponectin compared to those without GDM [51, 53, 268, 269]; 4) overweight pregnant patients have a lower adiponectin concentration than pregnant women of normal weight; and 5) preeclampsia is associated with altered maternal adiponectin concentrations [21, 29, 32–34, 36, 38, 45, 46]. Collectively, these findings suggest that adiponectin may play a regulatory role in metabolic and vascular complications of pregnancy. Adiponectin circulates in human plasma in distinct forms: 1) low-molecular-weight (LMW) trimers; 2) medium-molecular-weight (MMW) hexamers; and 3) high-molecular-weight (HMW) oligomers (12–18 subunits) [270]. These adiponectin multimers can exert distinct biological effects [270], activate different single transduction pathways [271, 272], and may have different affinities to the adiponectin receptors [273]. Consistent with these findings, the ratio of HMW to total adiponectin [270] has a better correlation with insulin resistance [270], obesity [274], cardiovascular diseases [275], and other impaired metabolic states [276, 277] than total adiponectin. Alterations in the relative distribution of adiponectin have been reported in normal gestation [17, 22, 26, 278, 279] as well as in preeclampsia [31, 280], gestational diabetes [52, 281], and delivery of SGA neonates [17, 71, 72, 278–281]. We have previously determined concentrations of circulating maternal adiponectin multimers in women with normal pregnancy and in those with preterm labor, with and without intra-amniotic inflammation/infection [66]. We have found that labor, per se, regardless of the presence of infection/inflammation, is associated with significant quantitative and qualitative alterations in adiponectin multimers. Taken together, the results of our previous and present studies suggest that the differences in the expression of GSTK1 in the subcutaneous adipose tissue between pregnant women with and without labor may provide a molecular mechanism for the altered regulation of adiponectin and adiponectin multimers associated with labor. This, in turn, may be important for the regulation of energy expenditure associated with parturition.
Heat shock 70 kDa protein 5 (HSPA5), also known as 78 kD glucose-regulated protein (GRP78) or immunoglobulin heavy chain-binding protein (BiP) [282, 283], is an ER-resident multifunctional molecular chaperone [284] belonging to the Hsp70 family of heat shock proteins [285]. HSPA5 is a key component of the unfolded protein response (UPR) signaling pathway that plays an important role in ER homeostasis [286]. HSPA5 increases the ER protein folding capacity by forming multiprotein complexes with other ER chaperones and regulates the activity of the ER-transmembrane sensor proteins PERK, IRE1, and ATF6 by sequestering them in inactive complexes [287, 288]. Recently, several studies proposed that increased endoplasmic reticulum stress may represent the proximal cause of the association between obesity and adipocyte insulin resistance [289–291]. Moreover, studies examining human adipose tissue have indicated that there is an increase in the ER stress transcript HSPA5 as a function of increased BMI [292, 293]. Thus, it can be hypothesized that parturition imposes increased metabolic demands and results in ER stress which, in turn, is attenuated by overproduction of HSPA5 in subcutaneous adipose tissue. Further studies are needed to test this hypothesis.
The additional gene affected by alternative splicing in subcutaneous adipose tissue of pregnant women with spontaneous labor at term is LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1). LIM domain proteins contain at least one double zinc-finger motif, and they express mainly in mammalian hearts, particularly in cardiomyocytes [294]. These proteins contain between one and five LIM domains and have been implicated in the development of the heart and heart disorders. There are two members in the five-domain LIM family: LIMS1 and LIMS2. They act as adaptor proteins forming ternary complexes and participate in cell-cell, cell-matrix adhesion, migration, growth, and cell survival [295, 296]. LIMS1 and LIMS2 also function as stress sensors that enable the heart to detect mechanical stretch and respond by increasing contractile force. Other members in this large family have been implicated in the development of the heart [297–302], kidney [303–305], and liver [306] as well as in cancer [307–313] and in neurodegenerative disease [312, 314]. Interestingly, a member of the LIM family, four and a half LIM domains (FHL1), was found to be differentially expressed between visceral and omental adipose tissue in humans. To our knowledge, this report represents the first evidence that LIMS1 is expressed in human adipose tissue. Based on previous reports concerning the physiological role of this gene in other organs, it is tempting to postulate that LIMS1 is involved in the remodeling of the subcutaneous adipose tissue.
Strengths and limitations of the study
The major strengths of this study include the novel findings reported herein: 1) the implementation of a high throughput technique in the investigation of different adipose tissue depots, 2) the evaluation of paired specimens, 3) the inclusion of well-matched controls, and 4) the relatively large sample size. Our results include the first description of the transcriptome of adipose tissue – visceral and subcutaneous – in parturient women. Significant differences in alternative spliced genes were found in the subcutaneous adipose tissue between pregnant women with and without labor, implicating that alternative splicing in labor may be associated with differences in subcutaneous adipose tissue for the first time. We have identified the LIMS1 gene, previously unrecognized, to be expressed in subcutaneous adipose tissue. Several limitations of our study should also be acknowledged. The cross-sectional nature of this study does not allow us to determine either a temporal or a causal relationship between labor and alterations in adipose tissue region-specific gene expression. In addition, as most of the participants in the study were African American, the generalization of our findings to pregnant women of different ethnic origins will require future investigation.
Conclusion
We provide evidence for the association between labor and changes in gene expression in adipose tissue. Specifically, alternative splicing has been implicated in human parturition for the first time, providing a putative molecular mechanism by which regulation of adipose tissue metabolic adaptations to the increased energy demand associated with labor occurs. In addition, we provide evidence that human parturition is characterized by a unique pattern of adipose tissue region-specific alterations in gene expression. Collectively, our data indicate that adipose tissue may play a role in the metabolic regulation of human parturition.
Acknowledgments
This project was supported, in part, by the Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services.
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