Transcriptional and DNA Methylation Signatures of Subcutaneous Adipose Tissue and Adipose-Derived Stem Cells in PCOS Women

Adeline Divoux,Edina Erdos,Katie Whytock,Timothy F Osborne,Steven R Smith

doi:10.3390/cells11050848

Abstract

Polycystic ovary syndrome (PCOS) is often associated with metabolic syndrome features, including central obesity, suggesting that adipose tissue (AT) is a key organ in PCOS pathobiology. In this study, we compared both abdominal (ABD) and gluteofemoral (GF) subcutaneous AT in women with and without PCOS. ABD and GF subcutaneous ATs from PCOS and BMI/WHR-matched control women were analyzed by RT-qPCR, FACS and histology. ABD and GF adipose-derived stem cell (ASC) transcriptome and methylome were analyzed by RNA-seq and DNA methylation array. Similar to the control group with abdominal obesity, the GF AT of PCOS women showed lower expression of genes involved in lipid accumulation and angiogenesis compared to ABD depot. FACS analysis revealed an increase in preadipocytes number in both AT depots from PCOS. Further pathway analysis of RNA-seq comparisons demonstrated that the ASCs derived from PCOS are pro-inflammatory and exhibit a hypoxic signature in the ABD depot and have lower expression of adipogenic genes in GF depot. We also found a higher CpG methylation level in PCOS compared to control exclusively in GF-ASCs. Our data suggest that ASCs play an important role in the etiology of PCOS, potentially by limiting expansion of the healthy lower-body AT.

Highlights

Polycystic ovary syndrome (PCOS) is a complex condition characterized by ovulatory dysfunction and androgen excess that affects 12–18% of reproductive-age women, depending on the diagnostic criteria used [1]
We identified only three differentially methylated sites (DMS) between PCOS and control adipose-derived stem cell (ASC) derived from the ABD fat depot, all of them being hypermethylated in PCOS (FDR < 0.05—Figure 4A)
BCAT1, EGFR and JAK2 are required for cell proliferation signaling in cancer cells [61,62] or preadipocytes [63]. These results indicate a dysregulation of GF-ASC proliferation rate in PCOS women and are consistent with an alteration of mesenchymal stem cell proliferation recently observed in a rat model of PCOS [64]

Summary

Introduction

Polycystic ovary syndrome (PCOS) is a complex condition characterized by ovulatory dysfunction and androgen excess that affects 12–18% of reproductive-age women, depending on the diagnostic criteria used [1]. Women with PCOS have an increased risk for dyslipidemia, an important risk factor for type 2 diabetes mellitus (T2D) and an overall increased prevalence of metabolic syndrome [2,3]. Insulin resistance (IR) prevalence rates are between 44 and 85% in this specific population [4], the variability observed being in part due to differences in PCOS phenotype and ethnicity [5]. PCOS women are more likely to be overweight and have central obesity compared to the general population [6], suggesting that adipose tissue (AT) distribution is part of the syndrome. Several studies confirmed the association with central obesity by emphasizing AT alterations in PCOS women such as hypertrophic adipocytes [7], impairments in lipolysis and insulin action [8] and dysregulation of adipokine expression and secretion implicated in IR [9]. In the majority of the studies, PCOS women were confounded by a higher BMI, waist to hip ratio (WHR)

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Conclusion