Abstract
BackgroundNormal-weight polycystic ovary syndrome (PCOS) women exhibit adipose resistance in vivo accompanied by enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with accelerated lipid accumulation per cell in vitro. The present study examines chromatin accessibility, RNA expression and fatty acid (FA) synthesis during SC abdominal ASC differentiation into adipocytes in vitro of normal-weight PCOS versus age- and body mass index-matched normoandrogenic ovulatory (control) women to study epigenetic/genetic characteristics as well as functional alterations of PCOS and control ASCs during adipogenesis.ResultsSC abdominal ASCs from PCOS women versus controls exhibited dynamic chromatin accessibility during adipogenesis, from significantly less chromatin accessibility at day 0 to greater chromatin accessibility by day 12, with enrichment of binding motifs for transcription factors (TFs) of the AP-1 subfamily at days 0, 3, and 12. In PCOS versus control cells, expression of genes governing adipocyte differentiation (PPARγ, CEBPα, AGPAT2) and function (ADIPOQ, FABP4, LPL, PLIN1, SLC2A4) was increased two–sixfold at days 3, 7, and 12, while that involving Wnt signaling (FZD1, SFRP1, and WNT10B) was decreased. Differential gene expression in PCOS cells at these time points involved triacylglycerol synthesis, lipid oxidation, free fatty acid beta-oxidation, and oxidative phosphorylation of the TCA cycle, with TGFB1 as a significant upstream regulator. There was a broad correspondence between increased chromatin accessibility and increased RNA expression of those 12 genes involved in adipocyte differentiation and function, Wnt signaling, as well as genes involved in the triacylglycerol synthesis functional group at day 12 of adipogenesis. Total content and de novo synthesis of myristic (C14:0), palmitic (C16:0), palmitoleic (C16:1), and oleic (C18:1) acid increased from day 7 to day 12 in all cells, with total content and de novo synthesis of FAs significantly greater in PCOS than controls cells at day 12.ConclusionsIn normal-weight PCOS women, dynamic chromatin remodeling of SC abdominal ASCs during adipogenesis may enhance adipogenic gene expression as a programmed mechanism to promote greater fat storage.
Highlights
Normal-weight polycystic ovary syndrome (PCOS) women exhibit adipose resistance in vivo accompanied by enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with accelerated lipid accumulation per cell in vitro
Patient characteristics Three normal-weight women with PCOS and three ageand body mass index (BMI)-matched normoandrogenic ovulatory women who participated in our National Institutes of Health (NIH) study of adipogenic dysfunction in PCOS were selected from a cohort of eight PCOS women and their age- and BMI-matched controls
ASC chromatin accessibility To determine the degree of separation between femaletype and time points, unsupervised principal component analysis of ATAC-seq data was based on read densities in consensus peak regions demonstrated grouping of samples primarily consistent with time-point and broadly with female type based on plots of the first two principal components (Additional file 2: Supplemental Fig. 2A)
Summary
Normal-weight polycystic ovary syndrome (PCOS) women exhibit adipose resistance in vivo accompanied by enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with accelerated lipid accumulation per cell in vitro. PCOS has a heritable component that interacts with the endocrine-metabolic environment to exert both acute and programmed effects on its phenotype [6, 7] In support of this concept, adult female monkeys with natural hyperandrogenemia have comparable PCOS-like traits, suggesting an evolutionary origin that originally favored PCOS in huntergatherers [8], when food deprivation during pregnancy programmed greater fat storage in the fetus to meet the increased metabolic demands of reproduction in later life [9]. In vitro studies have shown that androgen contributes to diminished insulin-stimulated glucose uptake and inhibition of catecholamine-stimulated lipolysis in this adipose depot [12, 15,16,17], with comparable findings in similar adipose of women with PCOS [18,19,20]
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