Dynamic changes in chromatin accessibility, altered adipogenic gene expression, and total versus de novo fatty acid synthesis in subcutaneous adipose stem cells of normal-weight polycystic ovary syndrome (PCOS) women during adipogenesis: evidence of cellular programming
Open accessAbstract
Background: 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. 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. Results: SC 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. Conclusions: In 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.
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Lean women with PCOS have shown decreased sensitivity to catecholamine-mediated lipolysis in subcutaneous adipose tissue, resulting in preservation of this tissue.
“Lean women with PCOS have shown decreased sensitivity to catecholamine-mediated lipolysis in subcutaneous adipose tissue (SAT), which results in the preservation of this tissue [45].”
From PCOS and nutritional approaches: Differences between lean and obese phenotype (2021) · cites this paper as [45]
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References 75 · Cited by 33
- Authors
- Leung, K. L., Sanchita, S., Pham, C. T., Davis, B. A., Okhovat, M., Ding, X., Dumesic, P., Grogan, T. R., Williams, K. J., Morselli, M., Ma, F., Carbone, L., Li, X., Pellegrini, M., Dumesic, D. A., & Chazenbalk, G. D.
- Affiliations
- University of California, Los Angeles (US)
- Oregon Health & Science University (US)
- Dana-Farber Cancer Institute (US)
- Oregon National Primate Research Center (US)
- Corresponding author
- Chazenbalk, Gregorio D.
- ORCID
- Venue
- Clinical Epigenetics
- Published
- 2020-11-23
- Volume
- 12
- Issue
- 1
- Pages
- 181-181
- ISSN
- 1868-7075 (ISSN-L)
- 1868-7083
- PMC
- PMC7686698
- OpenAlex
- W3107892275
- Cited by
- 33
- References
- 75
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 5
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Clinical Epigenetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD071836, P51 ODO11092)
- National Center for Advancing Translational Sciences
- UCLA Clinical and Translational Science Institute (UL1TR001881)
- National Human Genome Research Institute (R01HG010333)
- National Institutes of Health (P51 OD011092)
- Santa Monica Bay Woman's Club
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- polycystic ovary syndrome, adipogenesis, chromatin accessibility, fatty acid synthesis, de novo lipogenesis, Wnt signaling, PPARγ, C/EBPα, triglyceride synthesis, lipid oxidation, fatty acid beta-oxidation, TGF-β1, epigenetics, normal weight
- MeSH terms
- Adult, Cell Differentiation, Chromatin, Fatty Acids, Female, Humans, Polycystic Ovary Syndrome, RNA, Stem Cells, Gene Expression, Body Mass Index, Case-Control Studies, Adipocytes, Subcutaneous Fat, Adipogenesis, Lipid Metabolism, Transforming Growth Factor beta1, Epigenomics, Wnt Signaling Pathway
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