Accelerated subcutaneous abdominal stem cell adipogenesis predicts insulin sensitivity in normal-weight women with polycystic ovary syndrome

doi:10.1016/j.fertnstert.2020.10.003

. 2021 Jul;116(1):232-242.

doi: 10.1016/j.fertnstert.2020.10.003. Epub 2020 Dec 17.

Accelerated subcutaneous abdominal stem cell adipogenesis predicts insulin sensitivity in normal-weight women with polycystic ovary syndrome

Daniel A Dumesic¹, Ayli Tulberg², Karen L Leung², Samantha C Fisch², Tristan R Grogan³, David H Abbott⁴, Rajanigandha Naik², Gregorio D Chazenbalk²

Affiliations

¹ Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, California. Electronic address: ddumesic@mednet.ucla.edu.
² Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, California.
³ Department of Medicine Statistics Core, University of California, Los Angeles, Los Angeles, California.
⁴ OB/GYN, Wisconsin National Primate Research Center, University of Wisconsin, Madison, Madison, Wisconsin.

PMID: 33341231
PMCID: PMC8209112
DOI: 10.1016/j.fertnstert.2020.10.003

Accelerated subcutaneous abdominal stem cell adipogenesis predicts insulin sensitivity in normal-weight women with polycystic ovary syndrome

Daniel A Dumesic et al. Fertil Steril. 2021 Jul.

. 2021 Jul;116(1):232-242.

doi: 10.1016/j.fertnstert.2020.10.003. Epub 2020 Dec 17.

Authors

Daniel A Dumesic¹, Ayli Tulberg², Karen L Leung², Samantha C Fisch², Tristan R Grogan³, David H Abbott⁴, Rajanigandha Naik², Gregorio D Chazenbalk²

Affiliations

¹ Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, California. Electronic address: ddumesic@mednet.ucla.edu.
² Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, California.
³ Department of Medicine Statistics Core, University of California, Los Angeles, Los Angeles, California.
⁴ OB/GYN, Wisconsin National Primate Research Center, University of Wisconsin, Madison, Madison, Wisconsin.

PMID: 33341231
PMCID: PMC8209112
DOI: 10.1016/j.fertnstert.2020.10.003

Abstract

Objective: To examine whether subcutaneous (SC) abdominal adipose stem cell differentiation into adipocytes in vitro predicts insulin sensitivity (Si) in vivo in normal-weight women with polycystic ovary syndrome (PCOS) and controls.

Design: Prospective cohort study.

Setting: Academic medical center.

Patient(s): Eight normal-weight women with PCOS and 8 age- and body mass index-matched controls.

Intervention(s): Women underwent circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total-body dual-energy x-ray absorptiometry, and SC abdominal fat biopsy.

Main outcome measure(s): PPARγ and CEBPa gene expression and lipid content of adipocytes matured in vitro were compared between women with PCOS and control women, and correlated with patient characteristics, systemic Si, and adipose insulin resistance (adipose-IR).

Result(s): Serum androgen levels, adipose-IR, and percentage of android fat were greater in women with PCOS than control women. Stem cell PPARγ and CEBPa gene expression increased maximally by day 12 without a female-type effect. In control cells, gene expression positively correlated with fasting serum insulin levels (both genes) and adipose-IR (CEBPa) and negatively correlated with Si (CEBPa). Conversely, CEBPa gene expression in PCOS cells negatively correlated with adipose-IR and serum free testosterone, whereas total lipid accumulation in these cells positively corelated with Si.

Conclusion: In normal-weight women with PCOS, accelerated SC abdominal adipose stem cell differentiation into adipocytes in vitro favors Si in vivo, suggesting a role for hyperandrogenism in the evolution of metabolic thrift to enhance fat storage through increased cellular glucose uptake.

Keywords: Adipose; adipocyte; hyperandrogenism; polycystic ovary syndrome; stem cell.

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Figures

1.
Correlations between A) *PPARγ* gene expression on day 12 in A) control and B) PCOS subcutaneous abdominal adipocytes matured *in vitro* without androgen and endocrine-metabolic outcomes. Open circles, controls; filled circles, PCOS women. All x-axes for *PPARγ* gene expression on day 12 are identical in scale.

2.
Correlations between log *CEBPa* gene expression on day 12 in A) control and B) PCOS subcutaneous abdominal adipocytes matured *in vitro* without androgen and endocrine-metabolic outcomes. Open circles, controls; filled circles, PCOS women. All x-axes for log *CEBPa* gene expression on day 12 are identical in scale

3.
Correlations between lipid content on day 12 in A) control and B) PCOS subcutaneous abdominal adipocytes matured *in vitro* without androgen and endocrine-metabolic outcomes. Open circles, controls; filled circles, PCOS women. All x-axes for lipid content on day 12 are identical in scale

See this image and copyright information in PMC

Comment in

Adiposity in polycystic ovary syndrome: excess versus dysfunction.
Azziz R. Azziz R. Fertil Steril. 2021 Jul;116(1):87-88. doi: 10.1016/j.fertnstert.2021.04.033. Epub 2021 May 24. Fertil Steril. 2021. PMID: 34034909 No abstract available.

Cited by

The Subcutaneous Adipose Microenvironment as a Determinant of Body Fat Development in Polycystic Ovary Syndrome.
Dumesic DA, Rasouli MA, Katz JD, Lu GG, Dharanipragada D, Turcu AF, Grogan TR, Flores KE, Magyar CE, Abbott DH, Chazenbalk GD. Dumesic DA, et al. J Endocr Soc. 2024 Sep 17;8(11):bvae162. doi: 10.1210/jendso/bvae162. eCollection 2024 Sep 26. J Endocr Soc. 2024. PMID: 39345868 Free PMC article.
POLYCYSTIC OVARY SYNDROME: ORIGINS AND IMPLICATIONS: Polycystic ovary syndrome: an evolutionary metabolic adaptation.
Dumesic DA, Padmanabhan V, Abbott DH. Dumesic DA, et al. Reproduction. 2025 Mar 24;169(4):e250021. doi: 10.1530/REP-25-0021. Print 2025 Apr 1. Reproduction. 2025. PMID: 40080428 Review.
Randomized clinical trial: effect of low-dose flutamide on abdominal adipogenic function in normal-weight women with polycystic ovary syndrome.
Dumesic DA, Winnett C, Lu G, Grogan TR, Abbott DH, Naik R, Chazenbalk GD. Dumesic DA, et al. Fertil Steril. 2023 Jan;119(1):116-126. doi: 10.1016/j.fertnstert.2022.09.324. Epub 2022 Nov 15. Fertil Steril. 2023. PMID: 36400597 Free PMC article. Clinical Trial.
Induced Pluripotent Stem Cells as a Possible Approach for Exploring the Pathophysiology of Polycystic Ovary Syndrome (PCOS).
Khatun M, Lundin K, Naillat F, Loog L, Saarela U, Tuuri T, Salumets A, Piltonen TT, Tapanainen JS. Khatun M, et al. Stem Cell Rev Rep. 2024 Jan;20(1):67-87. doi: 10.1007/s12015-023-10627-w. Epub 2023 Sep 28. Stem Cell Rev Rep. 2024. PMID: 37768523 Free PMC article. Review.
Polycystic ovary syndrome.
Stener-Victorin E, Teede H, Norman RJ, Legro R, Goodarzi MO, Dokras A, Laven J, Hoeger K, Piltonen TT. Stener-Victorin E, et al. Nat Rev Dis Primers. 2024 Apr 18;10(1):27. doi: 10.1038/s41572-024-00511-3. Nat Rev Dis Primers. 2024. PMID: 38637590 Review.

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References

1. Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific Statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev. 2015;36:487–525. - PMC - PubMed
1. Dumesic DA, Abbott DH, Sanchita S, Chazenbalk GD. Endocrine-Metabolic Dysfunction in Polycystic Ovary Syndrome: an Evolutionary Perspective. Curr Opin Endocr Metab Res 2020;12:41–8. - PMC - PubMed
1. Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Repro Update. 2010;16:347–63. - PubMed
1. Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS, Ghazzi MN, PCOS/Troglitazone Study Group. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91:48–53. - PubMed
1. Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:1929–35. - PubMed

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[1] Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific Statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev. 2015;36:487–525. - PMC - PubMed

[2] Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific Statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev. 2015;36:487–525. - PMC - PubMed

[3] Dumesic DA, Abbott DH, Sanchita S, Chazenbalk GD. Endocrine-Metabolic Dysfunction in Polycystic Ovary Syndrome: an Evolutionary Perspective. Curr Opin Endocr Metab Res 2020;12:41–8. - PMC - PubMed

[4] Dumesic DA, Abbott DH, Sanchita S, Chazenbalk GD. Endocrine-Metabolic Dysfunction in Polycystic Ovary Syndrome: an Evolutionary Perspective. Curr Opin Endocr Metab Res 2020;12:41–8. - PMC - PubMed

[5] Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Repro Update. 2010;16:347–63. - PubMed

[6] Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Repro Update. 2010;16:347–63. - PubMed

[7] Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS, Ghazzi MN, PCOS/Troglitazone Study Group. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91:48–53. - PubMed

[8] Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS, Ghazzi MN, PCOS/Troglitazone Study Group. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91:48–53. - PubMed

[9] Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:1929–35. - PubMed

[10] Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:1929–35. - PubMed

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Accelerated subcutaneous abdominal stem cell adipogenesis predicts insulin sensitivity in normal-weight women with polycystic ovary syndrome

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Accelerated subcutaneous abdominal stem cell adipogenesis predicts insulin sensitivity in normal-weight women with polycystic ovary syndrome

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