Accessible Requires Authentication Published by De Gruyter December 22, 2020

PPARGC1A promoter DNA-methylation level and glucose metabolism in Ecuadorian women with Turner syndrome

Francisco Álvarez-Nava ORCID logo, Marco Salinas, Daniela Bastidas, Yosselin Vicuña and Marcia Racines-Orbe



Reduced gene expression of PPARGC1A in subjects with insulin resistance (IR) has been reported. Insulin resistance occurs early on the course of Turner syndrome (TS). The main objective of this study was to evaluate the relationship between PPARGC1A promoter DNA methylation status in lymphocytes and insulin sensitivity and secretion in Ecuadorian females with TS.


We examined a cohort of 34 Ecuadorian patients with TS along with a sex-, age- and BMI-matched reference group. All subjects received a standard 75 g oral glucose tolerance test. Insulin resistance and secretion indices were calculated. The PPARGC1A methylated DNA/unmethylated DNA ratio and mitochondrial content (mtDNA/nDNA ratio) were further determined.


Notably, the PPARGC1A DNA methylation level was significantly higher in TS subjects than the reference group and correlated with IR indices. Conversely, mitochondrial content was significantly lower in the study group than healthy controls and negatively correlated with the PPARGC1A methylated DNA/unmethylated DNA ratio in TS individuals. PPARGC1A promoter DNA methylation status contributed to 20% of the total variability in Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) independently of BMI or age in TS subjects.


Our collective findings suggest that expression of PPARGC1A and lower mitochondrial number affect the metabolic phenotype in TS subjects.

Corresponding author: Francisco Álvarez-Nava, Biological Sciences School, Faculty of Biological Sciences, Central University of Ecuador, Calle Iquique con Calle Sodiro Number N14-121, Parroquia San Blas, Quito170113, Pichincha, Ecuador, Phone: +593 252 8810, Fax: +593 252 8810, E-mail:

Funding source: Academie de Recherche et D’Enseignement Superieur of Belgique

Award Identifier / Grant number: 2016-157E


We are extremely grateful to all women with Turner syndrome who took part in this study. We acknowledge the contribution of the Ecuadorian Foundation in Support of Turner Syndrome.

  1. Research funding: This study was supported by the Academie de Recherche et D’Enseignement Superieur of Belgique (grant numbers 2016-157E).

  2. Author contributions: The authors’ contribution to the paper is as follow FAN: study concepts and design, data analysis and interpretation, statistical analysis, obtaining funding, critical revision of the manuscript for important intellectual content and manuscript preparation; MS: molecular and data analysis; DB: biochemical studies and data analysis; YV: molecular and data analysis; MR-O: biochemical studies and data analysis. All authors read and approved the final manuscript.

  3. Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: The procedures employed were in keeping with the principles of the Institutional Committee on Ethics in Human Research and the Declaration of Helsinki of 1964 and subsequent modifications.

  6. Data availability: The raw data supporting the conclusions of this manuscript will be made available upon request.


1. Gravholt, CH, Andersen, NH, Conway, GS, Dekkers, OM, Geffner, ME, Klein, KO, et al.. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 cincinnati international Turner syndrome meeting. Eur J Endocrinol 2017;177:G1–70. Search in Google Scholar

2. Lebenthal, Y, Levy, S, Sofrin-Drucker, E, Nagelberg, N, Weintrob, N, Shalitin, S, et al.. The natural history of metabolic comorbidities in Turner syndrome from childhood to early adulthood: comparison between 45,X monosomy and other karyotypes. Front Endocrinol 2018;9:27. Search in Google Scholar

3. Mortensen, KH, Andersen, NH, Gravholt, CH. Cardiovascular phenotype in Turner syndrome-integrating cardiology, genetics, and endocrinology. Endocr Rev 2012;33:677–714. Search in Google Scholar

4. Bakalov, VK, Cheng, C, Zhou, J, Bondy, CA. X-chromosome gene dosage and the risk of diabetes in Turner syndrome. J Clin Endocrinol Metab 2009;94:3289–96. Search in Google Scholar

5. Bondy, CA, Cheng, C. Monosomy for the X chromosome. Chromosome Res 2009;17:649–58. Search in Google Scholar

6. Alvarez-Nava, F, Lanes, R, Quintero, JM, Miras, M, Fideleff, H, Mericq, V, et al.. Effect of the parental origin of the X-chromosome on the clinical features, associated complications, the two-year-response to growth hormone (rhGH) and the biochemical profile in patients with Turner syndrome. Int J Pediatr Endocrinol 2013;2013:10. Search in Google Scholar

7. Rajpathak, SN, Vellarikkal, SK, Patowary, A, Scaria, V, Sivasubbu, S, Deobagkar, DD. Human 45,X fibroblast transcriptome reveals distinct differentially expressed genes including long noncoding RNAs potentially associated with the pathophysiology of Turner syndrome. PloS One 2014;9:e100076. Search in Google Scholar

8. Trolle, C, Nielsen, MM, Skakkebæk, A, Lamy, P, Vang, S, Hedegaard, J, et al.. Widespread DNA hypomethylation and differential gene expression in Turner syndrome. Sci Rep 2016;6:34220. Search in Google Scholar

9. Wisniewski, A, Milde, K, Stupnicki, R, Szufladowicz-Wozniak, J. Weight deficit at birth and Turner’s syndrome. J Pediatr Endocrinol Metab 2007;20:607–13. Search in Google Scholar

10. Baldin, AD, Siviero-Miachon, AA, Fabbri, T, de Lemos-Marini, SH, Spinola-Castro, AM, Baptista, MT, et al.. Early Hum Dev 2012;88:99–102. Search in Google Scholar

11. Barker, DJ. The origins of the developmental origins theory. J Intern Med 2007;261:412–7. Search in Google Scholar

12. Barker, DJ. The fetal and infant origins of adult disease. BMJ 1990;301:1111. Search in Google Scholar

13. Gemma, C, Sookoian, S, Alvariñas, J, García, SI, Quintana, L, Kanevsky, D, et al.. Maternal pregestational BMI is associated with methylation of the PPARGC1A promoter in newborns. Obesity 2009;17:1032–9. Search in Google Scholar

14. Relton, CL, Groom, A, St Pourcain, B, Sayers, AE, Swan, DC, Embleton, ND, et al.. DNA methylation patterns in cord blood DNA and body size in childhood. PloS One 2012;7:e31821. Search in Google Scholar

15. Reynolds, CM, Vickers, MH. Utility of small animal models of developmental programming. Methods Mol Biol 2018;1735:145–63. Search in Google Scholar

16. Bird, A. Perceptions of epigenetics. Nature 2007;447:396–8. Search in Google Scholar

17. Fernandez-Marcos, PJ, Auwerx, J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr 2011;93:884S–90S. Search in Google Scholar

18. Brøns, C, Jacobsen, S, Nilsson, E, Rönn, T, Jensen, CB, Storgaard, H, et al.. Deoxyribonucleic acid methylation and gene expression of PPARGC1A in human muscle is influenced by high-fat overfeeding in a birth-weight-dependent manner. J Clin Endocrinol Metab 2010;95:3048–56. Search in Google Scholar

19. Sookoian, S, Rosselli, MS, Gemma, C, Burgueño, AL, Fernández Gianotti, T, Castaño, GO, et al.. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter. Hepatology 2010;52:1992–2000. Search in Google Scholar

20. Clarke-Harris, R, Wilkin, TJ, Hosking, J, Pinkney, J, Jeffery, AN, Metcalf, BS, et al.. PGC1α promoter methylation in blood at 5–7 years predicts adiposity from 9 to 14 years (EarlyBird 50). Diabetes 2014;63:2528–37. Search in Google Scholar

21. Gillberg, L, Jacobsen, SC, Rönn, T, Brøns, C, Vaag, A. PPARGC1A DNA methylation in subcutaneous adipose tissue in low birth weight subjects--impact of five days of high-fat overfeeding. Metabolism 2014;63:263–71. Search in Google Scholar

22. Gianotti, TF, Sookoian, S, Dieuzeide, G, García, SI, Gemma, C, González, CD, et al.. A decreased mitochondrial DNA content is related to insulin resistance in adolescents. Obesity 2008;16:1591–5. Search in Google Scholar

23. Zhao, H, Zhao, Y, Ren, Y, Li, M, Li, T, Li, R, et al.. Epigenetic regulation of an adverse metabolic phenotype in polycystic ovary syndrome: the impact of the leukocyte methylation of PPARGC1A promoter. Fertil Steril 2017;107:467–74.e5. Search in Google Scholar

24. Álvarez-Nava, F, Bastidas, D, Racines-Orbe, M, Guarderas, J. Insulin sensitivity and pancreatic β-cell function in Ecuadorian women with Turner syndrome. Front Endocrinol 2020;11:1–9. Search in Google Scholar

25. Ling, C, Del Guerra, S, Lupi, R, Rönn, T, Granhall, C, Luthman, H, et al.. Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia 2008;51:615–22. Search in Google Scholar

26. Sun, L, Wang, Y, Zhou, T, Zhao, X, Wang, Y, Wang, G, et al.. Glucose metabolism in Turner syndrome. Front Endocrinol 2019;10:49. Search in Google Scholar

27. Salgin, B, Amin, R, Yuen, K, Williams, RM, Murgatroyd, P, Dunger, DB. Insulin resistance is an intrinsic defect independent of fat mass in women with Turner’s syndrome. Horm Res 2006;65:69–75. Search in Google Scholar

28. Liang, P, Hughes, V, Fukagawa, NK. Increased prevalence of mitochondrial DNA deletions in skeletal muscle of older individuals with impaired glucose tolerance: possible marker of glycemic stress. Diabetes 1997;46:920–3. Search in Google Scholar

29. Fromenty, B, Robin, MA, Igoudjil, A, Mansouri, A, Pessayre, D. The ins and outs of mitochondrial dysfunction in NASH. Diabetes Metab 2004;30:121–38. Search in Google Scholar

30. Longo, S, Bollani, L, Decembrino, L, Di Comite, A, Angelini, M, Stronati, M. Short-term and long-term sequelae in intrauterine growth retardation (IUGR). J Matern Fetal Neonatal Med 2013;26:222–5. Search in Google Scholar

31. Godfrey, KM, Sheppard, A, Gluckman, PD, Lillycrop, KA, Burdge, GC, McLean, C, et al.. Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes 2011;60:1528–34. Search in Google Scholar

32. Xie, X, Gao, H, Zeng, W, Chen, S, Feng, L, Deng, D, et al.. Placental DNA methylation of peroxisome-proliferator-activated receptor-γ co-activator-1α promoter is associated with maternal gestational glucose level. Clin Sci (Lond) 2015;129:385–94. Search in Google Scholar

33. Barrenäs, ML, Bratthall, A, Dahlgren, J. The association between short stature and sensorineural hearing loss. Hear Res 2005;205:123–30. Search in Google Scholar

Received: 2020-10-22
Accepted: 2020-11-29
Published Online: 2020-12-22

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