Original Article | Published:

Molecular Biology

Sexual dimorphism in miR-210 expression and mitochondrial dysfunction in the placenta with maternal obesity

International Journal of Obesity volume 39, pages 12741281 (2015) | Download Citation

Abstract

Background:

Maternal obesity is a major problem in obstetrics, and the placenta is involved in obesity-related complications via its roles at the maternal–fetal interface. We have recently shown a causative role for micro(mi)RNA-210, a so called ‘hypoxamir’ regulated by HIF-1α, in mitochondrial dysfunction in placentas from women with preeclampsia. We also reported mitochondrial dysfunction in placentas with maternal obesity. Here we hypothesized that expression of miR-210 is dysregulated in the placentas with obesity.

Methods:

Placentas from uncomplicated pregnancies were collected at term from healthy weight or control (CTRL, pre-pregnancy body mass index (BMI)<25), overweight (OW, BMI=25–24.9) and obese (OB, BMI>30) women following C-section with no labor. Expression of miRNA-210 and its target genes was measured by reverse transcription–PCR and Western Blot, respectively. Mitochondrial respiration was assessed by Seahorse Analyzer in syncytiotrophoblast (ST) 72 h after cytotrophoblast isolation.

Results:

Expression of miR-210 was significantly increased in placentas of OB and OW women with female but not male fetuses compared with CTRL placentas of females. However, expression of HIF-1α in these placentas remained unchanged. Levels of tumor-necrosis factor-alpha (TNFα) were increased in OW and OB placentas of females but not males, and in silico analysis suggested that activation of miR-210 expression in these placentas might be activated by NFκB1 (p50) signaling. Indeed, chromatin Immunoprecipitation assay showed that NFkB1 binds to placental miR-210 promoter in a fetal sex-dependent manner. Female but not male STs treated with TNFα showed overexpression of miR-210, reduction of mitochondrial target genes and decreased mitochondrial respiration. Pre-treatment of these STs with small interfering RNA to NFkB1 or antagomiR-210 prevented the TNFα-mediated inhibition of mitochondrial respiration.

Conclusions:

Our data suggest that the inflammatory intrauterine environment associated with maternal obesity induces an NFκB1-mediated increase in miR-210 in a fetal sex-dependent manner, leading to inhibition of mitochondrial respiration and placental dysfunction in the placentas of female fetuses.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , , . Maternal obesity up-regulates inflammatory signaling pathways and enhances cytokine expression in the mid-gestation sheep placenta. Placenta 2010; 31: 387–391.

  2. 2.

    , , , , . Longitudinal changes in energy expenditure and body composition in obese women with normal and impaired glucose tolerance. Am J Physiol Endocrinol Metab 2004; 287: E472–E479.

  3. 3.

    , , , . Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus. Am J Obstet Gynecol 1999; 180: 903–916.

  4. 4.

    , . Pregnancy and obesity. Obstet Gynecol Clin North Am 2009; 36: 285–300.

  5. 5.

    . Obesity, diabetes, and links to congenital defects: a review of the evidence and recommendations for intervention. J Matern Fetal Neonatal Med 2008; 21: 173–180.

  6. 6.

    , , . Fetal and perinatal consequences of maternal obesity. Arch Dis Child Fetal Neonatal Ed 2011; 96: F378–F382.

  7. 7.

    , , , , , et al. Maternal obesity and risk of stillbirth: a metaanalysis. Am J Obstet Gynecol 2007; 197: 223–228.

  8. 8.

    , , , , , et al. Maternal high-fat diet disturbs uteroplacental hemodynamics and increases the frequency of stillbirth in a nonhuman primate model of excess nutrition. Endocrinology 2011; 152: 2456–2464.

  9. 9.

    , . Maternal inflammation, growth retardation, and preterm birth: insights into adult cardiovascular disease. Life Sci 2011; 89: 417–421.

  10. 10.

    , . Role of the placenta in fetal programming: underlying mechanisms and potential interventional approaches. Clin Sci (Lond) 2007; 113: 1–13.

  11. 11.

    , . Review: the placenta and developmental programming: balancing fetal nutrient demands with maternal resource allocation. Placenta 2012; 33: S23–S27.

  12. 12.

    . Placental adaptive responses and fetal programming. J Physiol 2006; 572: 25–30.

  13. 13.

    , . Oxidative stress in the placenta. Histochem Cell Biol 2004; 122: 369–382.

  14. 14.

    , , , , , . Effect of increasing maternal body mass index on oxidative and nitrative stress in the human placenta. Placenta 2009; 30: 169–175.

  15. 15.

    , . Placental mechanisms and developmental origins of health and disease. In: Gluckman P, Hanson M (eds). Developmental Origins of Health and Disease. Cambridge University Press: Cambridge, UK, 2006. pp 130–142.

  16. 16.

    , , , , , et al. The effect of pre-existing maternal obesity on the placental proteome: two-dimensional difference gel electrophoresis coupled with mass spectrometry. J Mol Endocrinol 2012; 48: 139–149.

  17. 17.

    , , . MicroRNA control of signal transduction. Nat Rev Mol Cell Biol 2010; 11: 252–263.

  18. 18.

    , , , , , et al. Bisphenol A exposure leads to specific microRNA alterations in placental cells. Reprod Toxicol 2010; 29: 401–406.

  19. 19.

    , , , , , . Maternal cigarette smoking during pregnancy is associated with downregulation of miR-16, miR-21, and miR-146a in the placenta. Epigenetics 2010; 5: 583–589.

  20. 20.

    , , , , , et al. Distinct subsets of microRNAs are expressed differentially in the human placentas of patients with preeclampsia. Am J Obstet Gynecol 2007; 196: 261 e1–261 e6.

  21. 21.

    , , , , , . Placental microRNA expression in pregnancies complicated by preeclampsia. Am J Obstet Gynecol 2011; 204: 178 e12–178 e21.

  22. 22.

    , , . miR-16 and miR-21 expression in the placenta is associated with fetal growth. PLoS One 2011; 6: e21210.

  23. 23.

    , , , . miR-210: the master hypoxamir. Microcirculation 2011; 19: 215–223.

  24. 24.

    , , , , , et al. Overexpression of miR-210, a downstream target of HIF1alpha, causes centrosome amplification in renal carcinoma cells. J Pathol 2011; 224: 280–288.

  25. 25.

    , , , . miR-210: more than a silent player in hypoxia. IUBMB Life 2011; 63: 94–100.

  26. 26.

    , , , , , et al. Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. Mol Cell 2009; 35: 856–867.

  27. 27.

    , , , , , . MIR-210 modulates mitochondrial respiration in placenta with preeclampsia. Placenta 2012; 33: 816–823.

  28. 28.

    , , , . Impaired mitochondrial function in human placenta with increased maternal adiposity. Am J Physiol Endocrinol Metab 2014; 307: E419–E425.

  29. 29.

    , , , , , . Ultrastructural changes and immunocytochemical analysis of human placental trophoblast during short-term culture. Placenta 1989; 10: 179–194.

  30. 30.

    , , , . Measurement of mitochondrial respiration in trophoblast culture. Placenta 2012; 33: 456–458.

  31. 31.

    , , , . Oxidative stress and microRNAs in vascular diseases. Int J Mol Sci 2013; 14: 17319–17346.

  32. 32.

    . Maternal body weight and pregnancy outcome. Am J Clin Nutr 1990; 52: 273–279.

  33. 33.

    , , , . Maternal obesity: the interplay between inflammation, mother and fetus. J Perinatol 2010; 30: 441–446.

  34. 34.

    . Increasing maternal obesity and weight gain during pregnancy: the obstetric problems of plentitude. Obstet Gynecol 2007; 110: 743–744.

  35. 35.

    . Maternal obesity, metabolism, and pregnancy outcomes. Annu Rev Nutr 2006; 26: 271–291.

  36. 36.

    , . Impact of maternal obesity on offspring obesity and cardiometabolic disease risk. Reproduction 2010; 140: 387–398.

  37. 37.

    . Review: Reactive oxygen and nitrogen species and functional adaptation of the placenta. Placenta 2010; 31: S66–S69.

  38. 38.

    , . Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 2006; 83: 461S–465S.

  39. 39.

    , , , , , . MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab 2009; 10: 273–284.

  40. 40.

    , , , , , et al. MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation 2007; 116: 258–267.

  41. 41.

    , , . MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion. Stroke 2008; 39: 959–966.

  42. 42.

    , , , , , et al. hsa-mir-210 is a marker of tumor hypoxia and a prognostic factor in head and neck cancer. Cancer 2010; 116: 2148–2158.

  43. 43.

    , , , , , et al. MicroRNA-210 regulates mitochondrial free radical response to hypoxia and krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU. PLoS One 2010; 5: e10345.

  44. 44.

    , , , , , et al. Elevated levels of hypoxia-inducible microRNA-210 in pre-eclampsia: new insights into molecular mechanisms for the disease. J Cell Mol Med 2012; 16: 249–259.

  45. 45.

    , , , , , et al. miR-210 inhibits trophoblast invasion and is a serum biomarker for preeclampsia. Am J Pathol 2013; 183: 1437–1445.

  46. 46.

    , , , . Impaired mitochondrial function in human placenta with increased maternal adiposity. Am J Physiol Endocrinol Metab 2014; 307: E419–E425.

  47. 47.

    , , , , , et al. Metabolomic profiling reveals mitochondrial-derived lipid biomarkers that drive obesity-associated inflammation. PLoS One 2012; 7: e38812.

  48. 48.

    , , , , , et al. Transition from obesity to metabolic syndrome is associated with altered myocardial autophagy and apoptosis. Arterioscler Thromb Vasc Biol 2012; 32: 1132–1141.

  49. 49.

    , , , , , et al. Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes. Diabetologia 2013; 56: 2203–2212.

  50. 50.

    , , , , . MicroRNA modulation in obesity and periodontitis. J Dent Res 2012; 91: 33–38.

  51. 51.

    , , , , , . Circulating microRNAs and aerobic fitness—the HUNT-Study. PLoS One 2013; 8: e57496.

  52. 52.

    , , , , , et al. Maternal obesity is associated with a lipotoxic placental environment. Placenta 2014; 35: 171–177.

  53. 53.

    , . Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 2000; 18: 621–663.

  54. 54.

    , , , , . Why females live longer than males: control of longevity by sex hormones. Sci Aging Knowledge Environ 2005; 2005: pe17.

  55. 55.

    , , , , , et al. Highly dynamic and sex-specific expression of microRNAs during early ES cell differentiation. PLoS Genet 2009; 5: e1000620.

  56. 56.

    , , , . miRNA regulated pathways in late stage murine lung development. BMC. Dev Biol 2013; 13: 13.

  57. 57.

    , . Early prenatal stress epigenetically programs dysmasculinization in second-generation offspring via the paternal lineage. J Neurosci 2011; 31: 11748–11755.

  58. 58.

    , , . Review article: the metabolic syndrome—a chronic cardiovascular inflammatory condition. Aliment Pharmacol Ther 2005; 22: 20–23.

  59. 59.

    . A comprehensive definition for metabolic syndrome. Dis Model Mech 2009; 2: 231–237.

  60. 60.

    , , , , . Circulating microRNAs have a sex-specific association with metabolic syndrome. J Biomed Sci 2013; 20: 72.

Download references

Acknowledgements

We are thankful to the funding sources HD076259A (LM and AM), HL075297 (LM), and CTSA grant (UL1RR025767) from the Institute for Integration of Medicine and Science (IIMS) at UTHSCSA (AM).

Author information

Author notes

    • C Guo

    Current address: Department of Urology, Boston Children's Hospital, Boston, MA, USA.

Affiliations

  1. Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX, USA

    • S Muralimanoharan
    • , C Guo
    • , L Myatt
    •  & A Maloyan

Authors

  1. Search for S Muralimanoharan in:

  2. Search for C Guo in:

  3. Search for L Myatt in:

  4. Search for A Maloyan in:

Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to A Maloyan.

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/ijo.2015.45

Further reading