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Molecular Biology

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

International Journal of Obesity volume 39, pages 1274–1281 (2015)Cite this article

Subjects

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.

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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).

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Author notes

  1. C Guo

    Present address: 2Current address: Department of Urology, Boston Children's Hospital, Boston, MA, USA.,

Authors and Affiliations

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

    S Muralimanoharan, C Guo, L Myatt & A Maloyan

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Correspondence to A Maloyan.

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Muralimanoharan, S., Guo, C., Myatt, L. et al. Sexual dimorphism in miR-210 expression and mitochondrial dysfunction in the placenta with maternal obesity. Int J Obes 39, 1274–1281 (2015). https://doi.org/10.1038/ijo.2015.45

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