Maternal high-fat diet modulates the fetal thyroid axis and thyroid gene expression in a nonhuman primate model

Melissa A. Suter, Haleh Sangi-Haghpeykar, Lori Showalter, Cynthia Shope, Min Hu, Kathleen Brown, Sarah Williams, R. Alan Harris, Kevin Grove, Robert H. Lane, Kjersti M. Aagaard

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    Abstract

    Thyroid hormone (TH) is an essential regulator of both fetal development and energy homeostasis. Although the association between subclinical hypothyroidism and obesity has been well studied, a causal relationship has yet to be established. Using our well-characterized nonhuman primate model of excess nutrition, we sought to investigate whether maternal high-fat diet (HFD)-induced changes in TH homeostasis may underlie later in life development of metabolic disorders and obesity. Here, we show that in utero exposure to a maternal HFD is associated with alterations of the fetal thyroid axis. At the beginning of the third trimester, fetal free T4 levels are significantly decreased with HFD exposure compared with those of control diet-exposed offspring. Furthermore, transcription of the deiodinase, iodothyronine (DIO) genes, which help maintain thyroid homeostasis, are significantly (P = 0.05) disrupted in the fetal liver, thyroid, and hypothalamus. Genes involved in TH production are decreased (TRH, TSHR, TG, TPO, and SLC5A5) in hypothalamus and thyroid gland. In experiments designed to investigate the molecular underpinnings of these observations, we observe that the TH nuclear receptors and their downstream regulators are disrupted with maternal HFD exposure. In fetal liver, the expression of TH receptor β (THRB) is increased 1.9-fold (P = 0.012). Thorough analysis of the THRB promoter reveals a maternal diet-induced alteration in the fetal THRB histone code, alongside differential promoter occupancy of corepressors and coactivators. We speculate that maternal HFD exposure in utero may set the stage for later in life obesity through epigenomic modifications to the histone code, which modulates the fetal thyroid axis.

    Original languageEnglish (US)
    Pages (from-to)2071-2080
    Number of pages10
    JournalMolecular Endocrinology
    Volume26
    Issue number12
    DOIs
    Publication statusPublished - Dec 1 2012

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    ASJC Scopus subject areas

    • Molecular Biology
    • Endocrinology

    Cite this

    Suter, M. A., Sangi-Haghpeykar, H., Showalter, L., Shope, C., Hu, M., Brown, K., ... Aagaard, K. M. (2012). Maternal high-fat diet modulates the fetal thyroid axis and thyroid gene expression in a nonhuman primate model. Molecular Endocrinology, 26(12), 2071-2080. https://doi.org/10.1210/me.2012-1214