Maternal High-Fat Diet Modulates the Fetal Thyroid Axis and Thyroid Gene Expression in a Nonhuman Primate Model
Maternal High-Fat Diet Modulates the Fetal Thyroid Axis and Thyroid Gene Expression in a Nonhuman Primate Model
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DOI：
10.1210/me.2012-1214
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发表时间：
2012-12-01
影响因子：
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通讯作者：
Aagaard, Kjersti M.
中科院分区：
文献类型：
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作者：
Suter, Melissa A.;Sangi-Haghpeykar, Haleh;Aagaard, Kjersti M.
甲状腺激素（TH）是胎儿发育和能量稳态的重要调节因子。虽然亚临床甲状腺功能减退症和肥胖之间的关系已经得到了很好的研究，因果关系尚未建立。使用我们的非人灵长类动物模型的营养过剩，我们试图调查是否产妇高脂肪饮食（HFD）诱导的TH稳态的变化可能是代谢紊乱和肥胖的生活发展的基础。在这里，我们表明子宫内暴露于母体HFD与胎儿甲状腺轴的改变有关。在妊娠晚期开始时，与对照饮食暴露的后代相比，HFD暴露的胎儿游离T-4水平显著降低。此外，在胎儿肝脏、甲状腺和下丘脑中，帮助维持甲状腺稳态的脱碘酶、碘甲状腺原氨酸（DIO）基因的转录被显著（P < 0.05）破坏。下丘脑和甲状腺中参与TH产生的基因（TRH、TSHR、TG、TPO和SLC 5A 5）减少。在旨在研究这些观察结果的分子基础的实验中，我们观察到TH核受体及其下游调节因子随着母体HFD暴露而被破坏。在胎肝中，TH受体β（THRB）的表达增加1.9倍（P = 0.012）。对THRB启动子的彻底分析揭示了母体饮食诱导的胎儿THRB组蛋白密码的改变，以及辅抑制子和辅激活子的启动子占用率差异。我们推测母体子宫内HFD暴露可能通过对组蛋白编码的表观基因组修饰（其调节胎儿甲状腺轴）为以后的肥胖奠定基础。（分子内分泌学26：2071-2080，2012）
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 T-4 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 beta (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. (Molecular Endocrinology 26: 2071-2080, 2012)