Department of Molecular Endocrinology, Institute for Endocrinology and Diabetes, Center of Brain Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.
Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
Thyroid. 2020 Aug;30(8):1205-1216. doi: 10.1089/thy.2019.0705. Epub 2020 Apr 24.
Tachycardia, cardiac hypertrophy, and elevated body temperature are major signs of systemic hyperthyroidism, which are considered to reflect the excessive thyroid hormone (TH) action in the respective peripheral tissues. However, recent observations indicate that the central actions of TH also contribute substantially to cardiovascular regulation and thermogenesis. In this study, we dissect the individual contributions of peripheral TH action versus the central effects in body temperature regulation and cardiovascular functions by taking advantage of mice lacking the TH transporters monocarboxylate transporter 8 (MCT8) and organic anion transporting polypeptide 1C1 (OATP1C1) ( double knock-out [dko]), which exhibit elevated serum triiodothyronine (T3) levels while their brain is in a profoundly hypothyroid state. We compared these animals with wild-type (WT) mice that were treated orally with T3 to achieve similarly elevated serum T3 levels, but are centrally hyperthyroid. For the studies, we used radiotelemetry, infrared thermography, gene expression profiling, Western blot analyses, and enzyme linked immunosorbent assays (ELISA) assays. Our analyses revealed mild hyperthermia and cardiac hypertrophy in T3-treated WT mice but not in dko animals, suggesting that central actions of TH are required for these hyperthyroid phenotypes. Although the average heart rate was unaffected in either model, the dko exhibited an altered heart rate frequency distribution with tachycardic bursts in active periods and bradycardic episodes during resting time, demonstrating that the stabilization of heart rate by the autonomic nervous system can be impaired in centrally hypothyroid animals. Our studies unravel distinct phenotypical traits of hyperthyroidism that depend on an intact central nervous system, and provide valuable insight into the cardiovascular pathology of the Allan-Herndon-Dudley syndrome, a condition caused by the lack of MCT8 in humans.
心动过速、心脏肥厚和体温升高是全身性甲状腺功能亢进的主要征象，这些征象被认为反映了甲状腺激素（TH）在相应外周组织中的过度作用。然而，最近的观察表明，TH 的中枢作用也对心血管调节和产热有很大贡献。在这项研究中，我们利用缺乏 TH 转运体单羧酸转运蛋白 8（MCT8）和有机阴离子转运多肽 1C1（OATP1C1）（双敲除[dko]）的小鼠，通过优势解析外周 TH 作用与体温调节和心血管功能的中枢作用的个体贡献，这些小鼠的血清三碘甲状腺原氨酸（T3）水平升高，而其大脑处于明显的甲状腺功能减退状态。我们将这些动物与野生型（WT）小鼠进行了比较，后者通过口服 T3 治疗以达到类似的血清 T3 水平升高，但中枢性甲状腺功能亢进。在研究中，我们使用了无线电遥测、红外热成像、基因表达谱分析、Western blot 分析和酶联免疫吸附测定（ELISA）分析。我们的分析表明，T3 处理的 WT 小鼠有轻度的体温升高和心脏肥厚，但 dko 动物没有，这表明 TH 的中枢作用是这些甲状腺功能亢进表型所必需的。尽管两种模型的平均心率均不受影响，但 dko 表现出心率频率分布的改变，在活动期间有心律过速爆发，在休息时间有心律过缓发作，这表明中枢性甲状腺功能减退动物的自主神经系统稳定心率的能力可能受损。我们的研究揭示了依赖于完整中枢神经系统的甲状腺功能亢进的不同表型特征，并为 Allan-Herndon-Dudley 综合征的心血管病理学提供了有价值的见解，这种疾病是由于人类缺乏 MCT8 引起的。
