Thyroid-adrenergic synergism and adaptive thermogenesis

项目概要和摘要 甲状腺功能减退症影响10-15万美国人，其中大多数是女性，全世界有3 - 4亿人。约90 自世纪后期以来，甲状腺功能减退症一直用干燥的动物甲状腺胶囊治疗。它们含有 这两种激素都是由甲状腺产生的，即非活性前体T4和活性激素T3。1970年， 随着观察到T4由甲状腺分泌并通过D1在全身转化为T3而改变 (15%）或D2（85%）。这导致单独使用L-T4治疗，这一决定假设D1和D2可以产生足够的 T3，包括直接从甲状腺分泌的少量T3。同样在20世纪70年代，TSH的RIA被 开发我们了解到，D2对TSH反馈至关重要：低水平的T4会减少D2产生的T3。 下丘脑和垂体，升高促甲状腺激素。甲状腺功能减退患者开始L-T4治疗，剂量调整至 促甲状腺激素水平恢复正常。因此，在使血清TSH正常化的剂量下的L-T4单药疗法成为治疗的标准。 20世纪80年代初，L-T4成为美国排名第一的处方药，2010年每月有2150万张处方。 2014-15.然而，在缺乏T3的情况下，其中一种或两种脱碘酶是否能维持最佳的T3水平存在疑问。 甲状腺功能正常我们观察了9，981名参加美国NHANES的参与者，他们的TSH水平正常; 其中469人接受了L-T4治疗。与年龄、性别、种族和血清TSH相匹配的健康对照组比较， 我发现，尽管摄入的卡路里较少，但L-T4的人体重增加了10磅左右;他们也更有可能在 抗抑郁药他汀类药物或β受体阻滞剂令人着迷的是，D2是这一点的中心;甲状腺功能减退患者被给予 只有L-T4，必须依靠D2来产生体内所有T3的>85%。在这份提案中，我们不仅要调查 L-T4治疗如何影响D2调节和T3产生的分子基础，以及其对 新陈代谢.我们将重点关注非常重要的临床问题，例如Thr 92 Ala-D2的相关性 多态性？我们现在有一个小鼠模型来解决这个问题。

Project Summary and Abstract Hypothyroidism affects 10-15 million Americans, mostly women, and between 300-400 million worldwide. For about 90 years since the late 19th century, hypothyroidism was treated with capsules of desiccated animal thyroid. They contain both hormones produced by the thyroid gland, the inactive precursor T4 and the active hormone T3. In 1970, things changed with the observation that T4 is secreted by the thyroid gland and converted to T3 throughout the body via D1 (15%) or D2 (85%). This led to treatment with L-T4 alone, a decision that assumed D1 and D2 could generate sufficient T3, including the small amounts of T3 secreted directly from the thyroid. Also in the 1970s, the RIA for TSH was developed. We learned that D2 is critical for TSH feedback: low levels of T4 decrease D2-generated T3 in the hypothalamus and pituitary, elevating TSH. Hypothyroid patients are started on L-T4 and the dose is adjusted up until TSH levels are back to normal. Therefore, L-T4 monotherapy at doses that normalize serum TSH became the standard of care in the early 1980s; L-T4 became the #1 prescribed medication in the US, with 21.5 million prescriptions/month in 2014-15. However, there are doubts that either one, or both deiodinases can maintain optimal levels of T3 in the absence of a functional thyroid gland. We looked at 9,981 participants in the US NHANES who had normal TSH levels; among whom 469 were treated with L-T4. When comparing with matched healthy controls by age, sex, race and serum TSH, we saw that those on L-T4 were ~10 pounds heavier despite consuming fewer calories; they were also more likely to be on anti-depressants, statins or beta-blocker. It is fascinating that D2 is at the epicenter of this; hypothyroid patients are given only L-T4 and must rely on D2 to generate >85% of all T3 in their bodies. In this proposal, we will investigate not only the molecular basis of how L-T4 therapy affects D2 regulation and T3 production but also its broad implication for metabolism. We will focus on very significant clinical questions, e.g. what is the relevance of Thr92Ala-D2 polymorphism? We now have a mouse model to address this question.