Thyroid-adrenergic synergism and adaptive thermogenesis

项目摘要和摘要 甲状腺功能减退症影响着1000万到1500万美国人，其中大部分是女性，全世界有3亿到4亿人。大约90美元 自19世纪末以来的几年里，人们用干燥的动物甲状腺胶囊来治疗甲状腺功能减退。它们包含 这两种激素都是由甲状腺产生的，即不活跃的前体T4和活跃的激素T3。1970年，事情 随着观察到T4由甲状腺分泌并通过d1在全身转化为t3而改变的 (15%)或D2(85%)。这导致了单独使用L-T4治疗，这一决定假设d1和d2可以产生足够的 三碘甲状腺原氨酸，包括少量的三碘甲状腺原氨酸直接从甲状腺分泌。同样在20世纪70年代，TSH的RIA是 发展起来的。我们了解到D2对TSH反馈是至关重要的：低水平的T4会减少D2在体内产生的T3。 下丘脑和脑下垂体，升高促甲状腺激素。甲状腺功能低下患者开始服用L-T4，剂量向上调整，直到 促甲状腺激素水平已恢复正常。因此，L-T4单药治疗使血清TSH正常化的剂量成为 20世纪80年代初的护理；L-T4成为美国头号处方药，每年每月开2,150万张处方 2014-15年度。然而，人们怀疑其中一种或两种脱碘酶能否在缺乏的情况下保持最佳的T3水平 功能正常的甲状腺。我们观察了9981名TSH水平正常的美国NHANES参与者； 其中469人接受L-T4治疗。当按年龄、性别、种族和血清TSH与匹配的健康对照组进行比较时，我们 看到服用L-T4的人虽然摄入的卡路里较少，但体重增加了约10磅；他们也更有可能 抗抑郁药、他汀类药物或β-受体阻滞剂。令人着迷的是，D2处于这一事件的中心；甲状腺功能减退患者被给予 只有L-T4，必须依靠D2产生体内85%的T3。在这份提案中，我们不仅将调查 L-T_4疗法影响D2调节和T_3产生的分子基础及其广泛意义 新陈代谢。我们将专注于非常重要的临床问题，例如Thr92Ala-D2的相关性是什么 多态？我们现在有一个老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.