Thyroid Hormone Action

描述(申请人提供)：这项研究的长期目标是了解甲状腺激素作用的化学、药理和生理方面，以便能够开发出更安全、更有效的治疗药物，作用于甲状腺激素内分泌系统的靶点。我们最近发现了一类新的内源性化合物，称为甲状腺原胺，它是甲状腺素(T4)的化学衍生物，可能是T4的脱羧基和脱碘代谢物。3-碘甲状腺原胺(T1AM)是迄今为止发现的这类分子中最活跃的成员，与核甲状腺激素受体TR1和TR2没有亲和力；相反，T1AM是一种名为TAAR1的孤儿GPCR的有效激动剂，是儿茶酚胺质膜泡囊包装转运体的抑制剂。在啮齿动物和人类中，T1AM存在于循环和组织中，测量的组织水平显著高于循环水平，尽管测量的循环水平仍有可能是“游离的”而不是“完全的”T1AM循环中的T1AM与一种独特的血清结合蛋白紧密结合，我们最近确定该蛋白为apoB-100，它是低密度脂蛋白(LDL)和极低密度脂蛋白(VLDL)颗粒的主要蛋白质成分。急性给药T1AM可迅速引起啮齿动物体温过低、心动过缓和高血糖。此外，在西伯利亚仓鼠、冬眠啮齿动物和小鼠身上，急性、高剂量的T1AM诱导了从碳水化合物到脂肪燃烧的深刻转变。这种刺激变化的特征是呼吸商(RQ)变化到0.7，在冬眠的啮齿动物中，单次服用T1AM后，这种变化持续48小时。T1AM对一种生物原苯乙胺具有非常不寻常的药代动力学特性。在小鼠中，T1AM的血浆半衰期为5.5小时，而化学上相似的生物胺，如5-羟色胺和多巴胺的半衰期为1-2分钟。此外，我们还发现，每天服用T1AM 2周，剂量接近5g/kg，可以显著减轻饮食诱导的肥胖小鼠的体重。配对喂养研究的结果明确地表明，观察到的长期服用低剂量T1AM导致的体重减轻是由于能量摄入的减少，而不是能量消耗的增加。因此，T1AM是一种内源性厌食剂，具有与瘦素和黑素皮质素类似的摄食行为生物活性，后者是内源性信号分子，通过下丘脑激活核的中心通路发挥作用。建议在下一个资助期进行的研究旨在更好地确定T1AM的生物合成来源、运输和输送到组织的机制，以及观察到的体重下降背后的性质和机制。该研究计划围绕以下具体目标设计：(1)鉴定和鉴定T1AM血清结合蛋白(S)；(2)确定T1AM是否源于T4，以及这种转化是发生在甲状腺还是甲状腺外周；(3)建立T1AM的长期给药程序，并研究长期T1AM治疗对啮齿动物肥胖模型体重减轻的影响。

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the chemical, pharmacological, and physiological aspects of thyroid hormone action such that safer and more effective therapeutic agents can be developed that act at targets of the thyroid hormone endocrine system. We recently discovered a novel class of endogenous compounds called thyronamines that are chemical derivatives of thyroxine (T4) and may be decarboxylated and deiodinated metabolites of T4. 3-Iodothyronamine (T1AM), the most active member identified to date of this class, has no affinity for the nuclear thyroid hormone receptors TR1 and TR2; instead, T1AM is a potent agonist of an orphan GPCR called TAAR1 and is an inhibitor of catecholamine plasma membrane vesicular packaging transporters. In rodents and humans T1AM is found in circulation and tissues, and measured tissue levels are substantially higher than circulating levels, although it remains possible that the measured circulating levels are "free" and not "total" T1AM. Circulating T1AM is tightly bound to a unique serum binding protein which we have recently identified as apoB-100, the major protein component of low density lipoprotein (LDL) and very low density lipoprotein (VLDL) particles. Acute administration of T1AM rapidly induces hypothermia, bradycardia, and hyperglycemia in rodents. In addition, acute, high-dose T1AM induces a profound fueling shift away from carbohydrates and toward fat burning in Siberian hamsters, a hibernating rodent, as well as mice. This fueling change is characterized by a change in respiratory quotient (RQ) to 0.7 that persists for 48 hours after a single dose of T1AM in the hibernating rodent. T1AM has very unusual pharmacokinetic properties for a biogenic primary phenethylamine. The plasma half-life of T1AM is 5.5 hr in mice whereas half-lives of 1-2 min are the norm for chemically similar biogenic amines such as seratonin and dopamine. In addition, we have found that 2-week daily dosing of T1AM with doses approaching the 5g/kg range lead to significant weight loss in diet-induced obese mice. Results from pair-feeding studies unambiguously demonstrate that the observed chronically administered, low-dose T1AM induced reduction in body weight results from a decrease in energy intake and not an increase in energy expenditure. Thus it appears that T1AM is an endogenous anorectic agent, with a biological activity on feeding behavior similar to leptin and melanocortins, which are endogenous signaling molecules that act via central pathways in the actuate nucleus of the hypothalamus. The research proposed for the next grant period seeks to better define the biosynthetic origins of T1AM, the mechanisms by which it is transported and delivered to tissues, and the nature and mechanism behind the observed reduction in body weight. The research plan is designed around the following specific aims: (1) Identify and characterize T1AM serum binding protein(s); (2) Determine whether T1AM is derived from T4, and whether this conversion happens in the thyroid gland or in the extrathyroidal periphery; and (3) Develop chronic dosing procedures for T1AM and study the effects of chronic T1AM treatment on body weight loss in rodent obesity models.