Thyroid-adrenergic synergism and adaptive thermogenesis

描述(申请人提供)：脱碘酶启动或终止甲状腺激素(TH)的作用。我的实验室率先开展的研究揭示，激活的脱碘酶(D2)和失活的脱碘酶(D3)可以局部以组织和时间特异性的方式增加或减少TH信号。换句话说，D2和D3决定甲状腺信号的强度独立于血浆T3(生物活性TH。我们的研究表明，这些机制可以被广泛的信号分子调节，如刺猬蛋白家族、胆汁酸、HIF-1、NF-B和一些外来物质。这些研究表明，脱碘酶在新陈代谢控制中发挥着广泛的作用，对其的了解是本应用的重点。我们的出版物和初步数据表明，D2通路的激活加速了能量消耗。同时，D2途径的中断(D2KO)减少了冷诱导的和饮食诱导的棕色脂肪组织(BAT)的产热。此外，我们还发现D2KO小鼠出现了显著的代谢表型，包括肥胖、明显的肝脏脂肪变性、糖耐量异常和胰岛素抵抗。从机制上讲，我们发现成年D2KO蝙蝠有一个永久性的缺陷，这源于胚胎蝙蝠发育受损，决定蝙蝠特性的基因(Dio2，PGC-11，UCP1)表达减少(12)。这一发现强调了脱碘酶控制的TH信号在棕色脂肪形成中的作用，以及成年后能量平衡的代谢反应。在光谱的另一端，D3通路终止TH活动，减少能量消耗，正如我们在缺氧心肌和脑中所显示的那样。我们的研究表明，这种新的适应机制适用于从蝙蝠到大脑的各种环境。这项建议从代谢控制的角度研究脱碘酶范式，研究D2和D3对成年动物代谢功能的影响，以及它们在蝙蝠发育中的作用。新的发现，(I)D2在BAT的发育中起着重要作用，导致(Ii)成年动物的代谢表型，以及(Iii)D3是对低氧的响应而诱导的，这构成了这一提议的基础。 公共卫生相关性：实现TH的组织特异性控制是研究人员在抗击高脂血症方面的一个高价值目标。从这个角度来看，理解脱碘酶的代谢作用必须被认为是一个有价值的目标，因为这组酶代表了实现局部/选择性控制TH作用的最著名的生理机制。因此，我们对这种表型的潜在机制的研究可能对我们理解2型糖尿病、肥胖症和高脂血症具有重要意义，将D2确立为治疗代谢综合征的药物靶点。特别是，在D2KO动物身上发现的肝脏脂肪变性提供了一个诱人的线索，表明D2在调节肝脏脂质平衡方面发挥了先前意想不到的作用(无论是直接的还是间接的)。

DESCRIPTION (provided by applicant): The deiodinases initiate or terminate thyroid hormone (TH) action. Studies pioneered in my laboratory unveiled that the activating deiodinase (D2) and the inactivating deiodinase (D3) can locally increase or decrease TH signaling in a tissue- and temporal-specific fashion. In other words, D2 and D3 determine the intensity of thyroid signaling independently of plasma T3 (the biologically active TH. Our studies revealed that these mechanisms can be modulated by a wide variety of signaling molecules such as the hedgehog family of proteins, bile acids, HIF-1, NF-B, and a number of xenobiotic substances. These studies have indicated that deiodinases play a broad role in the control of metabolism, the understanding of which is the focus of this application. Our publications and preliminary data show that the activation of the D2 pathway accelerates energy expenditure. At the same time, disruption of the D2 pathway (D2KO) reduces cold-induced and also diet- induced brown adipose tissue (BAT) thermogenesis. Furthermore, we have found that the D2KO mouse develops a striking metabolic phenotype, including obesity, marked hepatic steatosis, glucose intolerance and insulin resistance. Mechanistically, we found that adult D2KO BAT has a permanent defect that stems from impaired embryonic BAT development, with decreased expression of genes defining BAT identity (Dio2, PGC- 11, UCP1) (12). This discovery underlies a role of deiodinase-controlled TH signaling in brown adipogenesis, with metabolic repercussions for energy homeostasis in adulthood. On the other end of the spectrum, the D3 pathway terminates TH action, decreasing energy expenditure as we have shown in hypoxic myocardium and brain. Our studies indicate that this novel adaptative mechanism is operant in settings ranging from BAT to brain. This proposal investigates the deiodinase paradigm from the perspective of metabolic control, examining the effects of D2 and D3 on metabolic function in adult animals, but also on their role in the development of BAT. The novel findings that (i) D2 plays an important role in the development of BAT, leading to (ii) a metabolic phenotype in adult animals, and that (iii) D3 is induced in response to hypoxia, form the basis of this proposal. PUBLIC HEALTH RELEVANCE: Achieving tissue-specific control of TH is a high-value objective for investigators in the fight against hyperlipidemia. Seen in this light, understanding the metabolic role of deiodinases must be considered a worthy goal, since this group of enzymes represents the best known physiologic mechanism for achieving local/selective control of TH action. Thus, our proposed investigations into the mechanisms underlying this phenotype could have significant implications for our understanding of type 2 diabetes, obesity, and hyperlipidemia, establishing D2 as a drug target in the treatment of the metabolic syndrome. In particular, the finding of hepatic steatosis in D2KO animals offers a tantalizing hint of a previously unexpected role (whether direct or indirect) for D2 in the regulation of hepatic lipid homeostasis.