Thyroid-adrenergic synergism and adaptive thermogenesis

描述（由申请人提供）：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了激活脱碘酶（D2）和灭活脱碘酶（D3）可以局部地以组织特异性和时间特异性的方式增加或减少TH信号。换句话说，D2和D3独立于血浆T3（生物活性TH）决定甲状腺信号的强度。我们的研究表明，这些机制可以被多种信号分子调节，如刺猬蛋白家族、胆汁酸、HIF-1、NF-B和一些外源物质。这些研究表明，脱碘酶在代谢控制中发挥着广泛的作用，对其的理解是本应用的重点。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通路（D2KO）的破坏减少了冷诱导和饮食诱导的棕色脂肪组织（BAT）产热。此外，我们发现D2KO小鼠具有显著的代谢表型，包括肥胖、显著的肝脂肪变性、葡萄糖耐受不良和胰岛素抵抗。在机制上，我们发现成人D2KO BAT具有永久性缺陷，这源于胚胎BAT发育受损，定义BAT身份的基因（Dio2, PGC- 11, UCP1）表达减少（12）。这一发现揭示了脱碘酶控制的TH信号在棕色脂肪形成中的作用，并对成年期能量稳态产生代谢影响。另一方面，D3通路终止TH的作用，减少能量消耗，正如我们在缺氧心肌和大脑中所显示的那样。我们的研究表明，这种新的适应机制在从BAT到大脑的各种环境中都有效。本研究拟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BAT发育中的作用。新的发现(i) D2在BAT的发育中起重要作用，导致（ii）成年动物的代谢表型，以及（iii） D3在缺氧反应中被诱导，构成了该提议的基础。

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.