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）作用。我的实验室开创性的研究表明，激活脱碘酶 (D2) 和失活脱碘酶 (D3) 可以以组织和时间特异性方式局部增加或减少 TH 信号传导。换句话说，D2 和 D3 独立于血浆 T3（生物活性 TH）决定甲状腺信号传导的强度。我们的研究表明，这些机制可以通过多种信号分子调节，例如刺猬蛋白家族、胆汁酸、HIF-1、NF-B 和许多异生物质。这些研究表明脱碘酶在代谢控制中发挥着广泛的作用，对此的理解是本应用的重点。我们的出版物和初步数据表明， D2 途径的激活会加速能量消耗，同时，D2 途径 (D2KO) 的破坏会减少寒冷诱导的和饮食诱导的棕色脂肪组织 (BAT) 的产热作用。此外，我们发现 D2KO 小鼠会出现显着的代谢表型，包括肥胖、明显的肝脂肪变性、葡萄糖耐受不良和胰岛素抵抗。定义 BAT 身份的基因（Dio2、PGC-11、UCP1）的表达减少（12），这一发现是脱碘酶控制的 TH 信号在棕色脂肪生成中的作用的基础，对成年期的能量稳态具有代谢影响。另一方面，D3 途径终止 TH 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，这种新的适应性机制在各种环境中都起作用。该提案从代谢控制的角度研究了脱碘酶范式，研究了 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。这一新发现构成了该提案的基础：(i) D2 在 BAT 的发育中发挥着重要作用，导致 (ii) 成年动物产生代谢表型；(iii) D3 因缺氧而被诱导。 公共卫生相关性：实现 TH 的组织特异性控制对于研究人员对抗高脂血症来说是一个高价值目标。从这个角度来看，了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 TH 作用局部/选择性控制的最著名的生理机制。因此，我们提出的对该表型潜在机制的研究可能对我们理解 2 型糖尿病、肥胖和高脂血症产生重大影响，从而将 D2 确立为治疗代谢综合征的药物靶点。特别是，D2KO 动物肝脂肪变性的发现提供了诱人的线索，表明 D2 在调节肝脂质稳态中发挥着先前意想不到的作用（无论是直接还是间接）。

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.