Thyroid-adrenergic synergism and adaptive thermogenesis

甲状腺-肾上腺素能协同作用和适应性产热

• 批准号: 8106874
• 负责人: ANTONIO C BIANCO
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8106874
• 关键词: Adrenergic Agents; Adult; Animals; Bile Acids; Brain; Brown Fat; Cell Nucleus; Cell membrane; Cytoskeleton; Data; Defect; Development; Diet; Drug Delivery Systems; Embryo; Embryonic Development; Employee Strikes; Endosomes; Energy Metabolism; Enzymes; Erinaceidae; Fatty Liver; Fatty acid glycerol esters; Figs - dietary; Gene Expression; Genetic Transcription; Glucose Intolerance; Goals; Hepatic; Homeostasis; Hyperlipidemia; Hypoxia; Insulin Resistance; Investigation; Iodide Peroxidase; Laboratories; Life; Light; Lipids; Liver; Mediating; Metabolic; Metabolic Control; Metabolic syndrome; Metabolism; Mus; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Envelope; Obesity; Oxidative Stress; Pathway interactions; Peripheral; Phenotype; Physiological; Plasma; Play; Protein Family; Proteins; Publications; Regulation; Research Personnel; Role; Signal Transduction; Signaling Molecule; Skeletal Muscle; Stimulus; Thermogenesis; Thyroid Gland; Thyroid Hormones; Time; Tissues; Xenobiotics; adrenergic; base; fight against; lipid biosynthesis; mature animal; novel; premature; response; stem; synergism

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.

性状（由申请方提供）：脱碘酶启动或终止甲状腺激素（TH）作用。在我的实验室开创性的研究揭示，激活脱碘酶（D2）和失活脱碘酶（D3）可以局部增加或减少TH信号在组织和时间特异性的方式。换句话说，D2和D3决定甲状腺信号传导的强度，而不依赖于血浆T3（生物活性TH）。我们的研究表明，这些机制可以通过各种各样的信号分子，如刺猬蛋白质家族，胆汁酸，HIF-1，NF-B和一些异生素物质来调节。这些研究表明，脱碘酶在代谢控制中起着广泛的作用，对它的理解是这一应用的焦点。我们的出版物和初步数据表明，D2途径的激活加速了能量消耗。同时，D2途径的破坏（D2 KO）减少了冷诱导的以及饮食诱导的棕色脂肪组织（BAT）产热。此外，我们已经发现D2 KO小鼠发展出显著的代谢表型，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。从机制上讲，我们发现成体D2 KO BAT具有源于受损的胚胎BAT发育的永久性缺陷，其中定义BAT身份的基因（Dio 2，PGC- 11，UCP 1）表达降低（12）。这一发现是脱碘酶控制的TH信号在棕色脂肪形成中的作用的基础，对成年期的能量稳态具有代谢影响。在光谱的另一端，D3途径终止TH作用，减少能量消耗，如我们在缺氧心肌和脑中所示。我们的研究表明，这种新的适应机制是可操作的设置范围从BAT到大脑。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。新发现（i）D2在BAT的发育中起重要作用，导致（ii）成年动物中的代谢表型，以及（iii）D3响应于缺氧而被诱导，形成了该提议的基础。 公共卫生相关性：实现TH的组织特异性控制是研究人员对抗高脂血症的高价值目标。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，因为这组酶代表了最知名的生理机制，实现局部/选择性控制TH行动。因此，我们对这种表型的机制的研究可能对我们理解2型糖尿病，肥胖和高脂血症，建立D2作为治疗代谢综合征的药物靶点具有重要意义。特别是，在D2 KO动物中发现的肝脂肪变性提供了一个诱人的提示，即D2在调节肝脏脂质稳态中具有先前意想不到的作用（无论是直接还是间接）。