Thyroid-adrenergic synergism and adaptive thermogenesis

描述（由申请人提供）：在人类新生儿和其他小型哺乳动物中，寒冷暴露会增加去甲肾上腺素的释放，以刺激能量消耗（适应性非寒战产热），主要发生在棕色脂肪组织（BAT）中。这一过程导致2型碘甲状腺原氨酸脱碘酶（D2）迅速增加约20倍，在BAT中产生组织特异性甲状腺毒症。定向破坏D2基因（Dio2-/-）的小鼠甲状腺功能正常，但暴露在寒冷中会出现急性体温过低。它仅靠颤抖这一消耗大量代谢的过程存活下来。因此，棕色脂肪细胞的最佳产热需要d2生成的细胞内T4到T3转换的增加，使核T3受体（TR）饱和。单次tr饱和剂量的T3在不到24小时内就能恢复Dio2-/-小鼠的BAT能量消耗，这一事实表明，T3的快速反应机制涉及其中，而我们对此知之甚少。在本文中详细的研究中，我们将确定这些t3反应机制，重点关注适应性产热、肾上腺素能信号转导和能量底物氧化两个主要领域。我们假设Dio2-/-表型是由于线粒体摄取和能量底物氧化不足，而不是低ucp -1依赖的线粒体解偶联。通过微阵列分析和实时PCR，我们在BAT中鉴定了4个已知不受T3调控的基因。这些表达的减少可以解释Dio2-/-小鼠的产热缺陷。其中两个基因编码与cAMP生成有关的蛋白质。另外两个编码调节细胞能量稳态的关键蛋白质。我们对这些t3依赖性通路的了解是至关重要的，因为它们不涉及线粒体解偶联，因此可能在BAT以外的组织中具有功能相关性。骨骼肌是大型哺乳动物（包括成人）适应性产热的主要部位。我们假设骨骼肌和BAT共享T3诱导底物利用和能量消耗的机制。这些包括对儿茶酚胺和T3的高代谢反应，以及最近描述的camp诱导的D2在人类骨骼肌细胞中的表达。从正常生理学的角度来看，了解这种以前未被探索的机制非常重要，而且对于理解饥饿和糖尿病的病理生理学也很重要。在这种情况下，由于泛素化和蛋白酶体蛋白水解，D2的损失提供了另一种促进能量节约的潜在机制。

DESCRIPTION (provided by applicant): In human newborns and other small mammals, cold exposure increases norepinephrine release to stimulate energy expenditure (adaptive non-shivering thermogenesis) mainly in brown adipose tissue (BAT). This process causes a rapid approximately 20-fold increase in type 2 iodothyronine deiodinase (D2), creating tissue-specific thyrotoxicosis in the BAT. A mouse with targeted disruption of the D2 gene (Dio2-/-) is euthyroid, but develops acute hypothermia when exposed to cold. It survives only by the metabolically costly process of shivering. Thus, optimal thermogenesis in brown adipocytes requires the D2-generated increase in intracellular T4 to T3 conversion that saturates the nuclear T3 receptors (TR). The fact that a single TR-saturating dose of T3 restores BAT energy expenditure in Dio2-/- mice in less than 24h indicates that rapidly T3-responsive mechanisms are involved, of which we know surprisingly little. In studies detailed in this submission we will identify these T3-responsive mechanisms, focusing on two major areas of adaptive thermogenesis, adrenergic signal transduction and oxidation of energy substrates. We hypothesize that the Dio2-/- phenotype is due to insufficient mitochondrial uptake and oxidation of energy substrates rather than lower UCP-1-dependent mitochondrial uncoupling. Using a micro-array analysis and real time PCR we have identified in four genes in BAT that were not known to be regulated by T3. The reduced expression of these could explain the thermogenic defect in the Dio2-/- mouse. Two of these genes encode proteins involved in cAMP generation. The other two encode key proteins that regulate the cellular energy homeostasis. Our knowledge about these T3-dependent pathways is crucial because they do not involve mitochondrial uncoupling and therefore could be functionally relevant in tissues other than BAT. Skeletal muscle is the main site of adaptive thermogenesis in large mammals, including adult humans. We hypothesize that skeletal muscle and BAT share the mechanisms by which T3 induces substrate utilization and energy expenditure. These include high metabolic responsiveness to catecholamines and T3, and the recently described cAMP-induced D2 expression in human skeletal muscle cells. Knowledge about this previously unexplored mechanism is important both from the point of view of normal physiology but also to understand the pathophysiology of starvation and diabetes. The loss of D2 under these circumstances due to ubiquitination and proteasomal proteolysis offers an additional potential mechanism to promote energy conservation.