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: 7174704
• 负责人: ANTONIO C BIANCO
• 金额: $ 33.72万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 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 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174704
• 关键词: 5' -AMP-activated protein kinase; A Mouse; Acute; Acyl Coenzyme A; Adenylate Cyclase; Adipocytes; Adrenergic Agents; Adrenergic Receptor; Adult; Affect; Area; Attenuated; Brown Fat; Burn injury; Catecholamines; Coenzyme A; Cyclic AMP; Defect; Dependence; Diabetes Mellitus; Disruption; Dose; Energy Metabolism; Enzymes; Event; Expenditure; Fatty Acids; Fatty acid glycerol esters; Figs - dietary; Functional disorder; Generations; Genes; Goals; Homeostasis; Human; Impairment; Iodide Peroxidase; Iodothyronine Deiodinase; Knowledge; Ligase; Mammals; Mediating; Metabolic; Mitochondria; Mus; Muscle Fibers; Newborn Infant; Norepinephrine; Nuclear; Oxis; Pathway interactions; Phenotype; Phosphotransferases; Physiology; Polymerase Chain Reaction; Process; Proteins; Proteolysis; RGS2 gene; Regulation; Research Personnel; Rodent; Role; Shivering; Signal Transduction; Signaling Protein; Site; Skeletal Muscle; Specificity; Starvation; Thermogenesis; Thyroid Gland; Thyrotoxicosis; Time; Tissues; Transcriptional Activation; Triiodothyronine Receptors; Ubiquitination; Up-Regulation; adenylate kinase; adrenergic; deiodination; glucose metabolism; human RGS2 protein; insight; lipid biosynthesis; natural hypothermia; novel; oxidation; proton-translocating pyrophosphatase; response; restraint; synergism; uptake

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.

描述（由申请人提供）：在人类新生儿和其他小型哺乳动物中，冷暴露增加去甲肾上腺素释放，以刺激主要在棕色脂肪组织（BAT）中的能量消耗（适应性非颤抖性产热）。这一过程导致2型碘甲状腺原氨酸脱碘酶（D2）快速增加约20倍，在BAT中产生组织特异性甲状腺毒症。D2基因（Dio 2-/-）靶向破坏的小鼠甲状腺功能正常，但暴露于寒冷时会出现急性体温过低。它只能通过颤抖的代谢过程存活下来。因此，棕色脂肪细胞中的最佳产热需要D2产生的细胞内T4至T3转化的增加，其使核T3受体（TR）饱和。事实上，单一TR饱和剂量的T3在不到24小时内恢复Dio 2-/-小鼠中的BAT能量消耗，表明涉及快速T3响应机制，我们对此知之甚少。在本次提交的详细研究中，我们将确定这些T3反应机制，重点关注两个主要领域的适应性产热，肾上腺素能信号转导和氧化的能量底物。我们假设Dio 2-/-表型是由于线粒体摄取不足和能量底物氧化，而不是较低的UCP-1依赖性线粒体解偶联。使用微阵列分析和真实的时间PCR，我们已经确定在BAT中的四个基因，不知道是由T3调节。这些的表达减少可以解释Dio 2-/-小鼠中的产热缺陷。其中两个基因编码参与cAMP生成的蛋白质。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依赖性途径的了解至关重要，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。骨骼肌是包括成年人类在内的大型哺乳动物适应性产热的主要场所。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的高代谢反应性，以及最近描述的cAMP诱导的人骨骼肌细胞中的D2表达。从正常生理学的角度来看，了解这种以前未探索的机制是重要的，但也要了解饥饿和糖尿病的病理生理学。在这些情况下，由于泛素化和蛋白酶体的蛋白水解，D2的损失提供了一个额外的潜在机制，以促进节能。