Hypothalamic Type 2 Deiodinase in Metabolism Regulation

下丘脑 2 型脱碘酶在代谢调节中的作用

• 批准号: 6829648
• 负责人: Sabrina Diano
• 金额: $ 23.5万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6829648
• 关键词: biological models; cell population study; computer data analysis; enzyme induction /repression; enzyme inhibitors; fasting; gene expression; glucocorticoids; hormone metabolism; hormone regulation /control mechanism; hypothalamus; immunocytochemistry; in situ hybridization; iodide peroxidase; iodination; laboratory rat; leptin; neurogenetics; neurons; neurophysiology; neuroregulation; protein structure function; radioimmunoassay; thyroid hormones; thyrotropin releasing hormone

DESCRIPTION: (provided by applicant) In the central nervous system, the majority of the active form of thyroid hormone, T3, derives from the cellular uptake and intracellular 5'-monodeiodination of T4 by type II 5'-monodeiodinase (DII). In the adult rat brain, high DII activity is present in the arcuate nucleus/median eminence region with minimal activity in the paraventricular nucleus where the central thyroid-regulating neurons, the thyrotropin releasing hormone (TRH)-containing cells are located. DII-producing cells are both astrocytes and tanycytes and provide a network of processes arcing between the third ventricle and the basal surface of the brain and the portal vessels of the median eminence. Arcuate nucleus DII-producing glial cells may actively participate in metabolism regulation, because they are in close proximity to T3-targeted neurons, including those producing neuropeptide Y (NPY), agouti-related protein (AgRP) and pro-opiomelanocortin (POMC), all of which project onto the paraventricular TRH cells and considered as primum movens in metabolism regulation. In support of this proposition, we found that arcuate nucleus DII activity is elevated during fasting, a paradigm during which negative feedback of circulating thyroid hormones is diminished in the hypothalamus. The aforementioned observations gave impetus to our hypothesis that it is activation of arcuate nucleus DII by diminishing leptin and elevating corticosterone levels that disrupts normal thyroid feedback during short-term food deprivation. The following Specific Aims will test our hypotheses: Specific Aim 1. Is increased arcuate nucleus DII activity responsible for the loss of thyroid hormone feedback in fasted rats? Specific Aim 2. Does the inactivation of DII by lOP infusion during fasting suppress activation of NPY/AgRP and suppression of POMC neurons? Specific Aim 3. Do leptin and glucocorticoids affect the mRNA levels and the enzymatic activity of 5'-iodothyronine deiodinase type II in the hypothalamus of fasted rats? The results of these studies will shed light on the role of DII in central metabolism regulation offering a novel hypothalamic target for drug development in the fighting of metabolic disorders, including diabetes, obesity and the so called "nonthyroidal illness syndrome" in humans.

描述：（由申请人提供）在中枢神经系统中 甲状腺激素T3的大部分活性形式源自细胞 通过II型5'-单座二二氨二替酶对T4的摄取和细胞内5'单次脱灭剂 （DII）。在成年大鼠大脑中，弧形中存在高DII活性 核中核/中位数区域，在室室中有最小的活性。 中央甲状腺调节神经元的细胞核，甲状腺蛋白释放 含激素（TRH） - 含有激素。二二产生的细胞都是 星形胶质细胞和tanycytes，并提供了在 第三脑室和大脑的基本表面和门户 中位数。弓形核核核产生的神经胶质细胞可能会积极地 参与新陈代谢调节，因为它们与 T3靶向神经元，包括产生神经肽Y（NPY）的神经元， 与Agouti相关的蛋白质（AGRP）和蛋白质类皮质素（POMC），所有这些 投射到旁牙的TRH细胞上，并被认为是培生的移动 代谢调节。为了支持这一主张，我们发现 在禁食期间，核DII活性升高，在此期间 循环甲状腺激素的负反馈在 下丘脑。 上述观察结果推动了我们的假设是 通过减少瘦素和升高来激活弧形DII 可破坏短期甲状腺反馈正常反馈的皮质酮水平 食物剥夺。以下具体目标将检验我们的假设： 具体目标1。是增加了弓形核DII的活性 禁食大鼠失去甲状腺激素反馈？ 特定的目标2。禁食期间的LOP输液灭活DII 抑制NPY/AGRP的激活和POMC神经元的抑制？ 特定目标3。瘦素和糖皮质激素会影响mRNA水平和 下丘脑中5'-碘甲状腺素脱碘酶II型的酶促活性 禁食的老鼠？ 这些研究的结果将揭示DII在中央的作用 代谢调节为药物开发提供新的下丘脑靶标 在代谢疾病的战斗中，包括糖尿病，肥胖和SO 人类称为“非甲状腺疾病综合症”。