Selenium metabolism in cold-induced adaptive thermogenesis

冷诱导适应性产热中的硒代谢

基本信息

批准号：
10186406
负责人：
Lucia Andreia Seale
金额：
$ 40.57万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-22 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10186406
关键词：
Active Sites Adipocytes Adipose tissue Adrenergic Agents Affect Amino Acids Antioxidants Binding Brown Fat CRISPR/Cas technology Cell Line Diet Dietary Selenium Dietary intake Energy Metabolism Enzymes Exposure to Future Glutathione Goals Homeostasis Human Immunoprecipitation In Vitro Intake Investigation Iodide Peroxidase Iodothyronine Deiodinase Link Lyase Mammals Mediating Metabolism Methods Micronutrients Mitochondria Modeling Molecular Mus Pathway interactions Peroxidases Pharmacological Treatment Physiological Physiology Play Process Proteins Reactive Oxygen Species Recycling Regulation Research Research Personnel Research Proposals Rodent Role Selenium Selenocysteine Signal Transduction Source Stress Thermogenesis Thyroid Hormones Trace Elements Transgenic Mice Weight Gain Wild Type Mouse cell growth regulation dietary energy balance improved in vivo in vivo Model innovation insight metabolomics neglect novel nutritional guideline obesity development response selenium deficiency selenocysteine lyase selenoprotein transcriptomics

项目摘要

Brown adipocytes exposed to cold dissipate heat via adaptive thermogenesis. Adaptive thermogenesis is a physiological response that contributes to energy homeostasis and restricts obesity development in rodents and humans. Activation of adaptive thermogenesis by cold exposure depends on sympathetic/beta-adrenergic signals and thyroid hormones (TH) and is induced by glutathione (GSH) depletion via elevation of reactive oxygen species. TH levels in BAT are locally regulated by iodothyronine deiodinase 2 (DIO2), while GSH is enzymatically converted into its reduced form by GSH peroxidase 1 (GPX1). Besides their crucial role in the activation of BAT adaptive thermogenesis, both DIO2 and GPX1 are selenoproteins, i.e. a class of proteins containing in their active site selenium (Se) as the amino acid selenocysteine (Sec). Sec is decomposed by the enzyme Sec lyase (Scly) into H2Se. Sec comes from either dietary sources or selenoprotein degradation. Hence Scly-mediated Sec decomposition triggers a Se recycling process required to maintain optimal levels of selenoproteins, particularly when Se is limiting. Se recycling is key for energy balance, as disruption of the Scly gene in mice (Scly KO) leads to weight gain worsened by Se deficiency. In wild-type rodents, Se deficiency upregulates Scly and decreases BAT Se levels, DIO2 and GPX1 activities. It is unknown if Se recycling modulates BAT Se levels, impacting DIO2 and GPX1 synthesis and activities, ultimately contributing to cold- induced adaptive thermogenesis. Our long-term research goal is to determine the molecular mechanisms through which Se metabolism regulates energy homeostasis. The overall objective of this research proposal is to determine the role of Se and Scly-mediated Se recycling in linking selenoprotein degradation and synthesis with adaptive thermogenesis in brown adipocytes. In Aim 1, we will determine if dietary Se intake regulates Se metabolism, especially Scly-mediated Se recycling, impacting responses to cold exposure in BAT. In Aim 2, we will determine if Scly is required for cold-induced adaptive thermogenesis in BAT. In Aim 3, we will determine if Scly participates in selenoprotein degradation in brown adipocytes. By studying both Se intake and metabolism, especially Se recycling, using novel in vitro and in vivo models, this conceptually and technically innovative project will clarify the modulatory effect of dietary Se on brown adipocyte physiology, providing new insights into the mechanistic role of Scly in the control of energy expenditure in mammals.

棕色脂肪细胞暴露于冷散热中，通过自适应热发生。自适应生热发生是一种生理反应，有助于能量稳态并限制啮齿动物和人类的肥胖。通过冷暴露来激活自适应生热的激活取决于交感/β-肾上腺素能信号和甲状腺激素（Th），并由谷胱甘肽（GSH）诱导通过反应性氧的升高来诱导。 BAT中的TH水平由碘甲醇脱二世酶2（DIO2）局部调节，而GSH则通过GSH过氧化物酶1（GPX1）将GSH酶转化为还原形式。除了它们在蝙蝠自适应热发生的激活中的关键作用外，dio2和gpx1都是硒蛋白，即在其活性部位硒中包含的一类蛋白质（SE），作为氨基酸硒吻苷（SEC）（sec）。 SEC被酶SEC裂解酶（SCLY）分解为H2SE。 SEC来自饮食来源或硒蛋白降解。因此，SCLY介导的SEC分解触发了维持最佳水平硒蛋白所需的SE回收过程，尤其是在SE限制时。 SE回收是能量平衡的关键，因为小鼠（SCLY KO）中SCLY基因的破坏会导致SE缺乏症的体重增加。在野生型啮齿动物中，SE缺乏会上调SCLY并降低BAT SE水平，DIO2和GPX1活动。尚不清楚SE回收是否会调节BAT SE水平，影响DIO2和GPX1的合成和活动，最终导致冷诱导的适应性热生成。我们的长期研究目标是确定SE代谢调节能量稳态的分子机制。该研究建议的总体目的是确定SE和SCLY介导的SE回收在将硒蛋白降解和合成与棕色脂肪细胞中的自适应热发生联系起来的作用。在AIM 1中，我们将确定饮食中的摄入量是否调节SE代谢，尤其是Scly介导的SE回收，从而影响对BAT冷暴露的反应。在AIM 2中，我们将确定蝙蝠中冷诱导的自适应热发生是否需要SCLY。在AIM 3中，我们将确定SCLY是否参与棕色脂肪细胞中的硒蛋白降解。通过使用新型体外和体内模型研究SE摄入和新陈代谢，尤其是SE回收，该在概念和技术上具有创新性的项目将阐明饮食中SE对棕色脂肪细胞生理学的调节作用，从而提供了新的洞察力，从而提供了新的洞察力，可以使Scly在哺乳动物的能量支出控制中的机械作用。