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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：
10713400
负责人：
Lucia Andreia Seale
金额：
$ 3.44万
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/10713400
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 Persons 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 cell immortalization 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.

暴露在寒冷中的棕色脂肪细胞通过适应性产热来散热。适应性产热是一种生理反应，有助于能量稳态和限制肥胖的发展在啮齿动物和人类。冷暴露的适应性产热激活依赖于交感神经/ β -肾上腺素能信号和甲状腺激素（TH），并由谷胱甘肽（GSH）消耗通过活性氧的升高诱导。BAT中的TH水平受碘甲状腺原氨酸脱碘酶2 （iodothyronine deiodinase 2, DIO2）的局部调控，而谷胱甘肽通过谷胱甘肽过氧化物酶1 （GSH过氧化物酶1，GPX1）转化为还原型。除了在BAT适应性产热激活中起关键作用外，DIO2和GPX1都是硒蛋白，即一类在其活性位点含有硒（Se）作为氨基酸硒半胱氨酸（Sec）的蛋白质。Sec被Sec裂解酶（Scly）分解成H2Se。硒要么来自膳食来源，要么来自硒蛋白的降解。因此，sly介导的硒分解触发硒循环过程，以维持硒蛋白的最佳水平，特别是当硒是有限的。硒的再循环是能量平衡的关键，因为小鼠体内的Scly基因（Scly KO）的破坏会导致体重增加，而硒缺乏会加剧体重增加。在野生型啮齿动物中，硒缺乏上调Scly，降低BAT硒水平、DIO2和GPX1活性。目前尚不清楚硒循环是否调节BAT硒水平，影响DIO2和GPX1的合成和活性，最终促进冷诱导的适应性产热。我们的长期研究目标是确定硒代谢调节能量稳态的分子机制。本研究计划的总体目标是确定硒和sly介导的硒循环在棕色脂肪细胞中硒蛋白降解和合成与适应性产热作用的联系中的作用。在Aim 1中，我们将确定膳食硒摄入量是否调节硒代谢，特别是sly介导的硒循环，影响BAT对冷暴露的反应。在Aim 2中，我们将确定BAT中是否需要Scly来进行冷诱导的适应性产热。在Aim 3中，我们将确定Scly是否参与棕色脂肪细胞中硒蛋白的降解。通过研究硒的摄入和代谢，特别是硒的循环利用，采用新的体外和体内模型，这一概念和技术上的创新项目将阐明膳食硒对棕色脂肪细胞生理的调节作用，为研究Scly在哺乳动物能量消耗控制中的机制作用提供新的见解。