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.

暴露于寒冷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，有助于啮齿动物和人类的能量稳态并限制肥胖的发展。寒冷暴露引起的适应性生热激活取决于交感神经/β-肾上腺素能信号和甲状腺激素 (TH)，并且是通过活性氧升高导致谷胱甘肽 (GSH) 消耗而诱导的。 BAT 中的 TH 水平由碘甲腺原氨酸脱碘酶 2 (DIO2) 局部调节，而 GSH 则由 GSH 过氧化物酶 1 (GPX1) 酶促转化为其还原形式。除了在 BAT 适应性产热激活中发挥关键作用外，DIO2 和 GPX1 都是硒蛋白，即一类在其活性位点含有硒 (Se) 作为氨基酸硒代半胱氨酸 (Sec) 的蛋白质。 Sec 被 Sec 裂合酶 (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 分解会触发维持硒蛋白最佳水平所需的 Se 回收过程，特别是当 Se 受到限制时。硒回收是能量平衡的关键，因为小鼠 Scly 基因的破坏（Scly KO）会导致硒缺乏导致体重增加加剧。在野生型啮齿动物中，缺硒会上调 Scly 并降低 BAT Se 水平、DIO2 和 GPX1 活性。目前尚不清楚硒回收是否会调节 BAT 硒水平，从而影响 DIO2 和 GPX1 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 Se 和 Scly 介导的 Se 回收在棕色脂肪细胞中硒蛋白降解和合成与适应性产热之间的联系中的作用。在目标 1 中，我们将确定膳食硒摄入量是否调节硒代谢，尤其是 Scly 介导的硒回收，从而影响 BAT 对冷暴露的反应。在目标 2 中，我们将确定 BAT 中冷诱导的适应性产热是否需要 Scly。在目标 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。通过使用新颖的体外和体内模型研究硒的摄入和代谢，特别是硒的回收，这个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学的调节作用，为 Scly 在棕色脂肪细胞生理学中的机制作用提供新的见解。哺乳动物能量消耗的控制。