Selenium metabolism in cold-induced adaptive thermogenesis

冷诱导适应性产热中的硒代谢

• 批准号: 10579270
• 负责人: Lucia Andreia Seale
• 金额: $ 40.44万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 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/10579270
• 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

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，有助于能量平衡，并限制啮齿动物和人类肥胖的发展。冷暴露激活适应性产热依赖于交感神经/β-肾上腺素能信号和甲状腺激素(TH)，它是由谷胱甘肽(GSH)耗竭通过增加活性氧诱导的。BAT中的TH水平受碘甲状腺原氨酸脱碘酶2(DIO2)的局部调节，而GSH则由GSH过氧化物酶1(GPX1)酶促转化为其还原形式。DIO2和GPX1除了在BAT适应性产热的激活中起重要作用外，都是硒蛋白，即在其活性部位含有硒(Se)的一类蛋白质，即氨基酸硒半胱氨酸(SEC)。SEC被SEC裂解酶(Scly)分解为H_2Se。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硒蛋白水平所需的Se循环过程，特别是当Se受到限制时。硒循环是能量平衡的关键，因为小鼠Scly基因(Scly KO)的破坏会导致体重增加因缺硒而恶化。在野生型啮齿动物中，缺硒会上调Scly，并降低Bt Se水平、DIO2和GPX1活性。目前尚不清楚Se循环是否调节BAT Se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动态平衡的分子机制。这项研究的总体目标是确定Se和Scly介导的Se循环在棕色脂肪细胞中将硒蛋白的降解和合成与适应性产热联系起来的作用。在目标1中，我们将确定膳食Se摄入是否调节Se代谢，特别是Scly介导的Se循环，从而影响蝙蝠对冷暴露的反应。在目标2中，我们将确定Scly是否是蝙蝠冷诱导适应性产热所必需的。在目标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。通过利用新的体外和体内模型研究Se的摄入和代谢，特别是Se的循环，这一概念和技术上的创新项目将阐明膳食Se对棕色脂肪细胞生理的调节作用，为了解Scly在哺乳动物能量消耗控制中的机制作用提供新的见解。