Selenium metabolism in cold-induced adaptive thermogenesis

棕色脂肪细胞暴露于冷通过适应性产热散热。适应性产热是一种生理反应，有助于能量稳态和限制啮齿动物和人类的肥胖发展。通过冷暴露激活适应性产热取决于交感神经/β-肾上腺素能信号和甲状腺激素（TH），并且通过活性氧升高由谷胱甘肽（GSH）耗竭诱导。BAT中的TH水平由碘甲腺原氨酸脱碘酶2（DIO 2）局部调节，而GSH由GSH过氧化物酶1（GPX 1）酶促转化为还原形式。除了它们在BAT适应性产热的激活中的关键作用之外，DIO 2和GPX 1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被酶Sec裂解酶（Scly）分解成H2Se。Sec来源于膳食来源或硒蛋白降解。因此，Scly介导的Sec分解触发了维持硒蛋白最佳水平所需的Se再循环过程，特别是当Se受限时。硒循环是能量平衡的关键，因为小鼠中Scly基因的破坏（Scly KO）会导致硒缺乏加重体重增加。在野生型啮齿类动物中，硒缺乏上调Scly并降低BAT Se水平、DIO 2和GPX 1活性。尚不清楚硒再循环是否调节BAT硒水平，影响DIO 2和GPX 1合成和活性，最终促成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。本研究的总体目标是确定硒和Scly介导的硒循环在连接硒蛋白的降解和合成与棕色脂肪细胞的适应性产热中的作用。在目标1中，我们将确定膳食硒摄入量是否调节硒代谢，特别是Scly介导的硒再循环，影响BAT对冷暴露的反应。在目标2中，我们将确定Scly是否是BAT中冷诱导的适应性产热所需的。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。通过研究硒的摄入和代谢，特别是硒的回收，使用新的体外和体内模型，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在控制哺乳动物能量消耗中的机制作用提供新的见解。

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.