The Role of Copper and CTR1 in the Regulation of Adipose Function

铜和 CTR1 在脂肪功能调节中的作用

• 批准号: 10615120
• 负责人: Byung-Eun Kim
• 金额: $ 38.92万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-19 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615120
• 关键词: Acute; Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Receptor; Affinity; Biochemical; Biogenesis; Biological; Biology; Brown Fat; Candidate Disease Gene; Cardiomyopathies; Cell Membrane Permeability; Cells; Cessation of life; Connective Tissue; Copper; Cyclic AMP; Defect; Diabetes Mellitus; Electron Transport; Endosomes; Energy Metabolism; Etiology; Exhibits; Exposure to; Fluorescence Microscopy; Funding; Generations; Genetic; Goals; Health; Hepatolenticular Degeneration; Homeostasis; Hormones; Hour; Human; Impairment; Injections; Ionophores; Iron; Knockout Mice; Life; Link; Lipids; Lipolysis; Location; Mediating; Mediator; Menkes Kinky Hair Syndrome; Metabolic; Metabolism; Metals; Methods; Minerals; Mitochondria; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Nature; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Obesity; Pathogenicity; Pathology; Pathway interactions; Patients; Physiologic Thermoregulation; Predisposition; Prevalence; Protein Family; RNA Interference; Regulation; Resistance; Roentgen Rays; Role; Signal Pathway; Signal Transduction; Site; Stimulation of Cell Proliferation; Sympathetic Nervous System; Testing; Thermogenesis; Tissues; Trace Elements; Transcript; Transition Elements; Wild Type Mouse; adipocyte differentiation; biophysical techniques; cofactor; cold stress; empowerment; human disease; hypocupremia; improved; in vivo; insight; lipid metabolism; natural hypothermia; novel; novel therapeutic intervention; pharmacologic; recruit; response; sensor; small molecule; subcutaneous; trafficking; transcriptome; uncoupling protein 1; uptake

Copper (Cu) is an essential trace element and Cu imbalance is the underlying etiology of several human diseases, including Menkes disease, Wilsonʼs disease, myeloneuropathy, and cardiomyopathy. Menkes disease, caused by mutations in the ATP7A Cu transporter, leads to organismal Cu deficiency that results in connective tissue defects and severe lethal neurodegeneration. Menkes patients also exhibit hypothermia, suggesting a link between Cu metabolism and mammalian thermogenic pathways. Thermogenesis is supported by several layers of metabolism coordinately regulated in multiple tissues. The major location for heat generation is adipose tissue, which responds to hormones generated by the sympathetic nervous system. For example, noradrenaline (NE) stimulation activates β3 adrenergic receptors expressed in adipose tissue, which in turn upregulates lipolysis, mitogenesis, and uncoupling protein 1 (Ucp1), culminating in a thermogenic response. It has generally been assumed that the hypothermia observed in Menkes patients is at least partly due to Cu deficiency in adipose tissue, where inadequate levels of any metal cofactor for the electron transport chain would impair the mitochondrial activity required for heat generation. However, the underlying mechanisms linking Cu homeostasis to adaptive thermogenesis have not yet been elucidated. The current proposal seeks to clarify the nature of this connection and improve our understanding of how Cu metabolism and adipose biology intersect. We plan to use genetic, pharmacological, and cell biological methods to study parallel thermogenesis models, including adipose-specific knockout mice, and cultured primary and immortalized adipocytes. Preliminary studies have shown a unique role for Cu in adaptive thermogenesis, as mice exposed to cold or adrenergic stimulators specifically import Cu (rather than both Cu and iron) into adipose tissue and mice lacking adipose expression of the high affinity Cu importer Ctr1 are more sensitive to cold exposure than mice lacking the iron importer Tfr1. We outline three specific aims to uncover how Cu homeostasis pathways intersect with thermogenic pathways in adipose tissue, and in doing so, uncover how Cu metabolism interacts with global energy regulation: (1) Establish a role for Cu in adipose thermoregulation and systemic energy homeostasis using tissue-specific Ctr1 and Atp7a mutant mice, (2) Determine how coordinated regulation of Ctr family proteins controls Cu availability in adipocytes upon β3-AR stimulation, and (3) Uncover mechanisms for CTR1-mediated thermogenesis and adipocyte browning.

铜（Cu）是人体必需的微量元素，铜失衡是多种人类疾病的潜在病因，包括Menkes病、Wilson病、脊髓神经病和心肌病。门克斯病由ATP 7A铜转运蛋白突变引起，导致机体铜缺乏，导致结缔组织缺陷和严重的致命性神经变性。Menkes患者也表现出体温过低，表明铜代谢和哺乳动物产热途径之间的联系。产热由多个组织中协调调节的几个代谢层支持。产生热量的主要部位是脂肪组织，它对交感神经系统产生的激素有反应。例如，去甲肾上腺素（NE）刺激激活脂肪组织中表达的β3肾上腺素能受体，进而上调脂解、有丝分裂和解偶联蛋白1（Ucp 1），最终导致产热反应。一般认为，在Menkes患者中观察到的体温过低至少部分是由于脂肪组织中的Cu缺乏，其中电子传递链的任何金属辅因子的水平不足将损害产生热量所需的线粒体活性。然而，铜稳态的适应性产热的潜在机制尚未得到阐明。目前的建议旨在澄清这种联系的性质，并提高我们对铜代谢和脂肪生物学如何交叉的理解。我们计划使用遗传学、药理学和细胞生物学方法来研究平行产热模型，包括脂肪特异性基因敲除小鼠和培养的原代和永生化脂肪细胞。初步研究表明，铜在适应性产热中具有独特的作用，因为暴露于冷或肾上腺素能刺激剂的小鼠特异性地将铜（而不是铜和铁）输入脂肪组织，并且缺乏高亲和力铜输入者Ctr 1的脂肪表达的小鼠比缺乏铁输入者Tfr 1的小鼠对冷暴露更敏感。我们概述了三个具体目标，以揭示铜稳态途径如何与脂肪组织中的产热途径相交，并在此过程中，揭示铜代谢如何与全球能量调节相互作用：（1）使用组织特异性Ctr 1和Atp 7a突变小鼠建立Cu在脂肪温度调节和全身能量稳态中的作用，（2）确定Ctr家族蛋白的协调调节如何控制β3-AR刺激后脂肪细胞中Cu的可用性，和（3）揭示CTR 1介导的产热和脂肪细胞布朗宁的机制。