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

基本信息

批准号：
10453595
负责人：
Byung-Eun Kim
金额：
$ 37.53万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
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：
2021-07-19 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10453595
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 Disease Electron Transport Energy Metabolism Etiology Exhibits Exposure to Fluorescence Microscopy Funding Generations Genetic Goals Health Homeostasis Hormones Hour Human Impairment Injections Ionophores Iron Knockout Mice Lead Life Link Lipids Lipolysis Location Mediating Mediator of activation protein Menkes Kinky Hair Syndrome Metabolic Metabolism Metals Methods Minerals Mitochondria Modeling Molecular Mus Mutant Strains Mice Nature Nerve Degeneration Non-Insulin-Dependent Diabetes Mellitus Norepinephrine Obesity Pathogenicity Pathology Pathway interactions Patients Pharmacology 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 base biophysical techniques cofactor cold stress disease-causing mutation empowered human disease hypocupremia improved in vivo insight lipid metabolism natural hypothermia novel novel therapeutic intervention recruit response sensor small molecule subcutaneous trafficking transcriptome uncoupling protein 1 uptake

项目摘要

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）是必不可少的痕量元素，Cu失衡是几种人类疾病的潜在病因，包括Menkes病，Wilson's Disision，Mereloneulopathy和Cardyomyopathy。由ATP7A CU转运蛋白突变引起的Menkes病导致有机CU缺乏，从而导致结缔组织缺陷和严重的致命神经变性。 Menkes患者还表现出体温过低，这表明CU代谢与哺乳动物的热途径之间有联系。热发生由多次协调调节的几层代谢支持。热产生的主要位置是脂肪组织，这对交感神经系统产生的激素做出反应。例如，去脂蛋白组织中表达的β3肾上腺素受体（NE）刺激会在脂肪组织中表达，从而在热反应中上调了脂解，有丝分裂发生和解偶联蛋白1（UCP1）。通常，人们认为在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，因为电子传输链的任何金属辅因子水平不足会损害发热所需的线粒体活性。但是，尚未阐明将CU稳态与适应性生热作用联系起来的基本机制。当前的建议我们计划使用遗传，药物和细胞生物学方法研究平行的热生成模型，包括脂肪特异性基因敲除小鼠以及培养的原代和永生的脂肪细胞。初步研究表明，Cu在自适应热发生中起着独特的作用，因为暴露于感冒或肾上腺素刺激剂的小鼠专门将Cu（而不是Cu和Iron）进口到脂肪组织中，而缺乏高亲和力Cu摄入量的脂肪表达的小鼠对缺乏IrAmprimporter tfr1的小鼠对冷的小鼠CTR1的脂肪表达更为敏感。我们概述了三个特定旨在发现CU稳态途径如何与脂肪组织中的热途径相交的方式，并在此过程中发现CU代谢如何与全球能量调节相互作用：（1）CU在脂肪中使用组织的CTR1和全身性稳态中CU在脂肪中的作用，使用CTR1和ATP7A Myteant inp7a ATP7A ATP7A ATPR1A ATP7A ATPR1 ATER菌丝（2）（2）在β3-AR刺激下控制脂肪细胞中的Cu可用性，（3）发现CTR1介导的热发生和脂肪细胞褐变的机制。