Sympathetic innervation of cold-activated brown and white fat in lean young adult

瘦年轻人冷激活棕色和白色脂肪的交感神经支配

基本信息

批准号：
8742239
负责人：
James G Granneman
金额：
$ 30.48万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-11 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8742239
关键词：
Accounting Address Adipocytes Adipose tissue Adult Animal Model Appearance Area Biopsy Blood flow Brain Brown Fat Cell Respiration Cells Data Deoxyglucose Disease Energy Metabolism Epigenetic Process Exhibits Fatty acid glycerol esters Functional Magnetic Resonance Imaging Gene Expression Genes Goals Human Image Indirect Calorimetry Individual Individual Differences Inferior Label Lead Link Lobule Maintenance Maps Measures Mediating Metabolic Metabolism Methodology Molecular Profiling Muscle Myocardium Nerve Obesity Parietal Pathway interactions Peripheral Phenotype Phosphorylation Positron-Emission Tomography Proteins Recruitment Activity Regulation Research Research Proposals Rodent Model Role Signal Transduction Site Stress Structure Supraclavicular Therapeutic Therapeutic Intervention Thermogenesis Tissues Variant Water Weight maintenance regimen Work base cingulate cortex density energy balance in vivo in vivo imaging kidney cortex man mind control mouse model nerve supply neural circuit progenitor public health relevance raphe nuclei response subcutaneous uptake young adult

项目摘要

DESCRIPTION (provided by applicant): Mounting data indicate that dysfunctional adipose tissue, rather than excessive fat mass, is the central means by which obesity promotes disease. Because adipose tissue (AT) exhibits pronounced metabolic and cellular plasticity, modulation of cellular phenotypes within AT offers a potential means for therapeutic intervention. For example, activation and expansion of brown adipocyte (BA) thermogenesis in classic brown and white AT depots has potent anti-obesity and antidiabetes effects in rodent models, and the recent identification of BA in supraclavicular AT of adult humans raises the prospect of expanding BA function for therapeutic benefit in man. Several labs have demonstrated functional BA in human supraclavicular AT; however, our group was the first to quantify the thermogenic activity of these cells in vivo. This work established two important facts: First, the quantity and activity of BA in supraclavicular AT varies greatly among individuals for unknown reasons. Second, activation of BA in supraclavicular AT is closely correlated with individual increases metabolic rate (200-300 Kcal/d), yet these cells account for only a small fraction of the increase in whole body metabolism. Thus, the overall goal of this research is to address the mechanisms underlying variations in human BA abundance, and to identify the extra-supraclavicular AT sites of cold-induced thermogenesis, using integrated approaches of PET, fMR and 3D tissue imaging as well as molecular profiling. Experimental results in mouse models indicate that the tonic level of sympathetic innervation greatly influences the ability to recruit A typical white fat depots. We hypothesize that the level and/or activity of the sympathetic innervation of human supraclavicular AT is a major determinant of whether this depot contains brown or white adipocytes. Furthermore, we propose that those individuals with high levels of BA in supraclavicular AT (and dense SNS innervation) will also have higher levels of BA in subcutaneous and epicardial AT depots, and that these widely dispersed cells mediate the bulk of the "missing" nonshivering thermogenesis (NST) observed in cold-stressed humans. Moreover, CNS pathways that link activation of brown AT and energy balance have not been investigated in humans. We hypothesize that cold stress will produce changes in the BOLD fMRI signal in areas responsible for regulating sympathetic activation of brown AT and this activation will correlate with the density of peripheral SNS innervation. Overall, we expect to integrate noninvasive imaging of metabolism and innervation with variations in adipocyte phenotypes in humans. This project builds on our previous collaborative work using 15O water and FDG PET imaging in young adult controls and will determine the relationship between sympathetic innervation and energy expenditure in supraclavicular, epicardial and subcutaneous AT of young lean adults. In addition, we will use fMRI to map the CNS circuits involved in cold-induced BA activation, and determine whether this activation differs between subjects with/without depots of supraclavicular brown AT. These in vivo imaging studies will be combined with 3D immunohistochemical and gene profiling studies of supraclavicular white AT, which will then be integrated with recent discoveries in animal models. We expect that the results of this study will lead to an in-depth analysis of the recruitment and epigenetic specification of human adipocyte progenitors and will potentially lead to more effective approaches to weight control in obese subjects.

描述（由申请人提供）：安装数据表明，肥胖促进疾病的核心手段是功能失调的脂肪组织而不是过多的脂肪质量。由于脂肪组织（AT）表现出明显的代谢和细胞可塑性，因此AT内部的细胞表型的调节提供了治疗干预的潜在手段。例如，在啮齿动物模型中，经典棕色和白色在仓库经典棕色和白色的激活和膨胀具有有效的抗肥胖和抗糖尿病，并且最近在成人人类上对BA的鉴定在成人人类的susplaclavicular中提高了BA功能的前景，从而为人类提供了治疗益处。几个实验室在人类锁骨上表现出功能性BA；但是，我们的组是第一个在体内量化这些细胞的热活性的人。这项工作确定了两个重要事实：首先，由于未知原因，个人在胸骨上的BA数量和活动在个体之间差异很大。其次，上锁骨AT中BA的激活与个体增加的代谢率密切相关（200-300 kcal/d），但这些细胞仅占一小部分全身代谢增加。因此，这项研究的总体目标是使用PET，FMR和3D组织成像的集成方法以及分子分析，以解决人类BA丰度中的机制，并在冷诱导的热生成部位鉴定在冷诱导的热生成部位的舒张外。小鼠模型中的实验结果表明，交感神经的滋补水平极大地影响了募集典型的白脂肪库的能力。我们假设人上锁骨上的交感神经的水平和/或活性是该仓库是否含有棕色或白色脂肪细胞的主要决定因素。此外，我们建议那些在suroplaclavicular at（和密集的SNS神经）中具有高水平的Ba的个体在仓库的皮下和表外心脏中也将具有较高的Ba水平，并且这些广泛分散的细胞介导了“缺失”的“缺失”的大容量，在冷效应（NST）中观察到了冷染色（NST）。此外，尚未在人类中研究将棕色AT和能量平衡联系起来的CNS途径。我们假设冷应力将在负责调节棕色AT交感神经激活的区域中大胆的fMRI信号发生变化，而这种激活将与周围SNS神经支配的密度相关。总体而言，我们期望将代谢和神经神经的非侵入性成像与人类脂肪细胞表型的变化相结合。该项目建立在我们以前使用15o水和FDG PET成像中的合作工作的基础上，并将确定在幼年成年人的肾上腺超，心外膜和皮下的交感神经支出与能量消耗之间的关系。此外，我们将使用fMRI来绘制与冷诱导的BA激活有关的中枢神经系统电路，并确定这种激活是否在具有/没有suroplaclavicular Brown的受试者之间有所不同。这些体内成像研究将与上白色AT的3D免疫组织化学和基因分析研究结合使用，然后将其与动物模型中的最新发现结合。我们预计这项研究的结果将导致对人脂肪细胞祖细胞的募集和表观遗传规范的深入分析，并有可能导致更有效的肥胖受试者体重控制方法。