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

描述（由申请人提供）：越来越多的数据表明，功能失调的脂肪组织，而不是过量的脂肪量，是肥胖促进疾病的主要手段。由于脂肪组织（AT）表现出明显的代谢和细胞可塑性，AT内的细胞表型的调制提供了一个潜在的手段进行治疗干预。例如，经典棕色和白色AT贮库中棕色脂肪细胞（BA）产热的活化和扩增在啮齿动物模型中具有有效的抗肥胖和抗糖尿病作用，并且最近在成年人锁骨上AT中BA的鉴定提高了扩增BA功能以用于人类治疗益处的前景。然而，我们的小组是第一个量化这些细胞在体内的产热活性。这项工作建立了两个重要的事实：第一，在锁骨上AT的BA的数量和活性差异很大，个体之间的未知原因。其次，锁骨上AT中BA的激活与个体代谢率的增加（200-300 Kcal/d）密切相关，但这些细胞仅占代谢率的一小部分。 增加全身新陈代谢。因此，本研究的总体目标是解决人类BA丰度变化的潜在机制，并使用PET，fMR和3D组织成像以及分子分析的综合方法来识别冷诱导产热的锁骨上AT位点。在小鼠模型中的实验结果表明，交感神经支配的紧张水平极大地影响募集典型的白色脂肪库的能力。我们假设人类锁骨上AT的交感神经支配的水平和/或活性是该贮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，这些人与高水平的BA在锁骨上AT（和密集的SNS神经支配）也将有较高水平的BA在皮下和心外膜AT仓库，这些广泛分散的细胞介导的大部分“失踪”nonshriving产热（NST）在冷应激的人。此外，尚未在人类中研究将棕色AT活化与能量平衡联系起来的CNS途径。我们假设，冷应激将产生变化的BOLD功能磁共振成像信号的区域负责调节交感神经激活的棕色AT，这种激活将与周围SNS神经支配的密度。总的来说，我们希望将代谢和神经支配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的合作工作，使用15 O水和FDG PET成像在年轻的成年人控制，并将确定交感神经支配和能量消耗之间的关系，在锁骨上，心外膜和皮下AT的年轻瘦成人。此外，我们将使用功能磁共振成像映射的CNS电路参与冷诱导BA激活，并确定是否有/无锁骨上棕色AT仓库的受试者之间的激活不同。这些体内成像研究将与锁骨上白色AT的3D免疫组织化学和基因分析研究相结合，然后将其与动物模型中的最新发现相结合。我们预计，这项研究的结果将导致对人类脂肪祖细胞的招募和表观遗传特化的深入分析，并可能导致更有效的方法来控制肥胖受试者的体重。

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.