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，而不是过多的脂肪量，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，因此在AT内调节细胞表型为治疗干预提供了潜在的手段。例如，在啮齿类动物模型中，经典棕色和白色AT库中棕色脂肪细胞（BA）产热的激活和扩增具有有效的抗肥胖和抗糖尿病作用，最近在成人锁骨上AT中发现BA，为扩大BA功能以治疗人类提出了前景。几个实验室已经证明了人类锁骨上AT的功能性BA；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。这项工作确立了两个重要的事实：首先，由于未知的原因，锁骨上AT中BA的数量和活性在个体之间存在很大差异。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，但这些细胞只占整个细胞代谢率的一小部分

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.