The Molecular, Cellular, and Genetic characterization of Human Adipose Tissue and its Role in Metabolism

关于人类BAT分布和缺乏血浆生物标志物的初步报告表明，这将是一个特别具有挑战性的器官研究。 迫切需要的是组织的精确解剖定位和人类来源的棕色和白色脂肪祖细胞模型的可用性，以了解其独特的生理学。 在与Yu-Hua Tseng的合作中，我的小组首次报告了该组织的解剖定位，并表明人类颈部BAT与啮齿动物肩胛间BAT具有相同的发育谱系，后者是世纪以来使用的主要模型系统。 与C合作。罗纳德卡恩，我们确定了白色，棕色和米色人类脂肪细胞的细胞表面标记，可用于分离和研究不同的脂肪细胞谱系。 与此同时，Tsengs博士的研究小组从人颈部脂肪中产生了克隆细胞系，并在移植到免疫缺陷裸鼠体内后，在体外和体内表征了它们的成脂分化和代谢功能。使用克隆分析和基因表达谱分析，我们确定了人类前脂肪细胞中独特的基因特征集，这些基因特征集可以预测这些细胞在培养中成熟为脂肪细胞后的产热潜力。这些数据突出了人类BAT和WAT中的细胞异质性，并提供了新的基因靶点来引发前脂肪细胞的产热分化。 其他发现包括证明改变的miRNA加工破坏棕色/白色脂肪细胞决定并与脂肪营养不良相关;患有代谢并发症的HIV感染受试者显示与BAT基因表达相关的FGF 21增加; IRF 4是产热基因表达和能量消耗程序的转录驱动因子。 在与能量代谢科代理科长Kong Chen和CRC正电子发射断层扫描科科长Peter Herscovitch的合作下，我们完成了第一个基于PET/CT的人体BAT图谱，称为BATlas 1.0。 关于每个贮库的解剖和功能信息正在被编目，作为理解人类棕色和白色脂肪组织块的功能和结构的更大努力的一部分。

The initial reports about human BAT distribution and lack of plasma biomarkers indicated that it would be a particularly challenging organ to study. An acute need was the precise anatomical localization of the tissue and the availability of human-derived brown and white fat progenitor cell models to understand its distinct physiology. In collaboration with Yu-Hua Tseng, my group first reported the anatomical localization of the tissue and showed that human neck BAT shared the same developmental lineage as rodent interscapular BAT, the principal model system used for more than half a century. In collaboration with C. Ronald Kahn, we identified cell surface markers of white, brown, and beige human adipocytes that could be used to isolate and study the different adipocyte lineages. In parallel, Dr. Tsengs group generated clonal cell lines from human neck fat and characterized their adipogenic differentiation and metabolic function in vitro and in vivo after transplantation into immune deficient nude mice. Using clonal analysis and gene expression profiling, we identified unique sets of gene signatures in human preadipocytes that could predict the thermogenic potential of these cells once matured in culture into adipocytes. These data highlight the cellular heterogeneity in human BAT and WAT and provide novel gene targets to prime preadipocytes for thermogenic differentiation. Additional discoveries included the demonstration that altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy; HIV-infected subjects with metabolic complications demonstrate increases in FGF21 in relationship to BAT gene expression; and IRF4 is a transcriptional driver of a program of thermogenic gene expression and energy expenditure. In collaboration with Kong Chen, Acting Chief of the Energy Metabolism Section, and Peter Herscovitch, Chief of the Positron Emission Tomography Department in the CRC, we have completed the first version of an PET/CT-based atlas of human BAT known as the BATlas 1.0. Anatomical and functional information about each depot is being catalogued as part of the larger effort of understanding the function and structure of the human brown and white adipose tissue mass.