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。我的团队与哈佛医学院的曾毓华（Yu-Hua Tseng）合作，首次报道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，这是半个多世纪以来使用的主要模型系统。与C. Ronald Kahn合作，我们鉴定了白色、棕色和米色人类脂肪细胞的细胞表面标记物，这些标记物可用于分离和研究不同的脂肪细胞谱系。与此同时，Tseng博士的研究小组从人类颈部脂肪中提取了克隆细胞系，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。通过克隆分析和基因表达谱，我们在人类前脂肪细胞中发现了一组独特的基因特征，这些基因特征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的细胞异质性，并为产热分化的主要前脂肪细胞提供了新的基因靶点。

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 at Harvard Medical School, 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. Tseng's 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. We are now in the process of expanding this collaboration with Bradford Wood, Director of NIH Center for Interventional Oncology, to be able to collect ultrasound-guided biopsies of the BAT. Previous collaborations with Dr. Siegfried Ussar and Dr. Chad Hunter have been established to better define human BAT lineage and adipogenesis. In addition, the ability of BAT activation to improve insulin sensitivity will be considered in the context of Covid-19 since patients with dysglycemia are at increased risk for complications. We will also determine if BAT is susceptible to Covid-19 entry. Finally, working in collaboration with ATCC, we have developed a paired set of immortalized clonal human brown and white adipocytes that can be used by the larger community as an in vitro model system to study human brown and white adipocyte cellular physiology.