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

人类脂肪组织的分子、细胞和遗传特征及其在代谢中的作用

• 批准号: 10253759
• 负责人: Aaron Cypess
• 金额: $ 25.28万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10253759
• 关键词: Acute; Adipocytes; Adipose tissue; Adult; Anatomy; Atlases; Biological Markers; Biological Models; Biopsy; COVID-19; Catalogs; Cell model; Cell surface; Cells; Chad; Clone Cells; Collaborations; Data; Development; Energy Metabolism; FGF21 gene; Fatty acid glycerol esters; Gene Expression; Gene Expression Profiling; Gene Targeting; Genetic; Genetic Transcription; Growth; HIV; Heterogeneity; Human; Human Cell Line; IRF4 gene; Immune; In Vitro; Intervention; Lead; Lipodystrophy; Maps; Metabolic; Metabolism; MicroRNAs; Molecular; Neck; Nude Mice; Oncology; Organ; PET/CT scan; Patients; Physiological; Physiology; Plasma; Positron-Emission Tomography; Process; Reporting; Risk; Rodent; Role; Structure; Testing; Tissues; Transplantation; Ultrasonography; United States National Institutes of Health; Wood material; base; genetic signature; improved; in vivo; insulin sensitivity; lipid biosynthesis; medical schools; novel; programs; stem cells

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. Recent 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.

关于人类蝙蝠分布和缺乏血浆生物标志物的最初报告表明，它将是一个特别具有挑战性的器官。迫切需要对组织进行精确的解剖定位，并建立人类来源的棕色和白色脂肪前体细胞模型，以了解其独特的生理学。与哈佛医学院的曾宇华合作，我的团队首次报告了该组织的解剖定位，并表明人类颈蝙蝠与啮齿动物肩间蝙蝠具有相同的发育谱系，后者是半个多世纪以来使用的主要模式系统。在与C.Ronald Kahn的合作中，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，这些标记可用于分离和研究不同的脂肪细胞系。与此同时，曾博士的团队从人的颈部脂肪中克隆出了细胞系，并在将其移植到免疫缺陷的裸鼠体内后，在体外和体内鉴定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分析，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生热潜力。这些数据突出了人类BAT和WAT的细胞异质性，并为启动前脂肪细胞的产热分化提供了新的基因靶点。 其他发现包括：miRNA加工改变扰乱了棕色/白色脂肪细胞的测定，并与脂肪营养不良有关；患有代谢并发症的艾滋病毒感染者表现出与BAT基因表达有关的FGF21增加；以及IRF4是一项产热基因表达和能量消耗计划的转录驱动因素。 在与能量代谢科代理科长孔陈和中国研究中心正电子发射断层摄影科科长彼得·赫斯科维奇的合作下，我们已经完成了基于PET/CT的人类蝙蝠图谱的第一版，称为BATlas 1.0。关于每个储存库的解剖和功能信息正在被编目，作为了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。我们现在正在扩大与NIH介入肿瘤学中心主任布拉德福德·伍德的合作，以便能够收集超声引导的蝙蝠活组织检查。 最近与西格弗里德·尤萨尔博士和查德·亨特博士的合作已经建立，以更好地确定人类蝙蝠的血统和脂肪生成。此外，BAT激活改善胰岛素敏感性的能力将在新冠肺炎的背景下被考虑，因为患有血糖异常的患者发生并发症的风险增加。我们还将确定BAT是否易受新冠肺炎进入的影响。