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: 10919506
• 负责人: Aaron Cypess
• 金额: $ 36.9万
• 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/10919506
• 关键词: Acute; Adipocytes; Adipose tissue; Adult; Anatomy; Atlases; Biological Markers; Biological Models; Biopsy; Brown Fat; COVID-19; COVID-19 susceptibility; Cell model; Cell physiology; Cell surface; Cells; Chad; Collaborations; Communities; 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; 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; United States National Institutes of Health; Wood material; fibroblast growth factor 21; genetic signature; improved; in vitro Model; in vivo; insulin sensitivity; lipid biosynthesis; medical schools; novel; programs; stem cells; ultrasound

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.

关于人蝙蝠分布和缺乏血浆生物标志物的最初报告表明，这将是一个特别具有挑战性的器官。 急性需求是组织的精确解剖学定位以及人类衍生的棕色和白脂肪祖细胞模型的可用性，以了解其独特的生理学。 与哈佛医学院的Yu-Hua Tseng合作，我的小组首先报道了组织的解剖学定位，并表明人颈蝙蝠具有与啮齿动物间蝙蝠相同的发育谱系，这是使用了半个多世纪的主要模型系统。 与C. Ronald Kahn合作，我们确定了可用于分离和研究不同脂肪细胞谱系的白色，棕色和米色人脂肪细胞的细胞表面标记。 同时，Tseng博士的组从人颈脂肪中产生克隆细胞系，并在移植到免疫缺陷裸体小鼠中的体外和体内表征其脂肪分化和代谢功能。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的独特基因特征集，这些基因特征可以预测这些细胞一旦在培养中成熟成脂肪细胞中的热潜能。这些数据突出了人蝙蝠和WAT中的细胞异质性，并为用于热分化的主要前脂肪细胞提供了新的基因靶标。 其他发现包括改变miRNA加工的演示会破坏棕色/白色脂肪细胞的测定，并与脂肪营养不良的伴侣。具有代谢并发症的HIV感染受试者表明，FGF21与BAT基因表达的关系增加。 IRF4是热基因表达和能量消耗程序的转录驱动力。 在与CRC的正电子发射断层扫描部负责人彼得·赫斯科维奇（Peter Herscovitch）与CRC上的主席彼得·赫斯科维奇（Peter Herscovitch）合作，我们完成了首个基于PET/CT的人类蝙蝠ATLA的版本，称为Batlas 1.0。 有关每个仓库的解剖学和功能信息正在分类，这是理解人棕色和白色脂肪组织质量功能和结构的更大努力的一部分。 现在，我们正在与NIH介入肿瘤学中心主任布拉德福德·伍德（Bradford Wood）扩大合作，以便能够收集蝙蝠的超声引导活检。 已建立了与Siegfried USSAR博士和Chad Hunter博士的先前合作，以更好地定义人类蝙蝠的谱系和脂肪形成。 此外，在Covid-19的背景下，将考虑BAT激活提高胰岛素敏感性的能力，因为血糖症患者的并发症风险增加。 我们还将确定BAT是否容易受到COVID-19进入。 最后，我们与ATCC合作，我们开发了一组不朽的克隆人棕色和白色脂肪细胞，较大的社区可以用作研究人类棕色和白色脂肪细胞生理学的体外模型系统。

项目成果

Identification and characterization of distinct brown adipocyte subtypes in C57BL/6J mice.

• DOI: 10.26508/lsa.202000924
• 发表时间: 2021-01
• 期刊: Life science alliance
• 影响因子: 4.4
• 作者: Karlina R;Lutter D;Miok V;Fischer D;Altun I;Schöttl T;Schorpp K;Israel A;Cero C;Johnson JW;Kapser-Fischer I;Böttcher A;Keipert S;Feuchtinger A;Graf E;Strom T;Walch A;Lickert H;Walzthoeni T;Heinig M;Theis FJ;García-Cáceres C;Cypess AM;Ussar S
• 通讯作者: Ussar S

Combining a β3 adrenergic receptor agonist with alpha-lipoic acid reduces inflammation in male mice with diet-induced obesity.

• DOI: 10.1002/oby.23309
• 发表时间: 2022-01
• 期刊: Obesity (Silver Spring, Md.)
• 作者: Abdul Sater Z;Cero C;Pierce AE;Lea HJ;Abdul Sater H;Zhu KY;Liu N;Ma Y;Gavrilova O;Cypess AM
• 通讯作者: Cypess AM

TGF-β receptor 1 regulates progenitors that promote browning of white fat.

• DOI: 10.1016/j.molmet.2018.07.008
• 发表时间: 2018-10
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Wankhade UD;Lee JH;Dagur PK;Yadav H;Shen M;Chen W;Kulkarni AB;McCoy JP;Finkel T;Cypess AM;Rane SG
• 通讯作者: Rane SG