Measurement of Bone Marrow-derived Adipocytes in Humans

描述（由申请人提供）：肥胖是慢性疾病的一个强有力的预测因素，但腹部脂肪的特异性积累已成为一个独立于整体肥胖的心脏代谢危险因素。认识到脂肪组织不仅仅是一个惰性的脂肪储存器官，而是一个活跃的内分泌器官，分泌多种具有广泛作用的细胞因子，这为局部肥胖与疾病风险之间的潜在机制联系提供了可能。最近脂肪细胞生物学的临床前研究进展表明，新的脂肪细胞来自于一个由常驻和非常驻祖细胞组成的异质群体，这一特征可能决定了所产生的脂肪细胞的表型。小鼠模型提供了一种独特的非常驻祖细胞谱系积累的初步证据，这种细胞起源于骨髓，可能以年龄和储存特异性的方式进行调节。由于其有害的表型特征（如胰岛素抵抗、炎症标志物增加和瘦素降低）以及随着年龄的增长在女性中优先积累，特别是在内脏库中，这一谱系特别有趣。本提案的总体目标是对人类脂肪组织中骨髓祖细胞（BMP）来源的脂肪细胞进行首次调查和表征。完成这个新项目的第一步将是利用类似于先前动物研究中使用的骨髓移植策略的方法，从有骨髓移植史的患者中获取脂肪组织样本。通过微嵌合分析（Aim 1），可以在该人群中鉴定骨髓来源的细胞，这是一种临床经常使用的技术，作为移植植入的指标。结合嵌合分析，我们将使用流式细胞术来确定一个独特的细胞表面标记（目标1）和基因表达分析来描绘一个独特的遗传“指纹”（目标2），这两者都将在未来的研究中用于识别普通人群（非骨髓移植患者）中bmp来源的脂肪细胞。最后，在目标1和目标2中鉴定的细胞表面标记物和遗传“指纹”将用于测量健康成人（无BMT病史）皮下和内脏脂肪组织中bmp来源的脂肪细胞（目标3）。这些研究将证实bmp来源的脂肪细胞存在于人类脂肪组织中，并且它们表现出与小鼠模型相同的阴性表型。这项研究的结果将为继续在许多人类疾病和肥胖模型中研究这种独特的脂肪细胞谱系提供必要的知识和工具，并可能揭示未来治疗的潜在机制靶点，以减少与腹部肥胖相关的负面健康结果。

DESCRIPTION (provided by applicant): Obesity is a strong predictor of chronic disease but the specific accumulation of abdominal fat has emerged as a cardiometabolic risk factor independent of overall obesity. The recognition that adipose tissue is not just an inert fat storag organ, but rather an active endocrine organ secreting a variety of cytokines that have wide reaching actions has provided a potential mechanistic link between regional adiposity and disease risk. Recent preclinical advances in adipocyte biology revealed that new adipocytes arise from a heterogeneous population of both resident and non-resident progenitor cells, a feature that may determine the phenotype of the resultant adipocytes. Mouse models have provided preliminary evidence for accumulation of a unique lineage of non- resident progenitor cells, arising from the bone marrow, which may be regulated in an age- and depot-specific manner. This lineage is of particular interest because of its detrimental phenotypic signature (e.g., insulin resistance, increased inflammatory markers, and decreased leptin) and its preferential accumulation in females with age, particularly in visceral depots. The global aim of this proposal is to perform the first investigation and characterization of bone marrow progenitor (BMP)-derived adipocytes in human adipose tissue. The first step in accomplishing this novel project will be to utilize an analogous approach to the bone marrow transplant strategy used in the previous animal studies, by obtaining adipose tissue samples from patients with a history of bone marrow transplantation. Identification of cells of bone marrow origin in this population is possible by microchimerism analysis (Aim 1), a technique regularly utilized clinically as an indicator of transplant engraftment. In conjunction with the chimerism analysis, we will use flow cytometry to determine a distinct cell surface marker (Aim 1) and gene expression analysis to delineate a unique genetic 'fingerprint' (Aim 2), both of which will be used in future studies to identify BMP-derived adipocytes in the general human population (non- bone marrow transplant patients). Finally, the cell surface marker and genetic 'fingerprint' identified in Aims 1 and 2 wil be utilized to measure BMP-derived adipocytes in subcutaneous and visceral adipose tissue from healthy adults (no history of BMT) (Aim 3). These studies will confirm that BMP-derived adipocytes are present in human adipose tissue and that they demonstrate the same negative phenotype as in the mouse model. The results of this investigation will provide the knowledge and tools necessary to continue studies of this unique adipocyte lineage in many models of human disease and obesity and may reveal potential mechanistic targets for future therapies to reduce the negative health outcomes associated with abdominal adiposity.