Clinical Research Center, Morehouse School of Medicine, Atlanta, GA, USA.
Obesity (Silver Spring). 2012 Jul;20(7):1481-90. doi: 10.1038/oby.2011.370. Epub 2012 Jan 19.
Progenitor cells (PCs) are key components of vasculogenic remodeling and hematopoietic development. Decreases in the number and function of angiogenic progenitors have been observed in coronary artery disease, hypertension, and diabetic vasculopathy. Several recent studies have also demonstrated a close relationship between increased visceral fat and cardiovascular disease, implying an association between obesity and vascular dysfunction. However, very little is known about the role of PCs in obesity. We generated whole genome expression profiles of cultured PCs from 18 obese and 6 lean African-American women on Agilent microarrays and analyzed the data through bioinformatic pathway analysis using multiple databases and analytic tools. False-discovery rates (FDR) were calculated to assess statistical significance while controlling for multiple testing. We identified 1,145 upregulated and 2,257 downregulated genes associated with obesity (1.5-fold or greater absolute fold-change). Pathway analysis further identified a statistically significant downregulation of immune-response pathways in the obese subjects, including T-cell receptor signaling, natural killer cell signaling, and chemokine-signaling pathways (FDR <5%). Chemokine gene-expression patterns were consistent with an angiogenic-angiostatic imbalance and a downregulation of CXCR3 receptor-mediated signaling in the PCs from obese subjects. Overall, these findings reveal a novel transcriptional signature in cultured PCs from obese African-American women and further suggest that obesity-associated immune-compromise may originate much earlier in cellular development than currently appreciated. Clinically, this may translate into a lengthier period of immune dysregulation in obese subjects exposing them to greater risks of infection and other morbidities.
祖细胞 (PCs) 是血管生成重塑和造血发育的关键组成部分。在冠状动脉疾病、高血压和糖尿病血管病变中，已观察到血管生成祖细胞的数量和功能减少。最近的几项研究还表明，内脏脂肪增加与心血管疾病密切相关，这意味着肥胖与血管功能障碍之间存在关联。然而，对于 PC 在肥胖中的作用知之甚少。我们生成了来自 18 名肥胖和 6 名瘦弱的非裔美国女性的培养 PC 的全基因组表达谱，并通过使用多个数据库和分析工具的生物信息学途径分析来分析数据。通过控制多次测试，计算了错误发现率 (FDR) 以评估统计显著性。我们确定了与肥胖相关的 1145 个上调基因和 2257 个下调基因（绝对倍数变化 1.5 倍或更大）。途径分析进一步确定了肥胖组中免疫反应途径的统计学显著下调，包括 T 细胞受体信号、自然杀伤细胞信号和趋化因子信号途径（FDR <5%）。趋化因子基因表达模式与血管生成-血管抑制失衡一致，并且肥胖组的 PC 中 CXCR3 受体介导的信号转导下调。总体而言，这些发现揭示了来自肥胖的非裔美国女性培养 PC 中的新型转录特征，并进一步表明肥胖相关的免疫缺陷可能比目前认识的更早出现在细胞发育中。从临床角度来看，这可能意味着肥胖个体的免疫失调时间更长，使他们面临更大的感染和其他病态风险。
