Multifaceted Roles for Pdgfrb+ Perivascular Cells in White Adipose Tissue Remodeling

肥胖会导致发生2型糖尿病和代谢综合征的显著风险;然而，并非所有肥胖个体都会发生这些代谢紊乱。这意味着BMI本身以外的因素推动了这些疾病的发展。比较“代谢健康的肥胖者”与患有代谢综合征的肥胖个体的临床研究已经揭示，肥胖中能量储存白色脂肪组织（WAT）重塑的方式是代谢健康的关键决定因素。与肥胖相关的WAT“重塑”可以被描述为脂肪细胞数量和基质/血管细胞组成的定量和定性变化。病理性WAT重塑与胰岛素抵抗密切相关，其特征在于脂肪细胞数量扩增不足（即缺乏脂肪生成）、存在增大的脂肪细胞、过度巨噬细胞积聚和纤维化。随后的脂肪组织功能障碍导致脂质在非脂肪外周组织中的有害积累。健康的WAT重塑涉及增生性脂肪组织扩张（脂肪细胞数量增加）和较低程度的慢性组织炎症和纤维化。代谢健康的肥胖者的这些脂肪表型与持续的胰岛素敏感性密切相关。 WAT重塑由脂肪细胞、免疫细胞和各种类型的定义不明确的基质/血管细胞之间的协调相互作用控制。迄今为止，决定肥胖症中健康与不健康WAT扩张的因素仍不清楚。我们已经确定了一种新的和独特的亚群PDGFRβ+血管周围（壁）细胞发挥促炎表型。我们假设这些细胞，被称为纤维炎性祖细胞（FIP），作为脂肪组织炎症的看门人，并影响WAT重塑。我们建议（1）表征这些细胞在不同脂肪库和影响WAT重塑的生理条件下的频率，功能和谱系可塑性（目的1），（2）定义这些细胞的重要性：壁细胞炎症信号是否以及如何影响脂肪组织重塑和炎症（目的2），和（3）评估C2 H2锌指转录因子的重要性，ZFP 423，在壁细胞炎症信号传导的控制中（目的3）。这些目标的成功完成将揭示一种新的，生理调节，在成人WAT血管周围细胞的人口，作为WAT炎症的看门人。对健康WAT扩展的分子决定因素的进一步了解将导致将代谢功能障碍与肥胖分开的策略。

Obesity confers significant risk for developing type 2 diabetes and metabolic syndrome; however, not all obese individuals develop these metabolic disorders. This implies that factors beyond BMI, per se, drive the development of these diseases. Clinical studies comparing the “metabolically healthy obese” to obese individuals with metabolic syndrome have revealed that the manner by which energy-storing white adipose tissue (WAT) remodels in obesity is a critical determinant of metabolic health. WAT “remodeling” associated with obesity can be described as both quantitative and qualitative changes in adipocyte numbers and stromal/vascular cell composition. Pathologic WAT remodeling, tightly linked to insulin resistance, is characterized by inadequate expansion of adipocyte number (i.e. lack of adipogenesis), the presence of enlarged adipocytes, excessive macrophage accumulation, and fibrosis. The ensuing fat tissue dysfunction leads to the deleterious accumulation of lipids in non-adipose peripheral tissues. Healthy WAT remodeling involves hyperplastic adipose tissue expansion (increase in adipocyte number) and a lower degree of chronic tissue inflammation and fibrosis. These adipose phenotypes of the metabolically healthy obese tightly correlate with sustained insulin sensitivity. WAT remodeling is controlled by coordinated interactions between adipocytes, immune cells, and various types of poorly defined stromal/vascular cells. To date, the factors dictating a healthy vs. unhealthy WAT expansion in obesity remain unclear. We have identified a novel and distinct subpopulation of PDGFRβ+ perivascular (mural) cells that exert a pro-inflammatory phenotype. We hypothesize that these cells, referred to as fibro-inflammatory progenitors (FIPs), serve as gatekeepers of adipose tissue inflammation and influence WAT remodeling. We propose to (1) characterize the frequency, function, and lineage plasticity of these cells across different adipose depots and physiological conditions influencing WAT remodeling (Aim 1), (2) define the importance of these cells: if and how mural cell inflammatory signaling influences adipose tissue remodeling and inflammation (Aim 2), and (3) evaluate the importance of the C2H2 zinc-finger transcription factor, ZFP423, in the control of mural cell inflammatory signaling (Aim 3). Successful completion of these aims will reveal a novel, physiologically regulated, population of perivascular cells in adult WAT that serve as gatekeepers of WAT inflammation. Further insight into the molecular determinants of healthy WAT expansion will lead to strategies to uncouple metabolic dysfunction from obesity.