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

肥胖会增加患2型糖尿病和代谢综合征的风险；然而，并不是所有的肥胖者都会患上这些代谢紊乱。这意味着，体重指数以外的因素本身推动了这些疾病的发展。临床研究表明，储存能量的白色脂肪组织(WAT)在肥胖症患者中的重塑方式是代谢健康的关键决定因素。与肥胖相关的重塑可以描述为脂肪细胞数量和间质/血管细胞组成的数量和质量的变化。病理性Wat重塑与胰岛素抵抗密切相关，其特征是脂肪细胞数量扩张不足(即缺乏脂肪生成)、脂肪细胞肥大、巨噬细胞过度聚集和纤维化。随之而来的脂肪组织功能障碍导致非脂肪外周组织中脂质的有害积聚。健康的WAT重塑包括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重塑是由脂肪细胞、免疫细胞和各种不明确的间质/血管细胞之间的协调作用控制的。到目前为止，肥胖症中健康和不健康的WAT扩张的因素仍然不清楚。我们已经确定了一种新的、独特的PDGFRβ+血管周围(壁细胞)细胞亚群，它们具有促炎表型。我们推测，这些细胞被称为纤维炎症前体细胞(FIP)，它们是脂肪组织炎症的守门人，并影响WAT的重塑。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(目标1)，(2)确定这些细胞的重要性：壁细胞炎症信号是否以及如何影响脂肪组织重塑和炎症(目标2)，以及(3)评估C2H2锌指转录因子ZFP423在控制壁细胞炎症信号中的重要性(目标3)。这些目标的成功完成将揭示出成年WAT中一种新的、生理调节的血管周围细胞群，它们充当WAT炎症的守门人。进一步深入了解健康的WAT扩大的分子决定因素将导致将代谢功能障碍与肥胖分离的策略。

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.