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

Pdgfrb 血管周围细胞在白色脂肪组织重塑中的多方面作用

• 批准号: 10164767
• 负责人: Rana K Gupta
• 金额: $ 44.12万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-09 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164767
• 关键词: Adipocytes; Adipose tissue; Adult; Anatomy; Automobile Driving; Blood Vessels; Body mass index; C2H2 Zinc Finger; Cells; Chronic; Clinical Research; Development; Disease; Fatty acid glycerol esters; Fibrosis; Frequencies; Functional disorder; Gatekeeping; Genes; Health; Heterogeneity; High Fat Diet; Hyperplasia; Hypertrophy; Immune; Inflammation; Inflammatory; Insulin Resistance; Knowledge; Link; Lipids; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathologic; Pericytes; Peripheral; Phenotype; Physiological; Population; Property; Publishing; Regulation; Risk; Role; Sentinel; Signal Pathway; Signal Transduction; Stromal Cells; TLR4 gene; TNF gene; Testing; Therapeutic; Tissue Expansion; Tissues; Transplantation; Visceral; adult obesity; cell type; design; diet-induced obesity; experimental study; feeding; in vivo; insight; insulin sensitivity; lipid biosynthesis; loss of function; macrophage; metabolic phenotype; mouse model; novel; obese person; precursor cell; progenitor; programs; single-cell RNA sequencing; transcription factor

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.

肥胖是罹患 2 型糖尿病和代谢综合征的重大风险；然而，并非所有肥胖者都会出现这些代谢紊乱，这意味着临床研究表明，除了 BMI 之外，还有其他因素导致这些疾病的发生。患有代谢综合征的肥胖个体表明，肥胖中能量储存白色脂肪组织（WAT）的重塑方式是与肥胖相关的代谢健康“重塑”的关键决定因素，可以说是定量的。脂肪细胞数量和基质/血管细胞组成的质变，与胰岛素抵抗密切相关，其特点是脂肪细胞数量扩张不足（即脂肪生成不足）、脂肪细胞增大、巨噬细胞过度积累和纤维化。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累。健康的 WAT 重塑涉及增生性脂肪组织扩张（脂肪细胞增加）。 WAT 重塑是由脂肪细胞、免疫细胞和各种类型不明确的基质/血管细胞之间的协调相互作用控制的。迄今为止，决定肥胖中健康与不健康 WAT 扩张的因素仍不清楚。发挥促炎表型的 PDGFRβ+ 血管周围（壁）细胞。我们认为这些细胞被称为纤维炎症祖细胞 (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中的频率、功能和谱系可塑性。影响 WAT 重塑的库和生理条件（目标 1），(2) 定义了这些细胞的重要性：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）， (3) 评估 C2H2 锌指转录因子 ZFP423 在控制壁细胞炎症信号传导中的重要性（目标 3），成功完成这些目标将揭示成人血管周围细胞的新型、生理调节群体。 WAT 作为 WAT 炎症的守门人，进一步深入了解 WAT 健康扩张的分子决定因素将有助于制定将代谢功能障碍与肥胖分开的策略。