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: 9975157
• 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/9975157
• 关键词: Adipocytes; Adipose tissue; Adult; Anatomy; Automobile Driving; Blood Vessels; C2H2 Zinc Finger; Cells; Chronic; Clinical Research; Development; Diet; Disease; Fatty acid glycerol esters; Fibrosis; Frequencies; Functional disorder; Gatekeeping; Genes; Health; Heterogeneity; High Fat Diet; Hyperplasia; Hypertrophy; Immune; Individual; 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; experimental study; feeding; in vivo; insight; insulin sensitivity; lipid biosynthesis; loss of function; macrophage; metabolic phenotype; mouse model; novel; 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.

肥胖承认患2型糖尿病和代谢综合征的重大风险；但是，并非所有肥胖的人都患上了这些代谢障碍。这意味着BMI超出了BMI的因素，可以推动这些疾病的发展。将“代谢健康肥胖”与代谢综合征肥胖个体进行比较的临床研究表明，肥胖症中能量储能的白脂肪组织（WAT）重塑的方式是代谢健康的关键决定剂。与肥胖相关的“重塑”可以描述为脂肪细胞数和基质/血管细胞组成的定量和定性变化。病理WAT重塑与胰岛素抵抗密切相关，其特征是脂肪细胞数量的扩张不足（即缺乏脂肪生成），脂肪细胞增加，巨噬细胞的积累过多和纤维化的存在。随之而来的脂肪组织功能障碍导致脂质在非脂肪周围组织中的有害积累。健康的WAT重塑涉及增生脂肪组织扩张（脂肪细胞数量增加）和慢性组织注射和纤维化的程度较低。这些代谢健康肥胖的这些脂肪表型与持续的胰岛素敏感性紧密相关。 WAT重塑由脂肪细胞，免疫细胞和各种类型定义的基质/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的盐水扩张的因素尚不清楚。我们已经确定了发挥促炎性表型的PDGFRβ+周围（壁画）细胞的新颖而独特的亚群。我们假设这些细胞被称为纤维炎性祖细胞（FIPS），是脂肪组织注射的守门人，并影响WAT重塑。 We propose to (1) characterize the frequency, function, and lineage plasticity of these cells across different adipose deposits and physical conditions influence 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控制壁细胞炎症信号传导（AIM 3）。这些目标的成功完成将揭示成人WAT中新型，身体调节的周围细胞种群，作为WAT注射的守门人。进一步洞悉健康WAT扩张的分子决定剂将导致策略使代谢功能障碍与肥胖症结合在一起。