Healthy Remodeling of Obese Adipose Tissue

肥胖脂肪组织的健康重塑

• 批准号: 9896820
• 负责人: STEPHEN ROBERT FARMER
• 金额: $ 47.03万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896820
• 关键词: Actins; Adipocytes; Adipose tissue; Adrenergic beta-Agonists; Alleles; Attenuated; Automobile Driving; Blood Vessels; Brown Fat; Cardiac; Cardiovascular Diseases; Cell Adhesion; Cells; Chronic; Consumption; Deposition; Development; Diabetes Mellitus; Diet; Dietary Fats; Disease; Energy Metabolism; Enterobacteria phage P1 Cre recombinase; Event; Extracellular Matrix; Fatty acid glycerol esters; Fibrosis; Health Expenditures; Heart; Homeostasis; Human; Hypertension; Hypertrophy; Incidence; Individual; Inflammation; Inflammatory; Insulin Resistance; Knowledge; Liver; Lung; Mediating; Metabolic; Metabolic Diseases; Metabolism; Modeling; Morphology; Mus; Myofibroblast; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Pathologic; Pathway interactions; Pharmacology; Play; Process; Reporting; Resistance; Role; Serum Response Factor; Signal Pathway; Signal Transduction; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Tumor-infiltrating immune cells; United States; Weight Gain; World Health; adipokines; adverse outcome; angiogenesis; bariatric surgery; comorbidity; cytokine; deprivation; design; effective therapy; factor A; fibrogenesis; genetic manipulation; human data; inflammatory milieu; insight; insulin sensitivity; lipid biosynthesis; myocardin; novel; obesity development; pandemic disease; preservation; prevent; progenitor; promoter; recruit; response; small molecule; subcutaneous; therapeutic target; transcription factor

Obesity has reached pandemic proportions contributing to the dramatic increases in several metabolic diseases, for which there is no effective therapy. Adipose (AT) is a dynamic tissue capable of dramatically changing its overall morphology (remodeling) in response to a host of effectors. These dynamic events can remodel the tissue to be both beneficial as well as harmful. Obese AT undergoes extensive remodeling, which includes fibrosis. In humans, fibrosis is a hallmark of obesity that is tightly associated with inflammation. Remodeling of AT can also be beneficial and coincide with conditions that enhance insulin sensitivity and reduce inflammation. A variety of pharmacological and natural agents can induce extensive remodeling of AT, which include recruitment of brown-like adipocytes (beige) to white adipose tissues (WAT). This browning process is considered to be beneficial because it contributes to an increase in energy expenditure resulting in decreased ectopic fat deposition and enhanced insulin sensitivity. Recent studies suggest that browning is compromised in chronically obese and fibrotic WAT. For browning to be a strategy to treat obesity-associated disorders, we need to be able to induce it in obese individuals. A strategy is to target pathways that inhibit fibrosis while enhancing beige adipocyte formation during obesity. We recently reported that myocardin related transcription factor A (MRTFA), regulates conversion of vascular progenitors to beige adipocytes. In fact, we reported that mice with a global deletion of MRTFA have extensive WAT browning and are resistant to short-term diet-induced obesity (DIO) and its associated insulin resistance. MRTFA is also a known regulator of myofibroblast (ECM producing cells) activation and fibrosis in other tissues including liver and heart. Since MRTFA appears to regulate the fate of vascular progenitors to beige adipocytes and myofibroblasts, it is very possible that beige adipocyte expansion is directly compromised in AT fibrosis. We suggest, therefore, that effectors that suppress MRTFA activity in AT are potential targets for development of obesity therapeutics. Our overall hypothesis proposes that deletion of MRTFA in vascular progenitors will limit fibrosis and sensitize obese AT to browning effectors. We propose four aims to test this hypothesis: 1. Determine the fate of WT and MRTFA–/– WAT vascular progenitors in response to diet and browning. 2. Does pharmacological inhibition of MRTFA regulate the fate of mural cells and enhance WAT browning? 3. Identify the mechanisms by which MRTFA regulates the fate of AT mural cells. 4. Does deletion of MRTFA exclusively in mural progenitors enhance browning of WAT and protect mice from diet-induced fibrosis during obesity? The successful completion of these aims will provide novel insights into pathways that regulate beige AT formation, thus advancing our understanding of how to therapeutically target adipose tissues for the treatment of human obesity.

肥胖症已经达到了大流行比例，导致了几种代谢疾病的急剧增加，没有有效的治疗。脂肪（AT）是一种动态组织，能够响应许多效果而大大改变其整体形态（重塑）。这些动态事件可以重塑组织既有益又有害。肥胖经历了广泛的重塑，其中包括纤维化。在人类中，纤维化是肥胖的标志，与炎症密切相关。 AT的重塑也可能是有益的，并且与增强胰岛素敏感性并降低感染的条件相吻合。多种药物和天然药物可以诱导AT的大量重塑，其中包括募集棕色的脂肪细胞（米色）到白色脂肪组织（WAT）。这种褐变过程被认为是有益的，因为它有助于增加能量消耗，从而减少依托脂肪的沉积和增强的胰岛素敏感性。最近的研究表明，在慢性肥胖和纤维化的WAT中，褐变受到损害。为了使Browning成为治疗与肥胖相关疾病的一种策略，我们需要能够在肥胖个体中诱导它。一种策略是靶向抑制纤维化的途径，同时增强肥胖期间米色脂肪细胞的形成。我们最近报道说，相关的转录因子A（MRTFA）调节血管祖细胞转化为米色脂肪细胞。实际上，我们报道说，具有全球MRTFA的全球缺失的小鼠具有广泛的水褐变，并且对短期饮食诱导的肥胖症（DIO）及其相关的胰岛素抵抗具有抵抗力。 MRTFA还是其他组织中其他组织中肌纤维细胞（ECM生产细胞）激活和纤维化的已知调节剂，包括肝脏和心脏。由于MRTFA似乎调节血管祖细胞的命运对米色脂肪细胞和肌纤维细胞，因此在纤维化时，米色脂肪细胞膨胀很有可能直接损害。因此，我们建议抑制AT中MRTFA活性的影响是肥胖治疗发展的潜在靶标。我们的总体假设提案，即在血管祖细胞中删除MRTFA将限制纤维化和敏感肥胖对褐变作用。我们提出了四个旨在检验这一假设的目的：1。确定WT和MRTFA - / - WAT血管祖细胞的命运，以响应饮食和褐变。 2。药理学抑制MRTFA是否调节壁细胞的命运并增强褐变？ 3。确定MRTFA调节壁细胞命运的机制。 4。在壁画祖细胞中仅删除MRTFA是否会增强WAT的褐变并保护小鼠在肥胖期间免受饮食诱导的纤维化的影响？这些目标的成功完成将为调节米色形成时调节米色的途径提供新的见解，从而促进我们对如何靶向脂肪组织的理解以治疗人类肥胖。