The role of vascular endothelium in BAT expansion and remodeling

血管内皮在 BAT 扩张和重塑中的作用

• 批准号: 10221681
• 负责人: Farnaz Shamsi
• 金额: $ 4万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221681
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Biological Assay; Biology; Blood Vessels; Brown Fat; Cardiovascular Diseases; Cell Line; Cell Proliferation; Communication; Culture Media; Data; Development; Diabetes Mellitus; Diet; Endothelial Cells; Endothelium; Energy Metabolism; Environment; Etiology; Exposure to; Fatty Acids; Fatty acid glycerol esters; Flow Cytometry; Gene Delivery; Gene Expression; Genes; Goals; Health; High Fat Diet; Homeostasis; Housing; Human; Impairment; In Situ; In Vitro; Inflammation; Investigation; K-Series Research Career Programs; Knowledge; Ligands; Link; Measures; Mediating; Mediator of activation protein; Mentors; Mesenchymal Stem Cells; Metabolic; Metabolic Diseases; Mitochondria; Modeling; Molecular; Mouse Strains; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Nutritional status; Obese Mice; Obesity; Obesity Epidemic; Pathway interactions; Play; Population; Positioning Attribute; Prevalence; Recombinant Proteins; Regulation; Reporter; Research; Research Personnel; Role; Series; Site; Source; Stimulus; Temperature; Testing; Therapeutic; Thermogenesis; Tissue Expansion; Tissues; Training; Triglycerides; Vascular Endothelium; Vascular remodeling; Visualization; Weight Gain; Western Blotting; angiogenesis; career development; cell motility; cell type; cold temperature; combat; comorbidity; density; diet-induced obesity; dietary control; environmental change; experimental study; feeding; global health; glucose metabolism; glucose tolerance; in vivo; insulin sensitivity; intercellular communication; lipid biosynthesis; multidisciplinary; novel; novel therapeutic intervention; obesity treatment; overexpression; prevent; progenitor; programs; protein expression; receptor; recruit; response; single-cell RNA sequencing; skill acquisition; stem cells; training opportunity; transcriptome sequencing; uncoupling protein 1; warm temperature

Project Summary/Abstract The rising prevalence of obesity and its comorbidities is a major global health concern. The development of strategies to prevent or treat human obesity is therefore of the utmost importance. Brown adipose tissue (BAT) and its related beige fat are specialized for energy expenditure. The identification of metabolically active brown and beige fat in adult humans has positioned this tissue at the center of investigations into human energy metabolism. Considering the formidable capacity of BAT for energy expenditure and its role in fatty acid and glucose metabolism, strategies leading to increased mass or enhanced activity of BAT can potentially be utilized to combat obesity and its related metabolic disorders. Different adipose depots undergo massive remodeling in response to environmental stimuli, such as cold and diet. Prolonged cold exposure leads to recruitment of new brown adipocytes as well as a coordinated expansion and remodeling of vascular endothelium in classical BAT to enable maximal thermogenic capacity. However, the cellular origin of the cold-induced brown adipocytes, and the identity of intracellular communication pathways coordinating the adipogenesis and angiogenesis are not known. The overall goal of this proposal is to identify the role of endothelial cells in BAT expansion and remodeling in response to cold exposure and high fat diet. To address this, we used single cell RNA-sequencing (scRNA-seq) to uncover the temperature-dependent remodeling of each cell type within BAT. The preliminary data have made the novel discovery that cold exposure triggers the induction of brown adipocyte thermogenic program in endothelial cells (ECs). Additionally, the cell-type specific gene expression data allowed the identification of a Slit3-Robo4 as a potential ligand-receptor interaction mediating the crosstalk between adipocyte progenitors and ECs. The central hypotheses are that ECs contribute to cold-induced BAT expansion through de novo differentiation to thermogenic adipocytes and that Slit3 secretion from adipocyte progenitors promotes EC proliferation and angiogenesis through interaction with EC Robo4 receptor. This proposal will determine the contribution of ECs to thermogenic adipocytes pool (Aim 1) and will address the role of Slit3- Robo4 interaction in regulating adipose tissue remodeling and angiogenesis in response to high fat feeding (Aim 2). Successful completion of this proposal will change the current premise and will establish novel molecular players linking adipogenesis and angiogenesis and will have profound biomedical implications. The mentored career development award will be used to achieve a series of training objectives including expanding applicant’s knowledge in vascular biology and professional development skills that are essential for transition to an independent investigator. The training plan will build upon applicant’s expertise in adipose tissue biology and will enable the establishment of a unique cutting-edge research program in obesity and diabetes field. The team of mentors and collaborators will provide an integrative and multidisciplinary training opportunity for the applicant to receive intellectual and technical support and career development advice.

项目摘要/摘要 肥胖症及其合并症的患病率上升是全球主要的健康问题。发展的发展 因此，预防或治疗人类肥胖的策略至关重要。棕色脂肪组织（蝙蝠） 它相关的米色脂肪专门用于能源消耗。代谢活性棕色的鉴定 成年人的米色脂肪已将这种组织定位在人类能量的研究中心 代谢。考虑到蝙蝠用于能量消耗的强大能力及其在脂肪酸中的作用 葡萄糖代谢，导致质量增加或增强BAT活性的策略可能会被使用 打击肥胖及其相关的代谢障碍。不同的脂肪沉积物在 对环境刺激的反应，例如冷和饮食。长时间的冷暴露导致新的招募 棕色脂肪细胞以及经典蝙蝠中血管内皮的协调膨胀和重塑 为了实现最大的热能力。但是，冷诱导的棕色脂肪细胞的细胞起源，以及 脂肪形成和血管生成的细胞内通信途径的身份不是 已知。该提案的总体目标是确定内皮细胞在BAT扩展中的作用和 响应冷暴露和高脂肪饮食的重塑。为了解决这个问题，我们使用了单细胞RNA-sevising （SCRNA-SEQ）发现BAT中每种细胞类型的温度依赖性重塑。初步 数据已经使新发现，即冷暴露会触发褐色脂肪细胞的诱导 内皮细胞（EC）中的程序。此外，细胞类型特异性基因表达数据允许 识别slit3-robo4是介导串扰的潜在配体 - 受体相互作用 脂肪细胞祖细胞和EC。中心假设是EC有助于冷诱导的蝙蝠扩展 通过从从头分化到热脂肪细胞，并从脂肪细胞祖细胞中分泌SLIT3 通过与EC Robo4受体相互作用来促进EC增殖和血管生成。该提议将 确定EC对热脂肪细胞池的贡献（AIM 1），并将解决slit3-的作用 ROBO4相互作用在控制脂肪组织重塑和血管生成方面响应高脂肪喂养（AIM 2）。该提案的成功完成将改变当前的前提，并将建立新的分子 连接脂肪形成和血管生成的参与者将具有深远的生物医学意义。事件 职业发展奖将用于实现一系列培训目标，包括扩大申请人的 关于血管生物学和专业发展技能的知识，这对于过渡至 独立研究者。培训计划将基于应用在脂肪组织生物学方面的专业知识，并将 启用在肥胖和糖尿病领域建立独特的尖端研究计划。团队 导师和合作者将为申请人提供综合和多学科的培训机会 获得智力和技术支持以及职业发展建议。