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: 10039668
• 负责人: Farnaz Shamsi
• 金额: $ 15.03万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10039668
• 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; 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; environmental change; experimental study; feeding; global health; glucose metabolism; glucose tolerance; in vivo; insulin sensitivity; intercellular communication; lipid biosynthesis; multidisciplinary; novel; novel therapeutics; 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.

项目概要/摘要 肥胖及其合并症患病率的上升是全球主要的健康问题。 因此，预防或治疗人类肥胖的策略至关重要。 及其相关的米色脂肪专门用于能量消耗的代谢活跃的棕色脂肪。 成年人的米色脂肪使该组织成为人体能量研究的中心 考虑到 BAT 强大的能量消耗能力及其在脂肪酸和代谢中的作用。 葡萄糖代谢，可以利用导致 BAT 质量增加或活性增强的策略 对抗肥胖及其相关的代谢紊乱。不同的脂肪库在体内经历大规模重塑。 对环境刺激的反应，例如寒冷和饮食，长时间的寒冷暴露会导致新的招募。 经典 BAT 中棕色脂肪细胞以及血管内皮的协调扩张和重塑 然而，冷诱导的棕色脂肪细胞的细胞起源，以及 协调脂肪生成和血管生成的细胞内通讯途径的身份并不相同 该提案的总体目标是确定内皮细胞在 BAT 扩增和增殖中的作用。 为了解决这个问题，我们使用了单细胞 RNA 测序。 (scRNA-seq) 揭示 BAT 内每种细胞类型的温度依赖性重塑。 数据有了新发现：寒冷暴露触发棕色脂肪细胞产热的诱导 此外，细胞类型特异性基因表达数据允许 鉴定 Slit3-Robo4 作为潜在的配体-受体相互作用介导之间的串扰 脂肪细胞祖细胞和 EC 的中心假设是 EC 有助于冷诱导的 BAT 扩张。 通过从头分化为产热脂肪细胞以及脂肪细胞祖细胞分泌 Slit3 通过与 EC Robo4 受体相互作用促进 EC 增殖和血管生成。 确定 EC 对产热脂肪细胞库的贡献（目标 1），并将解决 Slit3- 的作用 Robo4 在调节脂肪组织重塑和血管生成以响应高脂肪喂养方面的相互作用（目标 2）该提案的成功完成将改变当前的前提并建立新的分子。 将脂肪生成和血管生成联系起来的参与者，并将产生深远的生物医学影响。 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 血管生物学知识和专业发展技能对于过渡到血管生物学至关重要 培训计划将以申请人在脂肪组织生物学方面的专业知识为基础，并将 使该团队能够在肥胖和糖尿病领域建立独特的前沿研究项目。 导师和合作者将为申请人提供综合、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。