Adipose Tissue Angiogenesis and Metabolic Disease

脂肪组织血管生成和代谢疾病

• 批准号: 8187450
• 负责人: Silvia Corvera
• 金额: $ 41.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8187450
• 关键词: Abdomen; Adipocytes; Adipose tissue; Adult; Angiogenic Factor; Animal Feed; Biochemical; Blood Vessels; Blood capillaries; Body mass index; Calories; Cell Count; Cell Proliferation; Cells; Chemosensitization; Coculture Techniques; Consumption; Data; Deposition; Development; Diabetes Mellitus; Diet; Differentiation and Growth; Endothelial Cells; Energy Intake; Fasting; Fatty acid glycerol esters; Fibroblast Growth Factor 1; Goals; Growth; Growth Factor; Heart Diseases; Hematopoietic; Homeostasis; Human; Hyperphagia; Immunofluorescence Immunologic; Individual; Infiltration; Inflammation; Insulin; Insulin Resistance; Insulin Signaling Pathway; Lead; Limb structure; Lipids; Liver; Longevity; Mediating; Metabolic; Metabolic Diseases; Methods; Microscopy; Modeling; Molecular; Mus; Muscle; Obesity; Overweight; Physiological; Process; Production; Proliferating; Proteomics; Recruitment Activity; Regulation; Reproductive Health; Resolution; Risk Factors; Role; Satiation; Serum; Signal Pathway; Simulate; Stem cells; T-Lymphocyte; Techniques; Tissues; Visceral; adipocyte differentiation; angiogenesis; capillary; cell growth; feeding; insulin signaling; interest; lipid biosynthesis; macrophage; novel; nutrition; research study; response; subcutaneous

DESCRIPTION (provided by applicant): The goal of this project is to understand the mechanisms that control the development and function of human adipose tissue. Adipose tissue fulfills critical physiological roles, including the regulation of satiety, whole body energy homeostasis, longevity and reproductive health. Abnormalities of adipose tissue development result in ectopic lipid deposition in liver and muscle, accompanied by insulin resistance and metabolic disease. How the growth and differentiation of adipocytes is coordinated with the growth of the capillary network necessary to form functional adipose tissue in adults is not known. Using a novel method to assess adipose tissue capillary formation we find that insulin levels in humans positively correlate with enhanced adipose tissue angiogenesis. Moreover, insulin directly stimulates capillary outgrowth from explants from mouse epidydimal fat pads, in a manner that is strongly synergized by high-fat diet (HFD) feeding. These data support the hypothesis that adipose tissue angiogenesis and adipogenesis are coordinated to expand adipose tissue in response to excess caloric intake. We seek to uncover the cellular and molecular mechanisms by which adipose tissue angiogenesis is stimulated synergistically by high fat diet and insulin. Specific Aim 1. To define the mechanisms by which high fat diet stimulates adipose tissue capillary sprout formation. We shall a) determine whether HFD feeding alters the number of potential endothelial cell precursors, in conjunction with increasing endothelial cell proliferation, b) define whether HFD induces the recruitment of hematopoietic-derived precursors into adipose tissue, and c) define the role of adipose tissue macrophages in mediating the increased capillary outgrowth seen in HFD. This latter is relevant for our understanding the relationships between inflammation, obesity, angiogenesis and insulin resistance. Specific Aim 2. To define the mechanisms by which insulin stimulates capillary sprout formation. High- resolution microscopy techniques will be used to identify the cells that a) respond to insulin signaling, and b) proliferate in response to insulin. Probes for insulin signaling pathways, as well as BrDU tracing will be used to define the responsiveness of endothelial cells, adipose tissue-derived stem cells, or putative endothelial progenitor cells in the tissue. Preliminary data indicate that insulin stimulates the production of pro-angiogenic factors by adipocytes. We propose strategies to identify these factors through proteomic techniques. Specific Aim 3. To define the mechanism by which HFD potentiates insulin stimulation of capillary sprout formation. We have identified growth factors and signaling pathways that are up-regulated by short term HFD, and that may mediate the synergistic effect of insulin on capillary outgrowth. We will directly determine the effects of these factors on capillary sprout formation and on the effects of insulin on this process. In addition, we will conduct an unbiased search for secreted factors from adipose tissue from HFD-fed animals that could enhance insulin action, using co-culture and biochemical approaches to indentify such factors. ! PUBLIC HEALTH RELEVANCE: We will be studying how blood vessels form in adipose tissue, a process known as "angiogenesis." This process is required for adipose tissue to expand and adequately store excess calories. These studies will help us understand how adipose tissue expands and why adipose tissue is distributed into different regions (abdomen or limbs) in different individuals. It will also help us understand the potential mechanisms by which some but not all overweight individuals develop heart disease and diabetes.

描述（由申请人提供）：该项目的目的是了解控制人脂肪组织的发展和功能的机制。脂肪组织履行关键的生理角色，包括调节饱腹感，全身能量稳态，寿命和生殖健康。脂肪组织发育的异常导致肝脏和肌肉异位脂质沉积，并伴有胰岛素抵抗和代谢疾病。尚不清楚脂肪细胞的生长和分化与成人形成功能性脂肪组织所必需的毛细血管网络的增长。使用一种新的方法来评估脂肪组织毛细血管形成，我们发现人类的胰岛素水平与增强的脂肪组织血管生成呈正相关。此外，胰岛素直接刺激小鼠附属脂肪垫中外植体的毛细血管产物，这种方式通过高脂饮食（HFD）喂养强烈协同。这些数据支持以下假设：脂肪组织血管生成和脂肪形成是协调的，以扩大脂肪组织，以响应过量的热量摄入。我们试图揭示细胞和分子机制，通过高脂饮食和胰岛素协同刺激脂肪组织血管生成。特定目的1。定义高脂饮食刺激脂肪组织毛细血管芽形成的机制。我们应a）确定HFD喂养是否会随着内皮细胞增殖的增加而改变潜在的内皮细胞前体的数量组织巨噬细胞在介导HFD中看到的毛细血管产物增加时。后者与我们理解炎症，肥胖，血管生成和胰岛素抵抗之间的关系有关。特定目的2。定义胰岛素刺激毛细血管发芽形成的机制。高分辨率显微镜技术将用于识别a）对胰岛素信号响应的细胞，b）响应胰岛素的响应。胰岛素信号通路以及BRDU跟踪的探针将用于定义内皮细胞，脂肪组织衍生的干细胞或组织中假定的内皮祖细胞的反应性。初步数据表明，胰岛素刺激脂肪细胞促进血管生成因子的产生。我们提出了通过蛋白质组学技术来识别这些因素的策略。特定目的3。定义HFD增强胰岛素刺激毛细血管发芽形成的机制。我们已经确定了由短期HFD上调的生长因子和信号通路，这可能介导胰岛素对毛细血管产物的协同作用。我们将直接确定这些因素对毛细血管发芽形成的影响以及胰岛素对此过程的影响。此外，我们将使用共培养和生化方法从HFD喂养的动物中对脂肪组织的分泌因子进行公正搜索，从而可以增强胰岛素作用，从而抑制这些因素。呢 公共卫生相关性：我们将研究脂肪组织中的血管形成是如何形成的，这是一种称为“血管生成”的过程。脂肪组织需要此过程才能扩展并充分储存多余的卡路里。这些研究将有助于我们了解脂肪组织如何扩展，以及为什么在不同个体中将脂肪组织分布到不同的区域（腹部或四肢）。它还将帮助我们了解一些但不是全部超重个体患心脏病和糖尿病的潜在机制。