NPY,Neurovascular Niches and Stress-Induced Remodeling of Adipose Tissue

NPY，神经血管生态位和压力诱导的脂肪组织重塑

基本信息

批准号：
8286545
负责人：
ZOFIA ZUKOWSKA
金额：
$ 1.89万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8286545
关键词：
Abdomen Address Adipocytes Adipose tissue Adrenergic Agents Agonist Angiogenesis Inhibition Angiogenesis Inhibitors Angiogenesis Modulating Agents Angiogenic Factor Apoptosis Area Atherosclerosis Back Blood Vessels Blood capillaries Body Weight Body Weight decreased Catecholamines Cell Proliferation Cells Central obesity Chemicals Chronic stress Coculture Techniques Communication Conditioned Culture Media Coupled Data Denervation Dependence Deposition Diet Dipeptidyl-Peptidase IV Endocrine Glands Endothelial Cells Enzymes Epidemic Fatty acid glycerol esters Fibroblast Growth Factor 2 Gene Expression Genes Genetic Genetic Models Grant Growth Growth Factor Histology Human Imagery Implant In Vitro Ischemia Knock-out Knockout Mice Lead Left Leptin Life Style Lipolysis Magnetic Resonance Imaging Measures Mediating Mediator of activation protein Metabolic Modeling Mus Nerve Nerve Growth Factors Neuroblastoma Neurons Neurotransmitters Nude Mice Null Lymphocytes Obesity Pathway interactions Pilot Projects Rattus Regulation Reporting Research Resistance Retinal Diseases Risk Factors Role Signal Transduction Signaling Protein Site Source Staining method Stains Stimulus Stress Structure of superior cervical ganglion Suction Lipectomy Sympathectomy System Techniques Testing Time Tissues Tube Ultrasonography United States Vascular Endothelial Growth Factors Vascularization Weight Gain Wild Type Mouse Xenograft Model Xenograft procedure adrenergic angiogenesis base capillary cell type combat density feeding human NOS3 protein implantation in vivo inhibitor/antagonist lipid biosynthesis matrigel mouse model nerve supply neuroblastoma cell neuropeptide Y neurotrophic factor novel obesity treatment promoter protein expression receptor response sedentary tumor

项目摘要

DESCRIPTION (provided by applicant): White adipose tissue (WAT) is highly vascularized and its growth can be inhibited by anti-angiogenic drugs, promising new treatment for obesity. In the previous grant period, we discovered that neuropeptide Y (NPY), a sympathetic transmitter, is potently angiogenic via its Gi-coupled Y2 receptors, dipeptidyl peptidase IV (DPPIV, an enzyme forming Y2 agonist) and an endothelial nitric oxide synthase (eNOS) - and stimulates angiogenesis in ischemia, atherosclerosis, tumors and retinopathy. Since WAT has sympathetic nerves and stress activates them - we hypothesized that NPY is a neurogenic mediator of WAT angiogenesis and adipogenesis. In pilot studies, NPY increased, while Y2 antagonist decreased fat deposits (MRI) and vascular density when applied locally into abdominal WAT of ob/ob mice; similarly, cold stress- and high fat diet-induced abdominal obesity was reduced in Y2-/- mice. To determine if NPY activates angiogenic adipogenic trophic cycle, and by which mechanisms, angiogenesis and adipogenesis will be studied in human WAT and mice, wild type and null for Y2, DPPIV, eNOS (NPY's angiogenic signals), and cells derived from them. To mimic nerve-vessel-adipocyte cross-talk in WAT, we will use established co-culture of NPYergic sympathetic neuroblastoma or rat superior cervical ganglia with endothelial cells or preadipocytes from human and murine WAT. Upstream modulators of NPY neuronal expression and its downstream modulators of angiogenesis and adipogenesis/anti-lipolysis will be determined in Aims 1-2. Aim 3 will test if growth of human or murine fat pad in a xenograft nude mouse model is stimulated by NPY or host sympathetic innervation (sympathectomy) and dependent on angiogenesis (MRI, ultrasound, histology). In Aim 4, the role of NPY and Y2Rs will be confirmed in genetic or stress+high fat diet-induced obesity, using local treatment with Y2 antagonist and generating endothelial and adipocyte-specific conditional Y2 knockouts. If proven, NPY and its Y2Rs may become a new risk factor for stress-dependent obesity, due to its angiogenic activity.

描述（由申请人提供）：白色脂肪组织（WAT）是高度血管化的，其生长可以被抗血管生成药物抑制，并有望对肥胖症进行新的治疗方法。在上一个赠款期间，我们发现神经肽Y（NPY）是一种交感神经递质，通过其GI耦合Y2受体，二肽基肽酶IV（DPPIV，一种酶形成Y2 agonist）和一种内皮氧化物氧化物（Enogs） - 促进剂（Enersissiaze） - 促肽酶（DPPIV，一种酶），是有效的血管生成性。肿瘤和视网膜病。由于WAT具有交感神经和压力激活它们 - 我们假设NPY是WAT血管生成和脂肪生成的神经源性介体。在试点研究中，NPY增加，而Y2拮抗剂局部局部应用于OB/OB小鼠的腹部WAT，降低了脂肪沉积（MRI）和血管密度。同样，在Y2 - / - 小鼠中，冷应激和高脂肪饮食诱导的腹部肥胖也降低。为了确定NPY是否激活了血管生成的营养循环，并在人类WAT和小鼠，Y2，DPPIV，ENOS，ENOS（NPY的血管生成信号）以及源自其中的细胞中研究机制，血管生成和脂肪形成。为了模仿WAT中的神经毒剂 - 辅助细胞串扰，我们将使用已建立的NPYergic交感神经内神经母细胞瘤或大鼠上颈神经节的共同培养，以及来自人类和鼠类WAT的内皮细胞或前膜细胞。 NPY神经元表达的上游调节剂及其血管生成和脂肪生成/抗激素分解的下游调节剂将在目标1-2中确定。 AIM 3将测试异种移植小鼠模型中人类或鼠脂肪垫的生长是否受到NPY或宿主交感神经（交感神经切除术）的刺激并依赖于血管生成（MRI，超声，组织学）。在AIM 4中，使用Y2拮抗剂的局部治疗以及产生内皮和脂肪细胞特异性的条件Y2敲除，NPY和Y2RS的作用将在遗传或高脂肪饮食诱导的肥胖症中得到证实。如果经过证明，NPY及其Y2RS可能会因其血管生成活性而成为压力依赖性肥胖的新风险因素。