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：
8447871
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/8447871
关键词：
Abdomen Adipocytes Adipose tissue Affect Atherosclerosis Blood Platelets Blood Pressure CXCR4 gene Candidate Disease Gene Cardiovascular Diseases Cell Proliferation Cell division Cell physiology Cells Cellular Stress Chemicals Chronic stress CpG Islands DNA Methylation Data Diet Dipeptidyl-Peptidase IV Endothelial Cells Environment Epigenetic Process Exposure to Fatty acid glycerol esters Gene Expression Gene Expression Profile Genes Genetic Glucocorticoids Goals Graft Survival Grant Growth Histone Deacetylase Histone Deacetylase Inhibitor Histones Hormonal Hormones Human Image Immune In Vitro Infiltration Inflammation Knock-out Knockout Mice Lead Mediating Memory Metabolic Metabolic syndrome Metabolism Methylation Modification Molecular Monkeys Morphology Mus Natural regeneration Nerve Nude Mice Obesity Pathway interactions Pericytes Play Prevention Process Regulation Role Source Stem cells Stress Sympathectomy System Testing Therapeutic Time Tissues Transplantation Up-Regulation Vascularization Work abdominal fat angiogenesis cardiovascular disorder risk feeding genome wide association study genome-wide human embryonic stem cell in vivo inhibitor/antagonist lipid biosynthesis macrophage nerve supply neuropeptide Y obesity treatment postnatal prevent public health relevance research study stem cell differentiation stressor

项目摘要

DESCRIPTION (provided by applicant): Previously, we discovered that neuropeptide Y (NPY), its Y2Rs and an endothelial dipeptidyl peptidase IV form a potent angiogenic system. In addition to NPY's main secretory pool in sympathetic nerves activated by stress, other non-neuronal sources were identified in ECs and platelets, contributing to ischemic angiogenesis and atherosclerosis. As adipose tissue actively remodels, in the last period we studied NPY's role in fat angiogenesis and growth. This led to discovery of adipogenic actions of NPY and the phenomenon of "stress-induced obesity." Chronic stress augmented high fat diet-induced obesity and metabolic syndrome (MetSyn) by stimulating angiogenesis, inflammation and de-novo adipogenesis through up-regulated NPYY2R system, predominantly in the abdominal fat due to locally produced glucocorticoids. Stress/NPY-induced angio/adipogenesis and obesity were prevented by intra-fat Y2R inhibition or deletion; this work offered new avenues for fat remodeling and anti-obesity/MetSyn therapies. What characterizes "stressed fat", how lasting are its effects on fat tissue and metabolic consequences, and which NPY-Y2R carrying cells are responsible for it - is unknown and will now be studied. Stress appears to target neurovascular niches which contain nerves, adipose stem cells (ASCs), ECs and immune cells, each expressing NPY or its Rs. "Stressed" ASCs show both increased adipogenic potential and upregulated NPY system. In human Y2Rpositive fat grafted into nude mice, elevated NPY induces vascularization and long-lasting graft survival. These and new data of epigenetic regulation of NPY, prompted us to hypothesize that stress epigenetically upregulates the NPY system in ASCs, increasing adipogenic potential of "stressed" fat, specifically abdominal, accelerating diet-induced obesity and MetSyn. Inhibition of Y2Rs or altering DNA methylation of these or other adipogenic genes - inhibits these processes. We will use genetically modified mice, transfer of fat/ASCs between stressed and non-stressed mice, state-of-the-art 3D fat imaging, genome-wide epigenetic analyses, and relate the results to changes in human ASCs, stressed in vitro or in vivo, in nude mice. PUBLIC HEALTH RELEVANCE: Obesity is on the rise and with it, the risk of cardiovascular diseases. Our previous work have showed that stress may play a role by stimulating fat growth directly through nerves, which secrete Neuropeptide Y, a chemical causing ingrowth of new vessels and fat expansion. Identifying cellular molecular mechanisms of stress actions may lead to better ways of prevention or treatment of obesity and cardiovascular diseases.

描述（由申请人提供）：以前，我们发现神经肽Y（NPY），其Y2RS和内皮二肽基肽酶IV形成有效的血管生成系统。除了由压力激活的交感神经中NPY的主要分泌池外，在EC和血小板中发现了其他非神经元来源，从而导致缺血性血管生成和动脉粥样硬化。作为脂肪组织积极重塑，在最后一个时期，我们研究了NPY在脂肪血管生成和生长中的作用。这导致发现了NPY的成脂作用和“压力引起的肥胖症”的现象。慢性应激通过通过上调的NPYY2R系统刺激血管生成，炎症和脱诺沃的脂肪形成，从而增强了高脂饮食诱导的肥胖和代谢综合征（METSYN），主要是由于局部产生的糖皮质激素而引起的腹部脂肪。通过FAT Y2R内抑制或缺失，可以预防应力/NPY诱导的血管性/脂肪生成和肥胖。这项工作为脂肪重塑和抗肥胖/Metsyn疗法提供了新的途径。什么是“压力脂肪”，其对脂肪组织和代谢后果的影响，以及哪些NPY -Y2R携带细胞对其造成的 - 未知，现在将研究。应力似乎靶向包含神经，脂肪干细胞（ASC），ECS和免疫细胞的神经血管壁ni，每个神经壁ni，每种都表达NPY或其RS。 “应力” ASC显示出增加的成脂潜力和上调的NPY系统。在人类Y2RP阳性脂肪中移植到裸鼠中，升高的NPY诱导血管形成和持久的移植物存活。这些NPY表观遗传调节的新数据促使我们假设压力表观遗传在ASC中上调NPY系统，从而增加了“压力”脂肪的成脂潜力，特别是腹部，腹部，加速了饮食诱导的肥胖症和Metsyn。抑制Y2RS或改变这些或其他掺杂基因的DNA甲基化 - 抑制这些过程。我们将使用转基因的小鼠，在压力和非压力小鼠之间转移脂肪/ASC，最先进的3D脂肪成像，全基因组的表观遗传学分析，并将结果与人类ASC的变化，体外或体内压力的变化相关。公共卫生相关性：肥胖正在上升，随之而来的是心血管疾病的风险。我们以前的工作表明，压力可能通过直接通过神经刺激脂肪生长来发挥作用，神经肽y是一种化学物质，从而导致新血管内生成和脂肪膨胀。识别压力作用的细胞分子机制可能会导致更好的预防或治疗肥胖和心血管疾病。