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

描述（由申请人提供）：以前，我们发现神经肽Y（NPY）、其Y2 Rs和内皮二肽基肽酶IV形成有效的血管生成系统。除了应激激活的交感神经中NPY的主要分泌池之外，还在EC和血小板中鉴定了其他非神经元来源，其有助于缺血性血管生成和动脉粥样硬化。随着脂肪组织的积极重塑，在最后一个阶段，我们研究了NPY在脂肪血管生成和生长中的作用。这导致了神经肽Y的成脂作用的发现和“应激性肥胖”现象。“慢性应激通过上调NPYY 2 R系统刺激血管生成、炎症和新生脂肪生成，主要是由于局部产生的糖皮质激素，从而增加了高脂饮食诱导的肥胖和代谢综合征（MetSyn）。 压力/NPY诱导的血管/脂肪生成和肥胖通过脂肪内Y2 R抑制或缺失来预防;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“应激脂肪”，它对脂肪组织和代谢后果的影响有多持久，以及携带NPY-Y2 R的细胞对此负责-目前尚不清楚，现在将进行研究。应激似乎靶向神经血管小生境，其包含神经、脂肪干细胞（ASC）、EC和免疫细胞，每种细胞表达NPY或其Rs。“应激的”ASC显示增加的成脂潜能和上调的NPY系统。在人Y2 R阳性脂肪移植到裸鼠中，升高的NPY诱导血管化和长期的移植物存活。这些和NPY的表观遗传调节的新数据促使我们假设应激表观遗传上调ASC中的NPY系统，增加“应激”脂肪的成脂潜力，特别是腹部，加速饮食诱导的肥胖和MetSyn。抑制Y2 R或改变这些或其他脂肪形成基因的DNA甲基化-抑制这些过程。我们将使用转基因小鼠，在应激和非应激小鼠之间转移脂肪/ASCs，最先进的3D脂肪成像，全基因组表观遗传分析，并将结果与裸鼠体外或体内应激的人ASCs的变化相关。 公共卫生相关性：肥胖正在上升，心血管疾病的风险也在上升。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而发挥作用，神经分泌神经肽Y，一种引起新血管向内生长和脂肪扩张的化学物质。 确定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的方法。

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.