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

描述（由申请人提供）：先前，我们发现神经肽Y (NPY)，其Y2Rs和内皮二肽基肽酶IV形成一个有效的血管生成系统。除了交感神经中NPY的主要分泌池被应激激活外，ECs和血小板中还发现了其他非神经元来源，参与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，我们在上一阶段研究了NPY在脂肪血管生成和生长中的作用。这导致了NPY的成脂作用和“应激性肥胖”现象的发现。慢性应激通过上调NPYY2R系统（主要是由于局部产生的糖皮质激素导致腹部脂肪），刺激血管生成、炎症和去新生脂肪生成，从而增强了高脂肪饮食诱导的肥胖和代谢综合征（MetSyn）。通过抑制或删除脂肪内的Y2R，可以防止应激/ npy诱导的血管/脂肪生成和肥胖；这项工作为脂肪重塑和抗肥胖/MetSyn治疗提供了新的途径。“应激性脂肪”的特征是什么，它对脂肪组织和代谢后果的影响有多持久，以及携带NPY-Y2R的细胞对其负责——这些都是未知的，现在将进行研究。应激似乎针对神经血管壁龛，其中包含神经、脂肪干细胞（ASCs）、内皮细胞和免疫细胞，每种细胞都表达NPY或其Rs。“应激”ASCs显示出增脂潜能和NPY系统上调。在裸鼠移植的人y2r阳性脂肪中，NPY升高可诱导血管形成和移植物长期存活。这些和NPY表观遗传调控的新数据促使我们假设应激在ASCs中表观遗传上调NPY系统，增加“应激”脂肪（特别是腹部脂肪）的成脂潜力，加速饮食诱导的肥胖和MetSyn。抑制Y2Rs或改变这些或其他脂肪生成基因的DNA甲基化-抑制这些过程。我们将使用转基因小鼠，在应激小鼠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，并将结果与人类ASCs的变化联系起来，在体外或体内，在裸鼠中。

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.