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

描述(申请人提供)：之前，我们发现神经肽Y(NPY)及其Y2Rs和内皮细胞二肽基肽酶IV形成了一个强大的血管生成系统。除了NPY在应激激活的交感神经中的主要分泌池外，在内皮细胞和血小板中还发现了其他非神经源性来源，有助于缺血性血管生成和动脉粥样硬化。随着脂肪组织的主动重塑，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“应激诱导肥胖”现象的发现。慢性应激通过上调NPYY2R系统刺激血管生成、炎症和去新生脂肪生成，增加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导致的腹部脂肪。应激/NPY诱导的血管/脂肪生成和肥胖通过脂肪内Y2R抑制或缺失来预防；这项工作为脂肪重塑和抗肥胖/MetSyn治疗提供了新的途径。“应激脂肪”的特征是什么，它对脂肪组织和代谢结果的影响有多长，以及哪些携带NPY-Y2R的细胞对此负有责任--目前尚不清楚，现在将进行研究。应激似乎以神经血管为目标，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或其受体。“应激”的ASCs表现为成脂潜能增加和NPY系统上调。在移植到裸鼠体内的人类Y2R阳性脂肪中，升高的NPY诱导血管形成和移植物的长期存活。这些和NPY表观遗传调控的新数据促使我们假设，应激在表观遗传学上上调了ASCs中的NPY系统，增加了“应激”脂肪，特别是腹部脂肪的成脂潜力，加速了饮食诱导的肥胖和MetSyn。抑制Y2Rs或改变这些或其他成脂基因的DNA甲基化--抑制这些过程。我们将使用转基因小鼠，应激和非应激小鼠之间的脂肪/ASCs转移，最先进的3D脂肪成像，全基因组表观遗传学分析，并将结果与裸鼠体内或体外应激的人类ASCs的变化联系起来。 与公共健康相关：肥胖正在上升，心血管疾病的风险也随之上升。我们之前的工作表明，压力可能通过神经直接刺激脂肪生长发挥作用，神经分泌神经肽Y，一种导致新血管生长和脂肪膨胀的化学物质。识别应激反应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.