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

描述（由申请人提供）：白色脂肪组织（WAT）高度血管化，其生长可被抗血管生成药物抑制，有望成为肥胖症的新治疗方法。在上一个资助期，我们发现神经肽Y（NPY），一种交感神经递质，通过其G1-偶联的Y2受体，二肽基肽酶IV（DPPIV，一种酶形成Y2激动剂）和内皮一氧化氮合酶（eNOS），是有效的血管生成-并刺激缺血，动脉粥样硬化，肿瘤和视网膜病变的血管生成。由于WAT有交感神经，压力会激活它们-我们假设NPY是WAT血管生成和脂肪生成的神经原性介质。在初步研究中，当局部应用于ob/ob小鼠的腹部WAT时，NPY增加，而Y2拮抗剂减少脂肪沉积（MRI）和血管密度;同样，Y2-/-小鼠中冷应激和高脂饮食诱导的腹部肥胖减少。为了确定NPY是否激活血管生成脂肪生成营养周期，以及通过何种机制，将在人WAT和小鼠中研究血管生成和脂肪生成，野生型和无Y2、DPPIV、eNOS（NPY的血管生成信号）和源自它们的细胞。为了模拟WAT中的神经-血管-脂肪细胞串扰，我们将使用建立的NPY能交感神经母细胞瘤或大鼠上级颈神经节与来自人和小鼠WAT的内皮细胞或前脂肪细胞的共培养物。NPY神经元表达的上游调节剂及其血管生成和脂肪生成/抗脂解的下游调节剂将在目的1-2中确定。目的3将测试在异种移植裸鼠模型中人或鼠脂肪垫的生长是否由NPY或宿主交感神经支配（交感神经切除术）刺激并且依赖于血管生成（MRI、超声、组织学）。在目的4中，将使用用Y2拮抗剂局部治疗并产生内皮和脂肪细胞特异性条件性Y2敲除来证实NPY和Y2 Rs在遗传或应激+高脂肪饮食诱导的肥胖症中的作用。如果得到证实，由于其血管生成活性，NPY及其Y2 Rs可能成为压力依赖性肥胖的新风险因素。

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.