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.
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