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NPY FEEDS ADIPOSE TISSUE VIA VASCULARIZATION AND DIRECT PROLIFERATIVE EFFECTS ON PREADIPOCYTES Lydia E. Kuo1, Edward W. Lee1, Jenny M. Karlsson2, Zofia Zukowska1 1 Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington, DC; 2 Integrative Medical Biology Section for Anatomy, Umeå University, Sweden Peripherally, neuropeptide Y (NPY) is mainly known as a sympathetic vasoconstrictor cotransmitter, and centrally, as an appetite stimulant and mediator of obesity, particularly of the abdominal type. Recently, we found that NPY is also a potent angiogenic factor through activation of the Y2-receptor (Y2R) and endothelial nitric oxide synthase (eNOS). One of the most vascularized and dynamically growing tissues is the fat tissue, yet little is known about the role of angiogenesis in its growth. Therefore we sought to determine if NPY-mediated angiogenesis is a peripheral mechanism by which the peptide contributes to abdominal obesity. Using a murine obesity model, Ob/Ob mice, we demonstrated that subcutaneous administration of an NPY pellet (1 g/ 14 days) into the abdominal region increased fat weight (FW) by 45% and central fat percent of body weight (F/B) by 50%; the effect which was not observed in eNOS-/- mice, a murine model with impaired angiogenesis and the risk factors for obesity but not obese. Moreover, FW an F/B were also significantly lower in placebo-treated eNOS-/- mice as compared to its wild type (WT) controls. In contrast, subcutaneous injections of Y2 receptor antagonist (BII0246, 1 µM peri-abdominally/day/14 days) into Ob/Ob mice decreased both FW and F/B by 40%, while also reducing capillary density as compared to vehicle-treated mice (immunostaining with endothelial marker von Willebrand’s factor). Central fat harvested from Ob/Ob mice also expressed 64-fold more NPY mRNA and 7-fold more dipeptidyl peptidase IV (DPPIV, an enzyme that converts NPY to a Y2/Y5-selective agonist) compared with that of WT; the latter also increased their Y2R mRNA 5-fold in response to NPY treatment (Real-time RTPCR). To test if NPY has any direct effect on adipocyte growth, 3T3-L1 preadipocytes were exposed in vitro to synthetic (0.1 nM) and native NPY from a co-culture with neuroblastoma SKN-BE cells. In both cases, NPY evoked a proliferative response, which was inhibited by the Y2R antagonist. Together, these data suggest that local up-regulation of the NPY-Y2R system facilitates adipose tissue growth indirectly via stimulation of angiogenesis mediated by Y2R and directly by proliferative effects on preadipocytes. To our knowledge, this is the first demonstration of a potent peripheral (in addition to known central) regulation of fat tissue growth by Y2Rs, suggesting that peripherally acting Y2R antagonist may be a new therapy for abdominal obesity.