SPECIFIC-INHIBITION OF ENDOGENOUS NEUROPEPTIDE-Y SYNTHESIS IN ARCUATENUCLEUS BY ANTISENSE OLIGONUCLEOTIDES SUPPRESSES FEEDING-BEHAVIOR ANDINSULIN-SECRETION

Neuropeptide Y (NPY), which is synthesized in neurons of the arcuate n ucleus (ARC) that project to different hypothalamic nuclei, is known t o have potent effects on eating behavior and hormone secretion after h ypothalamic administration. To test the hypothesis that endogenous NPY is essential for the normal expression of these responses, the presen t study used two unmodified antisense oligodeoxynucleotides (ODNs) to disrupt the synthesis of NPY in the ARC and to examine the impact of t his disturbance on nutrient intake, as well as on circulating levels o f insulin and the adrenal steroids, corticosterone and aldosterone. Br ain-cannulated rats maintained on macronutrient diets were given daily , bilateral injections, over a 4-day period, of NPY antisense ODNs, se nse ODNs or saline into the ARC. The NPY antisense ODNs produced a sig nificant decline (- 33% relative to sense ODNs and - 40% relative to s aline, P < 0.05) in NPY levels in this nucleus, without causing any di rect neural damage. Peptide levels in other hypothalamic areas, namely , the paraventricular nucleus and medial preoptic nucleus, were not si gnificantly affected. In association with this reduction in ARC NPY, t he antisense-treated animals exhibited a significant decrease in feedi ng behavior measured during the first 90 min of the natural feeding cy cle, as well as over the 24-h period. In the 90-min interval, both car bohydrate and fat intake were suppressed by 65-70% (P < 0.05, relative to both saline and sense ODNs control scores). In addition, circulati ng insulin levels, in blood samples taken before the initiation of fee ding, were significantly reduced by 50-55% (P < 0.05 relative to both saline and sense ODNs groups), while levels of corticosterone, aldoste rone or glucose were unaltered. These findings provide the first evide nce for physiological disturbances that may result from an inhibition of endogenous NPY production within neurons of the ARC.