INSULIN AND INSULIN-LIKE GROWTH-FACTOR-II SUPPRESS NEUROPEPTIDE-Y RELEASE FROM THE NERVE-TERMINALS IN THE PARAVENTRICULAR NUCLEUS - A PUTATIVE HYPOTHALAMIC SITE FOR ENERGY HOMEOSTASIS

It has been recently recognized that a distinct signaling pathway in t he hypothalamus is involved in the stimulation of feeding in mammals. Neuropeptide Y (NPY), a member of the pancreatic polypeptide family, i s the most potent orexigenic signal, and its secretion in discrete hyp othalamic sites increases in response to insulinopenia produced by foo d deprivation or experimental diabetes. To establish the site of inter action between the hypothalamus and the pancreas, we examined the effe cts of insulin on NPY release in vivo and in vitro from hypothalamic s ites known to be involved in feeding behavior. In the first study we e valuated the effects of peripheral insulin injections (1 U/kg . day, s c) on NPY levels in seven hypothalamic nuclei in food-deprived (FD) an d ad libitum-fed rats. Whereas food deprivation for 3 days increased N PY levels in the medial preoptic area, paraventricular nucleus (PVN), and arcuate nucleus, insulin injections, which did not alter blood glu cose levels, returned NPY levels to the control range selectively in t he PVN. NPY levels in the hypothalamic nuclei remained unchanged after insulin injections in ad libitum-fed rats. The in vivo NPY release in the PVN of FD rats, evaluated by the push-pull cannula technique, als o decreased in response to peripheral insulin injections. Finally, the effects of insulin, insulin-like growth factor I (IGF-I), and IGF-II on NPY release in vitro from the microdissected PVN and two central ne ighboring sites, the ventromedial nucleus and the median eminence-arcu ate nucleus, of FD rats were evaluated. Both insulin (0.67 or 6.7 nw) and IGF-II (0.7 or 7.0 mM) decreased the release of NPY in a dose-depe ndent manner only from the PVN. On the other hand, IGF-I (0.07 or 7.0 nM) failed to alter the basal PVN NPY efflux. As the PVN is richly inn ervated by NPY-containing nerve terminals, the results of these in viv o and in vitro studies suggest that the site of insulin action on the hypothalamic NPY network may reside at the level of PVN nerve terminal s or at the interneurons in contact with NPY nerve terminals. Although insulin may have a direct effect in reducing NPY release from the PVN , the effectiveness of IGF-II in decreasing NPY release from the PVN r aises the possibility that insulin's action may also be mediated via h ypothalamic IGF-II neuronal pathways.