Effects of neuropeptide Y deficiency on hypothalamic agouti-related protein expression and responsiveness to melanocortin analogues

Central administration of neuropeptide Y (NPY) potently induces feeding and its abundance in the hypothalamus increases when energy stores fall. Conse quently, NPY is considered to be a physiological effector of feeding behavi or. Surprisingly, NPY-deficient (NPY - / -) mice feed and grow normally wit h ad libitum access to food and manifest a normal hyperphagic response afte r fasting, suggesting that other feeding effecters may compensate for the l ack of NPY. Agouti-related protein (AgRP), a melanocortin receptor antagoni st, can also stimulate feeding behavior when administered centrally and is coexpressed in a majority of hypothalmamic NPY-ergic neurons, making AgRP a candidate compensatory factor. To test this possibility, we evaluated,AgRP mRNA and protein expression, as well as responsiveness to centrally admini stered AgRP in NPY - / - mice. These studies demonstrate that hypothalamic AgRP mRNA and immunoreactivity are upregulated with fasting and that these increases are not affected by NPY deficiency. Interestingly, NPY - / - mice are hypersensitive to central administration of AgRP83-132, yet exhibit a normal response to centrally administered MTII, a melanocortin receptor ago nist. These data suggest that if AgRP compensates for the lack of NPY in NP Y - / - mice, it is not at the level of AgRP synthesis and may instead invo lve alterations in the postsynaptic signaling efficacy of AgRP. Moreover, t he effects of AgRP are not limited to its actions at the melanocortin-4 rec eptor (MC4R), because MC4R-deficient (MC4R - / -) mice manifest a significa nt response to centrally administered AgRP. These data imply that AgRP has additional targets in the hypothalamus. (C) 1999 Elsevier Science B.V. All rights reserved.