The Role of the Dorsal Vagal Complex and the Vagus Nerve in Feeding Effects of Melanocortin-3 / 4 Receptor Stimulation *

Fourth intracerebroventricular (4th-icv) administration of the melanocortin-3/4 receptor (MC3/4-R) agonist, MTII, reduces food intake; the antagonist, SHU9119, increases feeding. The dorsal motor nucleus of the vagus nerve (DMX) contains the highest density of MC4-R messenger RNA in the brain. To explore the possibility that the DMX contributes to 4th-icv MC4-R effects, we delivered doses of MTII and SHU9119 that are subthreshold for ventricular response unilaterally through a cannula centered above the DMX. MTII markedly suppressed 2-h (50%), 4-h (50%), and 24-h (33%) intake. Feeding was significantly increased 4 h (50%) and 24 h (20%) after SHU9119 injections. These results suggest that receptors in the DMX, or the dorsal vagal complex more generally, underlie effects obtained with 4th-icv administration of these ligands. We investigated possible vagal mediation of 4th-icv MTII effects by giving the agonist to rats with subdiaphragmatic vagotomy. MTII suppressed 2-, 4-, and 24-h liquid diet intake (;80%) to the same extent in vagotomized and surgical control rats. We conclude that stimulation or antagonism of MC3/4-Rs in the dorsal vagal complex yields effects on food intake that do not require an intact vagus nerve. (Endocrinology 141: 1332–1337, 2000) I EVIDENCE implicates central nervous system melanocortin-4 receptors (MC4-Rs) in the control of food intake and body weight. Similar obese phenotypes (maturity-onset obesity, hyperinsulinemia, and hyperglycemia) are exhibited by the Agouti mouse, which expresses the MC4-R antagonist agouti protein ectopically in the brain; transgenic mice expressing abnormally high levels of agoutirelated protein, an endogenous antagonist of MC3/4-Rs; and the MC4-R knockout mouse (MC4-RKO) (1–3). Further support for the feeding relevance of MC4-Rs has been provided by pharmacological studies. In mice and rats, forebrain intracerebroventricular (icv) injection of a MC3/4-R agonist, MTII, suppresses food intake (4–6), an effect not seen in MC4-RKOs (7). Administration of the selective MC4-R antagonist, HS014, or the MC3/4-R antagonists, SHU9119 or agouti-related protein-(83–132), yields increases in intake (5, 8, 9). The antagonist effects are consistent with the suggestion that the endogenous MC system plays a role in the normal physiology of intake and body weight control. The majority of studies on the MC system have focused on the hypothalamus (4, 6, 10). Anatomical evidence, however, clearly indicates that potentially relevant components of the MC system are present in the hindbrain. POMC, the precursor to the endogenous MC4-R agonist, aMSH, is produced in only two locations in the brain: the arcuate nucleus of the hypothalamus and the commissural nucleus of the solitary tract (cNTS) (11). Importantly, immunoreactivity for aMSH itself has been demonstrated in the cNTS (12). In addition, MC3/4-Rs in the cNTS and in the dorsal motor nucleus of the vagus nerve (DMX) were demonstrated in a binding study using the high affinity ligand, Nle,d-Phe-aMSH (13). The DMX, in fact, expresses the highest density of MC4-R messenger RNA (mRNA) in the brain, whereas weak expression is found in the medial NTS (14). The functional relevance of hindbrain MC3/4-Rs to feeding and body weight control was suggested in a recent report in which dose-dependent decreases or increases in feeding and body weight were obtained upon fourth intracerbroventricular (4th-icv) administration of MTII or SHU9119, respectively (5). The response to 4th-icv delivery of these ligands was no weaker than that obtained upon lateral icv delivery. The high MC4-R mRNA density in the DMX and the proximity of this nucleus to the fourth ventricle are consistent with the suggestion that receptors within the DMX, or in the dorsal vagal complex (DVC; including the DMX and NTS) more generally, at least partially mediate the effects of 4th-icv MTII and SHU9119. One aim of the present study was to explore this suggestion by delivery of MTII and SHU9119 unilaterally into the DVC at doses subthreshold for 4th-icv response. The second aim of the present work is to investigate the possibility that an intact vagus nerve is required for the anorexic effect of 4th-icv MTII. One would expect that vagotomized (VX) rats will not show a 4th-icv MTII effect if, in fact, the receptors on DMX motor neurons represent the substrate for the response. Indeed, the efferent branch of the vagus nerve is the only known output pathway for motor neurons in that nucleus. A reversal of the 4-icv effect with vagotomy would be consistent with but would not prove that DMX mediates MTII effects on intake. The integrity of vagus nerve may also be necessary for feeding effects obtained upon stimulation of receptors located some distance from the vagal complex. An appropriate example is the reversal by Received October 4, 1999. Address all correspondence and requests for reprints to: Diana L. Williams, Department of Psychology, University of Pennsylvania, 3815 Walnut Street, Philadelphia, Pennsylvania 19104. E-mail: dianaw@ psych.upenn. edu. * This study was supported by NIH DK-21397, DK-54080, and MH-43787. 0013-7227/00/$03.00/0 Vol. 141, No. 4 Endocrinology Printed in U.S.A. Copyright © 2000 by The Endocrine Society