Melanocortin Signaling in the Brainstem Influences Vagal Outflow to the Stomach

Abstract

Activation of melanocortin 4 receptors (MC4-Rs) in brain nuclei associated with food intake profoundly influences consummatory behavior. Of these nuclei, the dorsal motor vagal nucleus (DMV), which has a dense concentration of MC4-Rs, is an important regulator of gastric tone and motility. Hence, the present study sought to examine the role of MC4-Rs in this nucleus on these activities. Using an in vivo approach, MC4-R agonists, melanotan-II (MT-II) or ␣-melanocyte stimulating hormone (␣-MSH), were unilaterally microinjected into the DMV of rats, and their effects were noted on gastric activity. MT-II decreased phasic contractions, whereas ␣-MSH increased their amplitude. Both effects were blocked by the MC4-R antagonist SHU9119 or by ipsilateral vagotomy. Microinjection of the agonists (MT-II and ␣-MSH) into the overlying nucleus of the solitary tract (NTS), an important component of "vago-vagal" gastric circuitry, decreased phasic contractions. In addition, ␣-MSH reduced gastric tone and mean arterial blood pressure. To study the underlying mechanisms of the effect of MC4-R stimulation on gastric activity, electrophysiological recordings were made from labeled DMV antrum neurons in rat pups and MC4-R Ϫ/Ϫ mice. Bath application of MT-II or ␣-MSH significantly reduced spontaneous action potentials (but not in MC4-R Ϫ/Ϫ mice). However, in low-calcium ACSF, MT-II decreased neuronal firing, whereas ␣-MSH increased it. These effects mirror those of our in vivo DMV studies. Altogether, our novel findings show that activation of MC4-Rs in the brainstem, particularly in the medial NTS by the endogenous peptide ␣-MSH, modulates gastric activity, which may have physiological relevance for food intake and gastric function.

The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances

“…MC4Rs in the NTS may therefore respond to melanocortins produced locally to reduce food intake [89]. Instead, the PVH-DMV projection may modulate gut reflexes and gastric processes [90]. …”

The Melanocortin-4 Receptor Is Expressed in Enteroendocrine L Cells and Regulates the Release of Peptide YY and Glucagon-like Peptide 1 In Vivo

“…While details of the neuroanatomy and function of MC4R in the DMV remain to be determined (e.g. see (Richardson et al, 2013), caudal brainstem administration of melanocortin agonists inhibits food intake (Grill et al, 1998; Williams et al, 2000), and injection of melanocortin agonists into either the DMV or NTS decreases phasic gastric contractions (Richardson et al, 2013). Stereotaxic injections of melanocortin agonists, MT-II or α-MSH into either the DMV or the NTS can modulate gastric activity via vagal outflow to the stomach.…”

“…Stereotaxic injections of melanocortin agonists, MT-II or α-MSH into either the DMV or the NTS can modulate gastric activity via vagal outflow to the stomach. This effect was blocked by administration of melanocortin antagonist SHU9119, vagotomy, or knockout of the MC4R (Richardson et al, 2013). Thus, the melanocortin system is likely to affect food intake not only through effects on behavioral centers in the CNS, but also secondarily through MC4R signaling involved in the postprandial functions of the enteric nervous system (ENS) (Gautron et al, 2010).…”

NMDA-type glutamate receptors participate in reduction of food intake following hindbrain melanocortin receptor activation

“…*Significantly different (P Յ 0.05) from saline control treatment. edly is inhibitory (44,51). We found that MTII-induced ERK1/2 phosphorylation in the DMV was attenuated by an NMDAR antagonist, indicating that DMV ERK1/2 phosphorylation requires NMDAR activation.…”

“…From these data, one might be tempted to postulate a role for vagal efferents in the reduction of food intake by MTII. While NTS injection of MC4R agonists has been shown to modulate gastric activity (44), vagal efferents are not likely to play a role in MTIIinduced reduction of food intake. Williams et al (60) clearly demonstrated that vagotomy, which results in degeneration of peripheral endings of vagal efferents, does not attenuate reduction of food intake by fourth ventricle MTII.…”