Brainstem Application of Melanocortin Receptor Ligands Produces Long-Lasting Effects on Feeding and Body Weight

Abstract

Recent evidence suggests that the central melanocortin (MC) system is a prominent contributor to food intake and body weight control. MC receptor (MC-R) populations in the arcuate and paraventricular nuclei are considered probable sites of action mediating the orexigenic effects of systemically or intracerebroventricularly administered ligands. Yet, the highest MC4-R density in the brain is found in the dorsal motor nucleus of the vagus nerve, situated subjacent to the commissural nucleus of the solitary tract, a site of pro-opiomelanocortin mRNA expression. We evaluated the contribution of the caudal brainstem MC system by (1) performing respective dose-response analyses for an MC-R agonist (MTII) and antagonist (SHU9119) delivered to the fourth ventricle, (2) comparing, in the same rats, the fourth intracerebroventricular dose-response profiles to those obtained with lateral intracerebroventricular delivery, and (3) delivering an effective dose of MTII or SHU9119 to rats before a 24 hr period of food deprivation. Fourth intracerebroventricular agonist treatment yielded a dose-dependent reduction of short-term (2 and 4 hr) and longer-term (24 hr) food intake and body weight. Fourth intracerebroventricular antagonist treatment produced the opposite pattern of results: dose-related increases in food intake and corresponding increases in body weight change for the 24-96 hr observation period. Comparable dose-response functions for food intake and body weight were observed when these compounds were delivered to the lateral ventricle. Results from deprived rats (no effect of MTII or SHU9119 on weight loss) support the impression derived from the dose-response analyses that the body weight change that follows MC treatments is secondary to their respective effects on food intake. Results support the relevance of the brainstem MC-R complement to the control of feeding.

The Neuroanatomical Axis for Control of Energy Balance

“…We undertook to explore the functional relevance of brainstem MC-R via 4th-icv and brainstem parenchymal injection of MTII, a MC3/4-R agonist (see also 25), and of SHU-9119. Each treatment yielded dose-related short-and long-term intake effects that were not distinguishable from those obtained from lateral icv delivery (70). On face value, the finding is consistent with the suggestion that the lateral and 4th-icv injections stimulate different subsets of MC-R that independently can give rise to what is essentially the same response.…”

“…Consistent with this perspective: (i) leptin receptors are expressed on arcuate hypothalamic neurons that also express POMC or AgRP, (ii) leptin treatment increases expression of POMC mRNA and decreases AgRP mRNA, and (iii) the synthetic melanocortin 3/4 receptor (MC3/4-R) antagonist, SHU-9119, reverses the short-term intake inhibition that follows icv application of leptin (123,164,201). Direct agonist stimulation of MC3/4-R via icv treatment produces a short-latency, dose-related inhibition of food intake that lasts for 24 h, while antagonist treatment yields a robust hyperphagia that persists for several days after a single application (70,83).…”

Presynaptic Melanocortin-4 Receptors on Vagal Afferent Fibers Modulate the Excitability of Rat Nucleus Tractus Solitarius Neurons

“…Immunocytochemical, in situ hybridization, and binding studies have identified both MC3R and MC4R in the DVC, and their role in food satiation has been suggested by behavioral studies (Joseph et al, 1985;Palkovits et al, 1987;Bronstein et al, 1992;Grill et al, 1998;Williams et al, 2000;Kishi et al, 2003;Liu et al, 2003;Fan et al, 2004;Zheng et al, 2005). Although our pharmacological experiments could not differentiate between MC3R and MC4R, our reverse transcription-PCR results reveal that mRNA for only MC4R is present in the nodose ganglia and in the dorsal caudal brainstem area, suggesting the effects of melanocortin agonists occur via MC4R only.…”

“…Activation of brainstem melanocortin receptors inhibits food intake potently with a concomitant increase in energy expenditure (Grill et al, 1998;Williams et al, 2000;Fan et al, 2004;Zheng et al, 2005). Here, we provided a possible cellular mechanism (i.e., a melanocortin-mediated increase in glutamate transmission to NTS neurons).…”

“…Indeed, ␣MSH as well as MC3/4R have been detected in the brainstem (Joseph et al, 1985;Palkovits et al, 1987;Bronstein et al, 1992;Kishi et al, 2003;Liu et al, 2003). More recently, activation of brainstem MC4R has been shown to reduce meal size (Grill et al, 1998;Williams et al, 2000;Fan et al, 2004;Zheng et al, 2005) without affecting meal frequency (Zheng et al, 2005). Furthermore, the classical satiety hormone cholecystokinin (CCK) and the longer-lasting ␣MSH synthetic analog melanotan II (MTII) use the cAMP-ERK (extracellular signal-regulated kinase)-cAMP response elementbinding protein cascade in NTS circuits as a common pathway to integrate satiety signals from the gut and adiposity signals from the hypothalamus in the control of meal size and food intake (Sutton et al, 2005).…”