Elsevier

Peptides

Volume 22, Issue 1, January 2001, Pages 129-134
Peptides

Paraventricular hypothalamic α-melanocyte-stimulating hormone and MTII reduce feeding without causing aversive effects

https://doi.org/10.1016/S0196-9781(00)00367-3Get rights and content

Abstract

α-Melanocyte-stimulating hormone (α-MSH) appears to play a tonic inhibitory role in feeding and energy storage. MTII, a specific synthetic MC3-R/MC4-R agonist, has similar effects on feeding in rats. The current studies demonstrate that PVN administration of α-MSH or MTII decreases nocturnal and NPY-stimulated food intake without causing aversive effects. Co-administration with NPY of 600 pmol α-MSH or 1 pmol MTII into the PVN caused a significant decrease in NPY-induced feeding. PVN administration of MTII or α-MSH at doses effective to suppress feeding did not cause conditioned taste aversion (CTA). ICV administration of α-MSH, however, did cause weak CTA. These results indicate that the potent effects on feeding of MC3-R and MC4-R agonists when injected into the PVN are not due to aversive effects.

Introduction

α-Melanocyte-stimulating hormone (α-MSH) is an endogenous ligand for the melanocortin-3 and -4 receptors (MC3-R, MC4-R) and appears to play a tonic inhibitory role in feeding and energy storage [18]. MTII is a specific synthetic MC3-R/MC4-R agonist. Both peptides potently inhibit food intake in mice and rats when given intracerebroventricularly (ICV) [3], [8], [21] or into the paraventricular nucleus of the hypothalamus (PVN) [4], [9], [13]. Consistent with its presumed role in body weight regulation, the MC4-R is expressed in a number of hypothalamic sites which play important roles in the control of feeding behavior, including the ventromedial, lateral, dorsomedial and paraventricular nuclei [15]. Similarly, fibers containing proopiomelanocortin (POMC), the precursor of α-MSH, are found in these nuclei [10].

A number of studies indicate that the PVN is an important site of action of melanocortins on food intake. Of hypothalamic and extra-hypothalamic regions expressing the MC4-R, the PVN was one of the maximally responsive sites in terms of feeding response to injection of α-MSH and its antagonist, Agrp [13]. Studies also indicate that melanocortins and neuropeptide Y (NPY) interact to modulate feeding behavior, and that the PVN is one of the sites of integration of input from these peptides. NPY as well as POMC fibers are present in the PVN [1], [6], [7], and in vitro electrophysiology studies demonstrated that individual neurons in the PVN respond to and integrate melanocortin and NPY signals [4].

In general, α-MSH and MTII administered ICV suppress feeding stimulated by a variety of factors, such as onset of the dark phase, food deprivation, or administration of NPY [3], [8], [21]. Also, MTII blocks the NPY-induced feeding response when both peptides are injected into the PVN of mice [4]. Noteworthy, third ventricle administration of MTII was found to induce conditioned taste aversion (CTA) [21], which calls into question whether its effect on food intake is due to nonspecific aversive effects. However, it has been observed that some anorexigenic peptides induce CTA when administered ICV but not site-specifically [21]. In addition, subcutaneous (s.c.) administration of α-MSH has been shown to delay the extinction of LiCl-induced CTA [19], but the influence of this peptide alone on development of CTA has not been investigated, whether injected peripherally or centrally. It is important to investigate the ability to cause CTA by PVN administration of MC3-R/MC4-R agonists, as the PVN is known to be a site that mediates not only satiety but also aversive effects [22].

The current studies aim to (i) confirm the effect of α-MSH and MTII in the PVN to reduce food intake, in this case stimulated by NPY, and (ii) elucidate whether these effects on food intake are due to nonspecific aversive effects, i.e. whether α-MSH or MTII cause the development of CTA when injected into the PVN. As ICV MTII is associated with CTA, we also sought to investigate whether α-MSH induces CTA when injected ICV. In addition, only one study to our knowledge has investigated the effect on feeding of α-MSH injected site-specifically [13]; this study used only one dose of α-MSH and animals were stimulated to eat by food deprivation. Thus, here we report the response to several doses of α-MSH administered to the PVN at the onset of the dark phase, as well as during NPY-induced feeding.

Section snippets

Animals and housing

Male Sprague-Dawley rats (Charles River, Wilmington, MA), weighing 225–250 g, were individually housed in conventional hanging cages with a 12 h light/12 h dark photoperiod (lights on at 07:00) in a temperature controlled room (21–22°C). Food (Certified Rodent Chow, Teklad, Indianapolis IN) and water were allowed ad libitum until the start of each experimental trial.

Surgery

Rats were anesthetized with Nembutal (40 mg/kg) and fitted with a 21 gauge (ICV) or 26 gauge (PVN) stainless steel guide cannula

Results

When injected prior to the onset of the dark phase, α-MSH at a dose of 600 pmol significantly reduced 0–2 and 0–4 h cumulative food intake (0–4 h data shown in Fig. 2; F3,24 = 3.427, P = 0.018). By 24 h, this effect was no longer seen (data not shown). α-MSH at doses of 300 and 450 pmol did not significantly affect food intake (Fig. 2).

As seen previously, PVN injection of 110 pmol of NPY significantly stimulated food intake above control in non-deprived rats Fig. 3, Fig. 4.

Discussion

Previous studies have shown that ICV administration of the melanocortin agonist MTII inhibited food intake dose dependently in fasted mice and rats for prolonged periods of time [8], [21]. Prior work has also shown that α-MSH, as well as its analog, NDP-MSH, administered to the ventricle reduces food intake [3], [20], and NDP-MSH administered to hypothalamic sites such as the PVN suppresses deprivation-induced feeding [13]. The present studies demonstrate that α-MSH administered to the PVN also

Acknowledgements

This research was supported by the General Research Funds of the Veterans Administration Medical Center and by the Minnesota Obesity Center (NIDDK-DK 50456).

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