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Identification of Hypothalamic Nuclei Involved in the Orexigenic Effect of Melanin-Concentrating Hormone

Endocrine Unit, Imperial College London, Hammersmith Campus, London W12 ONN, United Kingdom

Address all correspondence and requests for reprints to: Professor S. R. Bloom, Endocrine Unit, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom. E-mail: s.bloom{at}imperial.ac.uk.

	Abstract

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The hypothalamic neuropeptide melanin-concentrating hormone (MCH) increases feeding when injected intracerebroventricularly in rats. To identify the hypothalamic nuclei responsible for the orexigenic effect, we injected the peptide into discrete hypothalamic nuclei known to express the MCH receptor, MCH1R. MCH (0.6 nmol) elicited a rapid and significant increase in feeding in satiated rats following injection into the arcuate nucleus (0–1 h: 421 ± 60%; P < 0.01). An elevation in feeding was also observed following injection into the paraventricular nucleus, which was sustained up to 4 h post injection (0–4 h: 218 ± 29%; P < 0.01). A significant increase in feeding during this time period was also observed following injection into the dorsomedial nucleus (0–4 h: 155 ± 12%; P < 0.05). No significant alteration in feeding was observed following injection into the supraoptic nucleus, lateral hypothalamic area, medial preoptic area, anterior hypothalamic area, or ventromedial nucleus of the hypothalamus. To identify the neurotransmitters that may be potentially involved in this effect, we examined their release from hypothalamic explants in vitro following exogenous MCH administration. MCH (1 µM) increased the release of the orexigenic neurotransmitters neuropeptide Y (37.8 ± 6.0 fmol/explant vs. basal 30.2 ± 4.3 fmol/explant; P < 0.05) and agouti-related peptide (4.1 ± 0.6 fmol/explant vs. basal 2.4 ± 0.2 fmol/explant; P < 0.05) and decreased the release of the anorectic neurotransmitters -MSH (41.7 ± 6.8 fmol/explant vs. basal 65.9 ± 11.0 fmol/explant; P < 0.01) and cocaine- and amphetamine-regulated transcript (112.3 ± 12.4 fmol/explant vs. basal 167.4 ± 13.0 fmol/explant; P < 0.001). These studies suggest that the orexigenic effect of MCH may be mediated via activation or inhibition of these feeding circuits within the arcuate nucleus and paraventricular nucleus of the hypothalamus.

	Introduction

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MELANIN-CONCENTRATING HORMONE (MCH) has been implicated in the control of appetite and body weight regulation and is widely targeted as a possible avenue for treatment of obesity. Hypothalamic MCH mRNA and peptide levels are increased in genetically obese Lep^ob/ Lep^ob mice compared with nonobese wild-type controls (1). In addition, fasting further increases the expression of MCH mRNA in both normal and obese animals (1). Intracerebroventricular (ICV) administration of MCH increases food intake in rats (1, 2) and, when administered chronically in rodents, results in weight gain and enhanced susceptibility to diet-induced obesity (3, 4). Targeted deletion of the MCH gene in mice reduces food intake and body weight (5). MCH^-/- mice also have an inappropriately elevated metabolic rate that may contribute to the reduction in body weight. Chronic overexpression of the MCH gene in mice results in obesity and insulin resistance (6). MCH therefore seems to be an important regulator of feeding and energy balance.

Within the hypothalamus, MCH expression is localized to perikarya in the lateral hypothalamic (LHA) and zona incerta regions (7). Immunohistochemical studies in the rat have shown widespread neuronal projections throughout the brain (8). MCH immunoreactive boutons are observed in particular areas of the hypothalamus implicated in feeding and body weight regulation (8).

Two MCH receptors, MCH1R and MCH2R, have recently been identified (9, 10, 11, 12, 13, 14, 15, 16, 17, 18). However, it has been shown that rodents only express functional MCH1R (19). MCH1R (or SLC-1) mRNA and immunoreactivity are found throughout the brain, with particularly high levels in the hypothalamus, in areas implicated in feeding regulation (20). Targeted deletion of the MCH1R gene resulted in mice that are hyperphagic and lean (21, 22). This is likely to be a consequence of the elevated metabolism and locomotor activity observed in these animals. MCH1R^-/- mice are resistant to diet induced obesity, with no alteration in body weight following chronic administration of MCH or a high-fat diet (21, 22). Further confirmation of the role of MCH1R in the mediation of MCH on feeding has been provided by recent studies using the selective high affinity MCH1R antagonist SNAP-7941 (23). Systemic administration of the antagonist inhibited the increase in food intake elicited by ICV MCH. In addition, chronic administration of the compound to rats with diet-induced obesity resulted in a marked reduction in body weight. These findings suggest MCH1R plays a physiological role in energy homeostasis.

To characterize the areas of the hypothalamus in which MCH influences feeding, MCH was injected into discrete hypothalamic nuclei known to both exhibit MCH1R immunoreactivity (20) and to have previously been implicated in feeding regulation, and food intake monitored. To investigate the mechanism by which MCH increases feeding, the effect of MCH on the release of other hypothalamic appetite-regulating neuropeptides in vitro from hypothalamic explants was examined.

	Materials and Methods

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Materials
MCH was purchased from Peninsula Laboratories Plc (St. Helens, Merseyside, UK). Reagents for static hypothalamic explant experiments and RIA were supplied by BDH (Poole, Dorset, UK).

Animals
Male Wistar rats (250–350 g) were maintained in individual cages under controlled temperature (21–23 C) and light (12-h light, 12-h dark, lights on at 0700 h) conditions with ad libitum access to food (RM1 diet, Special Diet Services UK Ltd., Witham, Essex, UK) and water. All animal procedures undertaken were approved by the British Home Office Animals Scientific Procedures Act 1986 (Project License No. 90/1077).

Intranuclear cannulation
Animal surgical procedures and handling were carried out as previously described (24). Animals were anesthetized by ip injection of a mixture of Ketalar (ketamine HCl 60 mg/kg; Parke-Davis, Pontypool, UK) and Rompun (xylazine 12 mg/kg; Bayer UK Ltd., Bury St. Edmunds, UK) and placed in a Kopf stereotaxic frame. Permanent 26-gauge stainless steel guide cannulae (Plastics One Inc., Roanoke, VA) were stereotactically placed into eight sites [medial preoptic area (MPO), supraoptic nucleus (SON), anterior hypothalamic area (AHA), paraventricular nucleus (PVN), ventromedial nucleus (VMN), dorsomedial nucleus (DMN), arcuate nucleus (ARC), and LHA] according to coordinates obtained from the Paxinos and Watson brain atlas (Table 1) (25). Animals were allowed a 7-d rest period before the onset of studies. All compounds were dissolved in 0.9% saline and administered, in the early light phase, as previously described (24, 26, 27, 28). The study was of a random cross over design, in which half of the animals in each group received 0.6 nmol MCH and the remainder received saline (n = 9–13/nucleus). The dose of MCH administered was based on previously published (2, 29) and pilot in vivo studies, and represented a half-maximal point on the dose-response curve. After a 4-d washout period, animals that had previously received MCH then received saline and vice versa. Following injection, animals were returned to their home cages containing a preweighed amount of chow. At 1, 2, 4, 8, and 24 h post injection, food remaining in the cage dispenser was weighed using an ATP Instrumentation GW 600 balance (ATP Instrumentations, Ltd., Ashby-De-la-Zouche, Leicestershire, UK) recording to the nearest 0.1 g.

This intranuclear injection method has previously been used to localize the hypothalamic feeding effects of -MSH, AgRP (83-132) (agouti-related peptide), ghrelin, CART (55-102) (cocaine- and amphetamine-regulated transcript), and neuromedin U (NMU) (Refs. 24 , 26 and 28).

Static incubation of hypothalamic explants
The static incubation system used was a modification of the method previously described (31). Male Wistar rats (n = 17–34) were killed by decapitation and the whole brain immediately removed. The brain was mounted with ventral surface uppermost and placed in a vibrating microtome (Microfield Scientific Ltd., Dartmouth, UK). A 1.7-mm slice was taken from the basal hypothalamus and incubated in individual tubes containing 1 ml of artificial cerebrospinal fluid (aCSF) (20 mM NaHCO₃, 126 mM NaCl, 0.09 mM Na₂HPO₄, 6 mM KCl, 1.4 mM CaCl₂, 0.09 mM MgSO₄, 5 mM glucose, 0.18 mg/ml ascorbic acid, and 100 µg/ml aprotinin), equilibrated with 95% O₂ and 5% CO₂. The hypothalamic explant includes all of the nuclei injected in the in vivo studies. The tubes were placed on a shaking platform in a water bath maintained at 37 C. After an initial 2-h equilibration period, the hypothalamic explants were incubated for 45 min in 600 µl aCSF (basal period) before being challenged with 1 µM MCH in 600 µl aCSF. Finally, the viability of the tissue was verified by a 45-min exposure to aCSF containing 56 mM KCl; isotonicity was maintained by substituting K⁺ for Na⁺. At the end of each period, the aCSF was removed and frozen at -20 C pending measurement of neuropeptide Y (NPY), AgRP, -MSH, CART, and orexin A by RIA.

RIAs
NPY, AgRP, -MSH, CART, and orexin A levels were measured using in house RIAs (26, 32, 33, 34, 35).

Statistical analysis
Food intake data are expressed as mean ± SEM % control. One-way ANOVA with post hoc bonferonni analysis was used for multiple comparisons of food intake of MCH and saline-treated groups at each nucleus and time point. Peptide release from hypothalamic explants is expressed as fmol release/explant. Paired Student’s t test was for comparison of peptide release from hypothalamic explants in basal, MCH, and potassium-stimulated periods. Values of P < 0.05 were considered significant.

	Results

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Effect of intranuclear administration of MCH on food intake
The data below are expressed as mean ± SEM % saline control. Mean food intake for saline-injected controls at each time point for all nuclei were: 0–1 h, 0.8 ± 0.1 g; 1–2 h, 0.4 ± 0.1 g; 2–4 h, 0.6 ± 0.1 g; 4–8 h, 2.0 ± 0.2 g; and 8–24 h, 18.9 ± 0.5 g. Injection of MCH into the ARC induced a dramatic 4-fold increase in feeding at 0–1 h post injection (421 ± 60% control; P < 0.01) (Fig. 1G). Food intake levels were indistinguishable from control levels from 2 h post injection. Administration of 0.6 nmol MCH caused a sustained elevation in feeding following administration into the PVN, although this failed to reach significance at any individual time point (0–1 h, 183 ± 25% control; 1–2 h, 214 ± 44% control; 2–4 h, 284 ± 78%, P = not significant) (Fig. 1D). Analysis of cumulative food intake data found total 4 h food intake to be significantly elevated from saline-injected control levels (218 ± 29% control; P < 0.01) (Fig. 2). This elevation was comparable to the 4-h cumulative food intake following MCH administration into the ARC (198 ± 26% control; P < 0.01 vs. saline control) (Fig. 2). In addition, 0.6 nmol MCH administered into the DMN significantly increased feeding during this 4-h period post injection (155 ± 12% control; P < 0.05) (Fig. 2). A trend toward increased feeding was observed following MCH administration into the SON (0–1 h, 216 ± 51% control) and AHA (0–1 h, 170 ± 36% control), although this failed to reach significance (Fig. 1, B and C). There was no significant alteration in feeding following administration of MCH into the MPO, VMN, or LHA at any time point measured (Fig. 1, A, E, and H).

View larger version (21K): [in this window] [in a new window]   FIG. 1. The effect on food intake of 0.6 nmol MCH into: A, MPO; B, SON; C, AHA; D, PVN; E, VMN; F, DMN; G, ARC; and H, LHA over a 24-h period in satiated rats (n = 9–13/nucleus). Expressed as % saline; **, P < 0.01 vs. saline.

View larger version (15K): [in this window] [in a new window]   FIG. 2. Comparative effects of MCH (0.6 nmol) in discrete hypothalamic nuclei on cumulative 4-h food intake of satiated rats (n = 9–13/nucleus). Expressed as % saline; *, P < 0.05; **, P < 0.01 vs. saline.

View larger version (14K): [in this window] [in a new window]   FIG. 3. Effect of MCH on A, NPY; B, AgRP; C, CART; D, -MSH; and E, orexin A release from rat hypothalamic explants (n = 17–34). Expressed as femtomoles of peptide released per explant. *, P < 0.05; **, P < 0.01; ***, P < 0.001 vs. basal release.

	Discussion

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The ARC contains a number of neuropeptides known to influence feeding and body weight regulation. NPY and AgRP are coexpressed in neuronal cell bodies in the ARC and both are up-regulated with fasting (39, 40). ICV administration of NPY or AgRP significantly increases food intake (41, 42). Proopiomelanocortin (POMC), the precursor of the neuropeptide -MSH, and CART are also colocalized in a subset of ARC neurons distinct from those that contain NPY and AgRP. ARC POMC and CART mRNA levels decrease with fasting (43, 44). CART is also coexpressed with MCH in the LHA (45). ICV administration of -MSH reduces food intake in rodents (46). ICV administration of CART (55–102), the putative active fragment, decreases feeding in rodents (43) but is associated with adverse behaviors thought to impair the ability to feed (24). Recent studies have found intranuclear injection of CART (55–102) to increase feeding following administration into several hypothalamic nuclei, including the ARC (24). It has been shown that these ARC neuropeptides are highly regulated by leptin. Kokkotou et al. demonstrated that MCH1R is also regulated by leptin, with expression levels in the ARC of Lep^ob/ Lep^ob mice being 5-fold higher than their wild-type counterparts (47). We found MCH to stimulate the release of NPY and AgRP and inhibit the release of -MSH and CART from hypothalamic explants in vitro. It is possible that the large orexigenic response following administration of MCH into the ARC may be mediated, at least in part, via a modulation of these ARC neuropeptide feeding circuits. MCH may increase feeding by activating the orexigenic NPY/AgRP neurons, while concurrently inactivating anorectic POMC/CART neurons. In agreement, recent studies have shown activation of ARC neurons by MCH in hyperphagic rats (48). Our data suggest that the LHA may have an influential effect on the regulation of appetite and body weight mediated by the ARC through MCH signaling mechanisms.

The PVN also plays an important role in feeding regulation. Virtually all known orexigenic and anorectic neuropeptides alter food intake following direct injection into the PVN (24, 26, 28, 49, 50). Although initially not as big as that induced following administration into the ARC, the orexigenic effect following administration into the PVN was sustained up to 4 h post injection. Food intake remained elevated to approximately 300% of control levels during the 2–4 h postinjection period, with 4-h cumulative food intake indistinguishable from that of the ARC administered rats. Because many of the cell bodies of appetite regulating neurones present in the ARC project to the PVN, it may be postulated that this sustained orexigenic effect following MCH administration may be through an action on the terminals of the same neurones projecting to the PVN.

Lesioning studies have implicated the DMN in the control of appetite and body weight (51). AgRP (83–132), CART (55–102) and galanin increase feeding when directly injected into this nucleus (24, 26, 50). Here we have found administration of MCH into the DMN also increases food intake. MCH stimulated the release of NPY from hypothalamic explants in vitro. It is possible, therefore, that the NPY system in the DMN plays a role in the effect of MCH on feeding. Further mechanistic studies are required to elucidate these pathways.

Although not significant, there was a trend toward an increase in feeding in the first hour post injection of MCH into the SON. The SON is not classically regarded as a center for feeding, however we have recently shown that CART (55–102) significantly increases feeding when administered here (24). In addition, it has been reported that injection of the dopamine D2 receptor antagonist, sulpiride, into the SON significantly increased the food intake of anorectic tumor-bearing rats (52). A similar trend was observed in the first hour post injection of MCH into the AHA. Several other neuropeptides including -MSH, AgRP (83–132), and CART (55–102) have been shown to alter food intake when administered into the AHA (24, 26).

MCH and the neuropeptide orexin A are localized to distinct cell bodies within the LHA. This area also contains MCH1R immunoreactivity (20), though the cell types expressing MCH1R have not been identified. MCH may feedback to regulate its own release, or may influence orexin A release. However, exogenous administration of MCH to hypothalamic explants did not alter orexin A release compared with basal levels. In addition, we did not observe any alteration in feeding following administration into the LHA.

No alteration in feeding was observed following administration of MCH into the MPO or VMN of the hypothalamus. Both the VMN and MPO contain moderate to extensive MCH1R immunoreactivity (20). The function of MCH1R in these areas remains unclear. It is possible that they mediate other actions of MCH such as regulation of sexual behavior or hormonal control (53).

Although low doses of peptide were administered in the intranuclear studies, the possibility of diffusion of peptide from one site to another must always be considered. However, no alteration in feeding was observed following administration of MCH into the VMN, which is anatomically closer to the responsive ARC than the DMN and PVN. In addition, if the feeding response elicited was due to diffusion of peptide then a delayed orexigenic response might be expected. Our data imply a rapid onset increase in feeding evident from the earliest time point measured. We therefore conclude that, for the doses chosen in this study, the diffusion effect from one nucleus to another is small. This method of intranuclear administration has previously been used to map the hypothalamic feeding effects of numerous peptides including NPY, -MSH, AgRP (83–132), galanin, ghrelin, CART (55–102), and NMU (Refs. 24 , 26, 27, 28 , 49 , and 50).

In conclusion, we have shown MCH increases feeding following administration into the ARC, PVN, and DMN of the hypothalamus of rats. The most prominent orexigenic effects are observed following administration into the ARC and PVN. These effects may be mediated via activation or inhibition of neuronal feeding circuits projecting from the ARC to the PVN because MCH increases the release of the orexigenic NPY and AgRP and decreases the release of -MSH and CART from hypothalamic explants. Further investigation of the role of MCH in the hypothalamic feeding circuitry may provide insight into potential routes of therapeutic intervention for human obesity.

	Acknowledgments

 
The authors wish to thank the hypothalamic group for help with the in vivo studies.

	Footnotes

 
A.R.K. is a GlaxoSmithKline Cooperative Awards in Science and Engineering student. A.M.W. and L.J.S. are Wellcome Clinical training fellows. The department is funded by a Medical Research Council programme grant. C.R.A. and K.G.M. are funded by the Wellcome trust.

Abbreviations: aCSF, Artificial cerebrospinal fluid; AgRP, agouti-related peptide; AHA, anterior hypothalamic area; ARC, arcuate nucleus; CART, cocaine- and amphetamine-regulated transcript; DMN, dorsomedial nucleus; ICV, intracerebroventricular; LHA, lateral hypothalamic area; MCH, melanin-concentrating hormone; MCH1R and MCH2R, MCH receptors; MPO, medial preoptic area; NMU, neuromedin U; NPY, neuropeptide Y; POMC, proopiomelanocortin; PVN, paraventricular nucleus; SON, supraoptic nucleus; VMN, ventromedial nucleus.

Received January 30, 2003.

Accepted for publication May 7, 2003.

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