Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba 300 - 2611, Japan
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ABSTRACT |
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Melanin-concentrating hormone (MCH) is a cyclic amino acid neuropeptide localized in the lateral hypothalamus. Although MCH is thought to be an important regulator of feeding behavior, the involvement of this peptide in body weight control has been unclear. To examine the role of MCH in the development of obesity, we assessed the effect of chronic intracerebroventricular infusion of MCH in C57BL/6J mice that were fed with regular or moderately high-fat (MHF) diets. Intracerebroventricular infusion of MCH (10 µg/day for 14 days) caused a slight but significant increase in body weight in mice maintained on the regular diet. In the MHF diet-fed mice, MCH more clearly increased the body weight accompanied by a sustained hyperphagia and significant increase in fat and liver weights. Plasma glucose, insulin, and leptin levels were also increased in the MCH-treated mice fed the MHF diet. These results suggest that chronic stimulation of the brain MCH system causes obesity in mice and imply that MCH may have a major role in energy homeostasis.
melanin-concentrating hormone; food intake; body weight; fat weight
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INTRODUCTION |
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MELANIN-CONCENTRATING HORMONE (MCH) is a cyclic amino acid peptide that was first isolated from salmon pituitaries (7). MCH is expressed predominantly in the lateral hypothalamus (18), which is well known to play an important role in the control of feeding. Hypothalamic expression of prepro-MCH (Pmch) mRNA is upregulated during starvation in lean mice as well as in genetically obese ob/ob mice (21). Bolus intracerebroventricular injection of MCH stimulates food intake in rats and mice (21, 23, 25). These observations are good evidence to support the role of MCH in the central regulation of feeding behavior. In addition, Pmch-deficient mice are lean, with accompanying hypophagia and an increased metabolic rate (28), and Pmch overexpression slightly increases food intake and body weight in mice (12), suggesting that MCH is also a major regulator of energy homeostasis. However, Pmch also encodes neuropeptide EI (NEI) and neuropeptide GE (NGE), although the physiological roles of NEI and NGE are not yet fully understood. Thus it is difficult to conclude that the phenotypes observed in the models that represent genetic manipulations of Pmch are attributable to the effects of MCH itself. Furthermore, repetitive intracerebroventricular injection of MCH is reported to cause tachyphylaxis in feeding stimulation and to have no effect on body weight (24), which casts doubt on the role of MCH in energy homeostasis.
In the present study, we assessed the effect of chronic intracerebroventricular infusion of MCH in mice fed a regular or a moderately high-fat (MHF) diet to clarify the role of MCH itself in the development of obesity.
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MATERIALS AND METHODS |
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Drugs. MCH was purchased from Peptide Institute, Osaka, Japan. All other chemicals were of analytical grade.
Animals. Male C57BL/6J mice (15 wk old, CLEA Japan, Tokyo, Japan) were used. Mice were housed individually in plastic cages under controlled temperature and humidity (23 ± 2°C, 55 ± 15%) and a 12:12-h light-dark cycle (7 PM lights off) with ad libitum access to regular diet (CE-2; CLEA Japan) and tap water for an acclimation period. All experimental procedures followed the Japanese Pharmacological Society Guideline for Animal Use.
Surgical procedure and experimental designs.
After 2-3 wk of acclimation, mice were anesthetized with
pentobarbital sodium (80 mg/k ip; Dainabot, Osaka, Japan). A sterile brain infusion cannula (28 gauge; Alzet, Palo Alto, CA) was
stereotaxically implanted into the right lateral ventricle. The
stereotaxic coordinates, using a flat skull position, were 0.4 mm
posterior to the bregma, 0.8 mm lateral to the midline, and 2.0 mm from
the surface of the skull. The cannula was fixed to the skull with
dental cement. The cannula was connected to an osmotic minipump (model
no. 2001, Alzet) filled with 30% propylene glycol (PG) with polyvinyl
chloride tubing. The pump was implanted under the skin of the back, and antibiotic (Cefamedine , 50 mg/kg; Fujisawa Pharmaceutical, Tokyo, Japan) was injected subcutaneously. After a 7- to 14-day recovery period, mice were divided into four groups to match average body weight
and food intake (n = 10). The infusion pump was
replaced with a new pump (model no. 2001, Alzet) filled with MCH (10 µg/day for 14 days) or its vehicle (30% PG) under ether anesthesia.
A pair of MCH- and vehicle-treated groups was fed the regular diet throughout the experiment. In the other two groups of mice, the diet
was changed from the regular diet to an MHF diet [slightly-modified diet reported by Lauterio et al. (10); Oriental
BioService, Tokyo, Japan] at the start of the MCH or vehicle infusion.
The MHF diet provided 52.4% energy as carbohydrate, 15.0% as protein, and 32.6% as fat (4.41 kcal/g). The regular diet provided 59.3% energy as carbohydrate, 29.2% as protein, and 11.5% as fat (3.42 kcal/g). Food intake and body weight were measured daily. After the
14-day intracerebroventricular infusion, mice were fasted for 2 h,
and blood samples were collected from the infraorbital vein for
measurement of plasma glucose, insulin, and leptin levels. Then the
mice were killed by collecting whole blood from the heart under ether
anesthesia. Epididymal, retroperitoneal, and mesenteric adipose tissues
and liver were excised and weighed.
Measurement of plasma biochemical parameters. Plasma leptin and insulin levels were measured with ELISA kits (Morinaga, Kanagawa, Japan). Plasma glucose, triglyceride (TG), total, HDL-, and non-HDL-cholesterol and free fatty acid levels were measured using commercial kits [Determiner GL-E, L TGII, L TCII, L HDL-C, and L LDL-C, Kyowa Medex, Tokyo, Japan; NEFA-HA Testwako (II), Wako Pure Chemical Industries, Osaka, Japan].
Motor activity. Another set of MCH- or vehicle-infused mice was prepared for measurement of spontaneous motor activity. MCH (10 µg/day) or the vehicle was infused for 14 days under the regular diet-fed condition. Motor activity was measured during the last 3 days of the 14-day infusion by an activity monitoring system (NS-AS01, Neuroscience, Tokyo, Japan) in home cages. In brief, the activity monitor was composed of an infrared ray sensor placed over a home cage (21 × 32 × 12.5 cm), a signal amplification circuit, and a control unit. The sensor detected the movement of animals on the basis of the released infrared ray associated with their body temperature (16, 19). The data of motor activity were collected at 10-min intervals and analyzed with a computer-associated analyzing system (AB System-24A, Neuroscience).
Statistics. Data are expressed as means ± SE. Significant differences in body weight changes and daily caloric intake were analyzed by repeated-measures one-way ANOVA and the Bonferroni test. For cumulative caloric intake, blood parameters, and tissue weights, analysis by one-way ANOVA and the Bonferroni test was performed. Two-way ANOVA was performed for the interaction between factors of diet and MCH infusion. P values <0.05 were considered to be significant.
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RESULTS |
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In the regular diet-fed mice, chronic intracerebroventricular
infusion of MCH (10 µg/day) slightly but significantly increased body
weight. Body weight gains for 14 days were 3.03 ± 0.52 g in
the MCH-infused group vs. 0.55 ± 0.19 g in the
vehicle-infused group (Fig. 1A
and Table 1). The MHF diet
alone did not affect body weight in the vehicle-infused mice during
this experiment. The MCH infusion in the presence of the MHF diet
caused a remarkable increase in body weight (gains of 6.17 ± 0.64 and 1.29 ± 0.50 g in the MCH- and in the vehicle-infused
group, respectively; Fig. 1A and Table 1). There was a
significant interaction between diet and the MCH infusion in the final
body weight gain [F(1,36) = 5.94, P = 0.0199], indicating that the MCH-infused mice
gained more weight when they were fed the MHF diet.
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In the regular diet-fed mice, the MCH infusion showed a tendency to increase cumulative caloric intake, whereas the difference was not statistically significant (Fig. 1C). The vehicle-infused mice on the MHF diet showed a transient increase in food intake on day 1. The food intake levels returned to the basal level on day 2. The MCH-infused mice on the MHF diet showed a sustained hyperphagia during the experiment, and total caloric intake was significantly increased compared with that of the vehicle-infused mice (Fig. 1, B and C). There was a significant interaction between diet and the MCH infusion in cumulative caloric intake [F(1,36) = 5.23, P = 0.0282]. Thus MCH stimulated caloric intake more in the MHF diet-fed mice than in the regular diet-fed mice. Water intake was slightly increased by the MCH infusion in the MHF diet-fed mice but not in the regular diet-fed mice (data not shown).
Fourteen-day infusion of MCH increased the adipose tissue weights in
both the regular diet-fed and the MHF diet-fed mice (Table 2). A significant interaction between
diet and the MCH infusion was observed in epididymal
[F(1,36) = 5.07, P = 0.0306] and mesenteric fat weights
[F(1,36) = 5.00, P = 0.0316], indicating that MCH stimulated fat accumulation more in the
MHF diet-fed than in the regular diet-fed mice. Exposure to the MHF
diet reduced liver weight compared with that of the regular diet-fed
mice. The MCH infusion significantly increased the liver weight in the
MHF diet-fed group (Table 2).
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In the regular diet-fed mice, the MCH infusion did not affect plasma
glucose and insulin levels, whereas MCH increased the plasma leptin
level fourfold (Fig. 2). Exposure to the
MHF diet resulted in significant increases in these parameters compared with those of the regular diet-fed mice. The MCH infusion with the MHF
diet significantly stimulated the increase in the plasma levels of
glucose 1.2-fold, insulin 2-fold, and leptin 3-fold (Fig. 2).
Significant interactions between diet and the MCH infusion were
observed in the insulin and leptin levels
[F(1,35) = 4.37, P = 0.0439 and F(1,36) = 10.04, P = 0.0031, respectively] but not in the glucose
level.
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The MCH infusion did not affect total, HDL-, or non-HDL-cholesterol
levels in the regular diet-fed group (Table
3). Although these parameters were
increased by the MHF diet in the vehicle-infused group, further changes
were not observed by the MCH treatment. The plasma TG level was
elevated by the MCH infusion under the regular diet-fed condition. The
MHF diet decreased the plasma TG level in the vehicle-infused mice. MCH
tended to increase the TG level in the MHF diet-fed mice, but the
effect was not statistically significant. There was a significant
interaction between diet and the MCH infusion in the TG level
[F(1,36) = 5.57, P = 0.0238]. The plasma FFA level was not changed in any of the four
groups (Table 3).
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Recently, it was reported that MCH 1 receptor-deficient mice showed
increased motor activity (3a, 13). To elucidate effects of
chronic activation of the MCH system, we measured spontaneous motor
activity. To correctly compare the results with the MCH 1 receptor-deficient mice, the experiments were conducted with mice on
the regular diet. The MCH infusion did not change spontaneous motor
activity during either the light or the dark cycle (Fig. 3). In addition, no notable changes were
observed during the MCH infusion in the gross behavior tests (data not
shown).
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DISCUSSION |
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In this study, we showed that chronic intracerebroventricular infusion of MCH for 14 days caused body weight gain in mice fed a regular diet. MCH also caused slight but significant increases in adipose tissue weight and leptin levels. The current observation is coincident with previous reports that transgenic mice overexpressing Pmch developed a slight increase in body weight gain compared with that in wild-type mice under the regular diet-fed condition (12). Therefore, the phenotypes observed in the transgenic mice overexpressing Pmch are caused mainly by activation of the brain MCH system. However, our results are inconsistent with the observation of Rossi et al. (24), showing that repetitive MCH administration did not cause obesity. The discrepancy between that observation and ours might be due to methodological differences. Bolus injection of MCH at high doses may easily induce tachyphylaxis or compensatory hypophagia. Alternatively, continuous activation of MCH systems might be necessary to produce obesity. The effect of stress that is induced by repetitive intracerebroventricular injection should also be considered.
Although the effect of MCH on body weight regulation was relatively mild under normal energy conditions, MCH caused sustained hyperphagia and a more greatly increased body weight accompanied by hyperglycemia, hyperinsulinemia, and hyperleptinemia when the MHF diet was given. The present data are in agreement with the report that the Pmch-transgenic mice are highly sensitive to diet-induced obesity (12). From these results, it is suggested that MCH could produce a crucial influence on the development of obesity, especially when combined with additional environmental factor(s) such as a high-calorie diet. However, this finding may also raise the possibility that MCH influences the food preference of mice. MCH neurons project to the parabrachial nucleus, which is thought to be involved in gustatory sensation processes (31). Further investigations will be needed to address this possibility.
Recently, it was reported that MCH 1 receptor-deficient mice showed increased motor activity (3a, 13). These findings may evoke the possibility that the MCH-induced obesity in the present study may be caused, in part, by sedentary or reduced activity. However, intracerebroventricularly infused MCH did not affect spontaneous motor activity during either the light or the dark cycle. Consequently, it is not likely that the MCH-induced obesity is due to sedentary changes in behavior.
Intracerebroventricular infusion of MCH stimulated adiposity. Because MCH caused hyperphagia, the MCH-induced fat accumulation may be partly due to feeding stimulation. It is reported that MCH neurons project to the brown adipose tissue, which has an important role in energy expenditure (20). In support, O2 consumption in the MCH-deficient mice was slightly higher than in control mice (28). Thus the MCH-induced fat accumulation might also be caused by the reduction of energy expenditure. To consider the mechanism of the MCH-induced fat accumulation, it is noteworthy that MCH suppresses the hypothalamo-pituitary-thyroid axis (8). Several hormones, such as thyroid hormone and corticosterone, might also be involved in the effect of MCH. Thus MCH might produce obesity with typical metabolic and endocrine changes. Further examination of the effect of MCH on sympathetic tone and hormonal balance is of importance.
MCH did not significantly change most of the lipid parameters studied under either the regular diet- or MHF diet-fed conditions. However, the plasma TG level was significantly increased in the regular diet-fed mice, suggesting that MCH might stimulate fat synthesis in the liver. This change was not clearly observed under the MHF diet condition. Presumably, dietary fatty acid on the MHF diet inhibited an intrinsic lipogenic activity (6, 33); hence, the effect of MCH on TG level might be diminished.
Two subtypes of MCH receptors have been cloned so far. SLC-1, an orphan G protein-coupled receptor, was identified as an MCH 1 receptor (2, 3, 11, 27, 29). Another receptor subtype, named MCH 2 receptor, was recently identified in human brain (1, 5, 15, 22, 26, 32). These receptors are similarly distributed in the hypothalamic regions. However, the MCH 2 receptor is reported not to exist in rodents (30). Furthermore, MCH failed to produce body weight gain in MCH 1 receptor-deficient mice (13). Consequently, the typical obese phenotypes evoked by MCH in the present experiment are mediated by the MCH 1 receptor.
In summary, chronic intracerebroventricular infusion of MCH stimulated fat accumulation, especially when combined with the MHF diet. These results imply that MCH may have a major role in energy homeostasis. Taken together with the observation that the MCH expression level was increased in several obesity models (4, 9, 14, 17, 28), MCH may be involved in the pathogenesis of obesity syndrome. Consequently, MCH antagonists may be useful drugs for the treatment of obesity.
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ACKNOWLEDGEMENTS |
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We thank K. Marcopul and J. Winward (Merck) for critical reading of the manuscript, and K. Watanabe, T. Iguchi, R. Moriya, and R. Yoshimoto (Banyu Pharmaceutical) for technical assistance.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. Ishihara, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba 300-2611, Japan (E-mail: isihraan{at}banyu.co.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published November 26, 2002;10.1152/ajpendo.00350.2002
Received 8 August 2002; accepted in final form 18 November 2002.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
An, S,
Cutler G,
Zhao JJ,
Huang SG,
Tian H,
Li W,
Liang L,
Rich M,
Bakleh A,
Du J,
Chen JL,
and
Dai K.
Identification and characterization of a melanin-concentrating hormone receptor.
Proc Natl Acad Sci USA
98:
7576-7581,
2001
2.
Bachner, D,
Kreienkamp HJ,
Weise C,
Buck F,
and
Richter D.
Identification of melanin concentrating hormone (MCH) as the natural ligand for the orphan somatostatin-like receptor 1 (SLC-1).
FEBS Lett
457:
522-524,
1999[ISI][Medline].
3.
Chambers, J,
Ames RS,
Bergsma D,
Muir A,
Fitzgerald LR,
and
Hervieu G.
Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1.
Nature
400:
261-265,
1999[ISI][Medline].
3a.
Chen, YY,
Hu C,
Hsu CK,
Zhang Q,
Bi C,
Asnicar M,
Hsiung HM,
Fox N,
Slieker LJ,
Yang DD,
Heiman ML,
and
Shi Y.
Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity.
Endocrinology
143:
2469-2477,
2002
4.
Hanada, R,
Nakazato M,
Matsukura S,
Murakami N,
Yoshimatsu H,
and
Sakata T.
Differential regulation of melanin-concentrating hormone and orexin genes in the agouti-related protein/melanocortin-4 receptor system.
Biochem Biophys Res Commun
268:
88-91,
2000[ISI][Medline].
5.
Hill, J,
Duckworth M,
Rennie G,
David CS,
Ames RS,
Szekeres P,
Wilson S,
Bergsma DJ,
Gloger IS,
Levy DS,
Chambers JK,
and
Muir AI.
Molecular cloning and functional characterization of MCH2, a novel human MCH receptor.
J Biol Chem
276:
20125-20129,
2001
6.
Jump, DB,
Clarke SD,
Thelen A,
and
Liimatta M.
Coordinate regulation of glycolytic and lipogenic gene expression by polyunsaturated fatty acids.
J Lipid Res
35:
1076-1084,
1994[Abstract].
7.
Kawaguchi, H,
Kawazoe I,
Tsubokawa M,
Kishida M,
and
Baker BI.
Characterization of melanin-concentrating hormone in chum salmon pituitaries.
Nature
305:
321-323,
1983[ISI][Medline].
8.
Kennedy, AR,
Todd JF,
Stanley SA,
Abbot CR,
Small CJ,
Ghatei MA,
and
Bloom SR.
Melanin-concentrating hormone (MCH) suppresses thyroid stimulating hormone (TSH) release, in vitro and in vivo, via the hypothalamus and the pituitary.
Endocrinology
142:
3265-3268,
2001
9.
Krongrad, AS,
Dimitrov T,
and
Beck B.
Central and peripheral dysregulation of melanin-concentrating hormone in obese Zucker rats.
Mol Brain Res
92:
43-48,
2001[ISI][Medline].
10.
Lauterio, TJ,
Bond JP,
and
Ulman EA.
Development and characterization of a purified diet to identify obesity-susceptible and resistant rat populations.
J Nutr
124:
2172-2178,
1994[ISI][Medline].
11.
Lembo, PMC,
Grazzini E,
Cao J,
Hubatsch DA,
Pelletier M,
Hoffert C,
St-Onge S,
Pou C,
Labrecque J,
Groblewski T,
O'Donnell D,
Payza K,
Ahmad S,
and
Walker P.
The receptor for the orexigenic peptide melanin-concentrating hormone is a G-protein-coupled receptor.
Nat Cell Biol
1:
267-271,
1999[ISI][Medline].
12.
Ludwig, DS,
Tritos NA,
Mastatris JW,
Kulkarni R,
and
Flier EM.
Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance.
J Clin Invest
107:
379-386,
2001
13.
Marsh, DJ,
Weingarth DT,
Novi DE,
Chen HY,
Trumbauer ME,
Chen AS,
Guan XM,
Jiang MM,
Feng Y,
and
Camacho RE.
Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism.
Proc Natl Acad Sci USA
99:
3240-3245,
2002
14.
Mizuno, T,
Kleopoulos ST,
Bergen HT,
Roberts JL,
Priest CA,
and
Mobbs CV.
Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting in ob/ob and db/db mice, but is stimulated by leptin.
Diabetes
47:
294-297,
1997[Abstract].
15.
Mori, M,
Harada M,
Terao Y,
Sugo T,
Watanabe T,
Shimomura Y,
Abe M,
Shintani Y,
Onda H,
Nishimura O,
and
Fujino M.
Cloning of a novel G protein-coupled receptor, SLT, a subtype of the melanin-concentrating hormone receptor.
Biochem Biophys Res Commun
283:
1013-1018,
2001[ISI][Medline].
16.
Mori, T,
Baba J,
Ichimaru Y,
and
Suzuki T.
Effects of Rolipram, a selective inhibitor of phosphodiesterase 4, on hyperlocomotion induced by several abused drugs in mice.
Jpn J Pharmacol
83:
113-118,
2000[ISI][Medline].
17.
Mystkowski, P,
Seeley RJ,
Hahn TM,
Baskin DG,
Havel PJ,
Matsumoto AM,
Wilkinson W,
Kinzig KP,
Blake KA,
and
Schwartz MW.
Hypothalamic melanin-concentrating hormone and estrogen-induced weight loss.
J Neurosci
20:
8637-8642,
2000
18.
Nahon, JL.
The melanin-concentrating hormone: from the peptide to the gene.
Crit Rev Neurobiol
8:
221-262,
1994[ISI][Medline].
19.
Narita, M,
Mizuo K,
Shibasaki M,
and
Suzuki T.
Upregulation of the Gq/11 protein kinase C during the development of sensitization to morphine-induced hyperlocomotion.
Neuroscience
111:
127-132,
2002[ISI][Medline].
20.
Oldfield, BJ,
Giles ME,
Watson A,
Anderson C,
Colvill LM,
and
Mckinley MJ.
The neurochemical characterization of hypothalamic pathways projecting polysynaptically to brown adipose tissue in the rat.
Neuroscience
110:
515-526,
2002[ISI][Medline].
21.
Qu, D,
Ludwig DS,
Gammeltoft S,
Piper M,
and
Pelleymounter MA.
A role for melanin-concentrating hormone in the central regulation of feeding behaviour.
Nature
380:
243-247,
1996[ISI][Medline].
22.
Rodriguez, M,
Beauverger P,
Naime I,
Rique H,
Ouvry C,
Souchaud S,
Dromaint S,
Nagel N,
Suply T,
Audinot V,
Boutin JA,
and
Galizzi JP.
Cloning and molecular characterization of the novel human melanin-concentrating hormone receptor 2.
Mol Pharmacol
60:
632-639,
2001
23.
Rossi, M,
Beak SA,
Choi SJ,
Small CJ,
and
Morgan DGA
Investigation of the feeding effects of melanin concentrating hormone on food intake-action independent of galanin and the melanocortin receptors.
Brain Res
846:
164-170,
1999[ISI][Medline].
24.
Rossi, M,
Choi SJ,
Miyoshi T,
Ghatei MA,
and
Bloom SR.
Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight.
Endocrinology
138:
351-355,
1997
25.
Sahu, A.
Leptin decreases food intake induced by melanin-concentrating hormone (MCH), galanin (GAL) and neuropeptide Y (NPY) in the rat.
Endocrinology
139:
4739-4742,
1998
26.
Sailer, AW,
Sano H,
Zeng Z,
Mcdonald TP,
Pan J,
Pong SS,
Feighner SD,
Tan CP,
Fukami T,
Iwaasa H,
Hreniuk DL,
Morin NR,
Sadowski SJ,
Ito M,
and
Bansal A.
Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R.
Proc Natl Acad Sci USA
98:
7564-7569,
2001
27.
Saitou, Y,
Nothcker HP,
Wang Z,
Lin SHS,
Leslie F,
and
Civelli O.
Molecular characterization of the melanin-concentrating-hormone receptor.
Nature
400:
265-269,
1999[ISI][Medline].
28.
Shimada, M,
Tritos NA,
Lowell BB,
Flier JS,
and
Flier EL.
Mice lacking melanin-concentrating hormone are hypophagic and lean.
Nature
396:
670-674,
1998[ISI][Medline].
29.
Shimomura, Y,
Mori M,
Sugo T,
Ishibashi Y,
Abe M,
Kurokawa T,
Onda H,
Nishimura O,
Sumino Y,
and
Fujino M.
Isolation and identification of melanin-concentrating hormone as the endogenous ligand of the SLC-1 receptor.
Biochem Biophys Res Commun
261:
622-626,
1999[ISI][Medline].
30.
Tan, CP,
Sano H,
Iwaasa H,
Pan J,
Sailer AW,
Hreniuk DL,
Feighner SD,
Palyha OC,
Figueroa DJ,
Austin CP,
Jiang MM,
Yu H,
Ito J,
Ito M,
Ito M,
Guan X,
Kanatani A,
Van der Ploeg LH,
and
Thoward AD.
Melanin-concentrating hormone receptor subtypes 1 and 2: species-specific gene expression.
Genomics
79:
785-792,
2002[ISI][Medline].
31.
Touzani, K,
Traumu G,
Nahon JL,
and
Velley L.
Hypothalamic melanin-concentrating hormone and -neoendorphin-immunoreactive neurons project to the medial part of the rat parabrachial area.
Neuroscience
53:
865-876,
1993[ISI][Medline].
32.
Wang, S,
Behan J,
O'Neill K,
Weig B,
Fried S,
Laz T,
Bayne M,
Gustafson E,
and
Hawes BE.
Identification and pharmacological characterization of a novel human melanin-concentrating hormone receptor, MCH-R2.
J Biol Chem
276:
34664-34670,
2001
33.
Xu, J,
Nakamura M,
Cho HP,
and
Clarke SD.
Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids.
J Biol Chem
274:
23577-23583,
1999