Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1

Chambers, Jon; Ames, Robert S.; Bergsma, Derk J.; Muir, Alison I.; Fitzgerald, Laura Rydelek; Hervieu, Guillaume; Dytko, George; Foley, James J.; Martin, John D.; Liu, Wu-Schyong; Park, Janet; Ellis, Catherine; Ganguly, Subinay; Konchar, Susan; Cluderay, Jane E.; Leslie, R.A.; Wilson, Shelagh; Sarau, Henry M.

doi:10.1038/22313

Cited by 475 publications

(299 citation statements)

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“…Two MCH receptor subtypes have been identified, the MCH1 receptor (MCH1-R, originally named SLC-1) and the MCH2-R, but only the MCH1-R is found in rodents [6,21,28]. The MCH1-R is expressed in numerous areas of the brain [3], and mediates the orexigenic actions of MCH in rodents.…”

Section: Introductionmentioning

confidence: 99%

Effects of MCH and a MCH1-receptor antagonist on (palatable) food and water intake

Morens

Nørregaard²,

Receveur³

et al. 2005

Brain Research

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Receveur, J-M. (2005). Effects of MCH and a MCH1-receptor antagonist on (palatable) food and water intake. Brain-research, 1062(1-2), 32-38. DOI: 10.1016DOI: 10. /j.brainres.2005 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. AbstractMelanin concentrating hormone (MCH) is a regulator of ingestive behavior, but several issues regarding its effects on specific components of ingestive behavior remain to be elucidated. Therefore, we injected, in the 3rd ventricle of male Wistar rats, saline, MCH (5 Ag), MCH (5 Ag) together with a MCH1-R antagonist (A, 10 Ag) and the antagonist alone (A, 10 Ag). Our results show that (1) central administration of MCH stimulates food intake (lab chow and medium high fat diet) and this can be blocked by a MCH1-R antagonist; (2) the MCH-induced increase in food intake is mediated through increased meal number, meal duration and meal size; (3) the MCH1-R antagonist is able to significantly reduce the intake of a highly palatable food (condensed sweet milk) and is more effective in blocking MCH-induced food intake when rats are fed a palatable medium high fat food; and (4) MCH stimulated water intake independently from and disproportionately to food intake. In conclusion, our results point to an involvement of endogenous MCH in the enhanced intake of palatable food. Furthermore, they confirm that MCH stimulates not only food intake but also water intake. D

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Section: Introductionmentioning

confidence: 99%

Effects of MCH and a MCH1-receptor antagonist on (palatable) food and water intake

Morens

Nørregaard²,

Receveur³

et al. 2005

Brain Research

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“…Pmch mRNA is upregulated after fasting or leptin deficiency (32, 50); third ventricle intracerebroventricular injections of MCH increase food intake and body weight (11,19,22,28,53); Pmch knockout mice are lean due to a decreased food intake and an increased metabolic rate (31, 59); and overexpression of MCH causes obesity (35). In rodents MCH binds to melanin-concentrating hormone receptor 1 (MCH1R), a G protein-coupled receptor expressed throughout the brain (7,33,55,56). MCH1R is particularly enriched in the nucleus accumbens shell (33,47,56), thus forming a potential hypothalamiclimbic circuit modulating the hedonic, or rewarding, aspects of feeding (16, 47).…”

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Pmchexpression during early development is critical for normal energy homeostasis

Mul

Berg³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Mul JD, Yi CX, van den Berg SAA, Ruiter M, Toonen PW, van der Elst MCJ, Voshol PJ, Ellenbroek BA, Kalsbeek A, la Fleur SE, Cuppen E. Pmch expression during early development is critical for normal energy homeostasis. Am J Physiol Endocrinol Metab 298: E477-E488, 2010. First published November 24, 2009 doi:10.1152/ajpendo.00154.2009.-Postnatal development and puberty are times of strong physical maturation and require large quantities of energy. The hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates nutrient intake and energy homeostasis, but the underlying mechanisms are not completely understood. Here we use a novel rat knockout model in which the MCH precursor Pmch has been inactivated to study the effects of loss of MCH on energy regulation in more detail. Pmch Ϫ/Ϫ rats are lean, hypophagic, osteoporotic, and although endocrine parameters were changed in pmch Ϫ/Ϫ rats, endocrine dynamics were normal, indicating an adaptation to new homeostatic levels rather than disturbed metabolic mechanisms. Detailed body weight growth and feeding behavior analysis revealed that Pmch expression is particularly important during early rat development and puberty, i.e., the first 8 postnatal weeks. Loss of Pmch resulted in a 20% lower set point for body weight that was determined solely during this period and remained unchanged during adulthood. Although the final body weight is diet dependent, the Pmch-deficiency effect was similar for all diets tested in this study. Loss of Pmch affected energy expenditure in both young and adult rats, although these effects seem secondary to the observed hypophagia. Our findings show an important role for Pmch in energy homeostasis determination during early development and indicate that the MCH receptor 1 system is a plausible target for childhood obesity treatment, currently a major health issue in first world countries. melanin-concentrating hormone; hypothalamus; childhood obesity; rat knockout model CHILDHOOD OBESITY IS NOW WIDELY recognized as a severe public health issue (43). Treatment with drugs aimed at neural systems involved in the determination of the energy balance could potentially result in a lower energy balance during puberty as well as later in adulthood. Therefore, neuropeptides involved in body weight regulation during early development and puberty are attractive targets for anti-childhood obesity drugs.The neuronal metabolic systems in humans and primates develop prenatally, while in rodents these systems develop during the first 3 postnatal weeks (5, 21). This results in the activation and optimization of neuronal systems during early rodent development. A second important metabolic period is puberty, a period of major growth, hormonal changes, and sexual maturation. In the rat, puberty is characterized by different responses of young-adolescent [postnatal day (PND) 40] and young-adult (PND 60) male rats to environmental cues like stress and cold (17,18). In addition to these age-dependent behavioral differences, the amount of food consumed durin...

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“…In vivo results with two of these antagonists indicate efficacy in several animal models of body weight regulation and feeding behavior (21). At least when expressed in heterologous cell lines, the MCH-1 receptor is able to regulate signal transduction through both G i -and G q -coupled pathways (2)(3)(4)(5)(6). Despite this, little is known about the regulation of this receptor.…”

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confidence: 99%

“…The orexigenic cyclic 19 amino acid peptide melanin-concentrating hormone (MCH) 1 (1) is the natural ligand for the G protein-coupled receptor (GPCR) originally designated SLC-1 (also called GPR24 in some studies) because of its relatedness to the receptors for somatostatin (2)(3)(4)(5)(6). This polypeptide was thus renamed the MCH-1 receptor.…”

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confidence: 99%

Periplakin Interferes with G Protein Activation by the Melanin-concentrating Hormone Receptor-1 by Binding to the Proximal Segment of the Receptor C-terminal Tail

Murdoch

Feng

Bächner

et al. 2005

Journal of Biological Chemistry

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The orexigenic cyclic 19 amino acid peptide melanin-concentrating hormone (MCH) 1 (1) is the natural ligand for the G protein-coupled receptor (GPCR) originally designated SLC-1 (also called GPR24 in some studies) because of its relatedness to the receptors for somatostatin (2-6). This polypeptide was thus renamed the MCH-1 receptor. A second MCH receptor (MCH-2 receptor) has also been identified (7-11), and there is some evidence of an MCH binding site that is distinct from these two receptors (12).Even before identification of the MCH receptors a clear role for MCH in feeding and energy balance and homeostasis had been established (1). A solid body of genetic and pharmacological evidence now supports a role for MCH and the MCH-1 receptor in the modulation of food intake and energy expenditure. Key data derive from the genetic ablation of both MCH (13) and the MCH-1 receptor (14, 15) in mice. These alterations produced animals that were both lean and resistant to dietinduced obesity. Mice lacking the MCH-1 receptor have been reported to be hyperphagic (14, 15) but to be both hyperactive and to have altered metabolism, and this may explain the apparent paradox of being resistant to obesity but eating more. Studies also indicate that acute and chronic administration of MCH enhances food intake and body weight (16) and that overexpression of MCH in transgenic mice leads to obesity and insulin resistance (17). A role for the MCH-2 receptor in these effects is unlikely because genetic evidence indicates that mice do not express a functional form of this receptor (18). Furthermore, the distribution of the MCH-1 receptor in the central nervous system (19) also suggests that antagonists at the MCH-1 receptor might provide a treatment for obesity (for review, see Refs. 20 and 21). High throughput screening efforts have led to the identification of small molecule MCH-1 receptor antagonists with diverse structural features and drug-like properties. In vivo results with two of these antagonists indicate efficacy in several animal models of body weight regulation and feeding behavior (21). At least when expressed in

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Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1

Cited by 475 publications

References 23 publications

Effects of MCH and a MCH1-receptor antagonist on (palatable) food and water intake

Effects of MCH and a MCH1-receptor antagonist on (palatable) food and water intake

Pmchexpression during early development is critical for normal energy homeostasis

Periplakin Interferes with G Protein Activation by the Melanin-concentrating Hormone Receptor-1 by Binding to the Proximal Segment of the Receptor C-terminal Tail

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