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T V Novoselova, D Jackson, D C Campbell, A J L Clark and L F Chan

expression in the hypothalamus. Melanocortin 2 receptor is a critical component of the HPA axis Melanocortin receptors (MCRs) are a subfamily of seven-transmembrane (TM)-domain G-protein-coupled receptors (GPCRs) that mediate signalling of hormones derived

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Dawid Szczepankiewicz, Ewa Pruszynska-Oszmalek, Przemyslaw Kaczmarek, Marek Skrzypski, Karolina Andralojc, Tatiana Wojciechowicz, Maciej Sassek and Krzysztof W Nowak

al . 2002 , Pritchard et al . 2002 ). In 1997, a protein with a high homology to agouti protein was identified and called agouti-related protein (AGRP). This protein is an antagonist to melanocortin receptors, mainly MC3R and MC4R ( Ollmann et al

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Stephen C Harmer, David J Pepper, Katy Cooke, Hugh P J Bennett and Andrew B Bicknell

, skeletal muscle and macrophage cells ( Small et al . 1989 , 1991 , Langfort et al . 1999 , Mulder et al . 1999 ). In 1983, before the identification of the five members of the melanocortin receptor (MC-R) family, Pedersen & Brownie used ligand binding

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T V Novoselova, R Larder, D Rimmington, C Lelliott, E H Wynn, R J Gorrigan, P H Tate, L Guasti, The Sanger Mouse Genetics Project, S O’Rahilly, A J L Clark, D W Logan, A P Coll and L F Chan

Introduction Melanocortin receptor accessory protein (MRAP) and its paralogue MRAP2 are a recently identified class of small, single-pass transmembrane domain accessory proteins ( Chan et al . 2009 , Novoselova et al . 2013 ). Both MRAP and

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Malathi Srinivasan, Paul Mitrani, Gigani Sadhanandan, Catherine Dodds, Suhad Shbeir-ElDika, Shanthie Thamotharan, Hussam Ghanim, Paresh Dandona, Sherin U Devaskar and Mulchand S Patel

-melanocortin-stimulating hormone (α-MSH), one of the products of the pro-opiomelanocortin (POMC) gene, is the primary neuropeptide responsible for the regulation of food intake by the central melanocortin system and functions by binding to the melanocortin receptors (MCR), the

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Anshu Gupta, Malathi Srinivasan, Supaporn Thamadilok and Mulchand S Patel

NPY were increased by 1.77-fold ( P ≤0.05) and 3.41-fold ( P ≤0.05 respectively ( Fig. 4 ) and POMC and melanocortin receptor 4 (MC4R) levels were elevated by 4.29-fold ( P ≤0.05) and 3.14-fold ( P ≤0.05) respectively in the FHF hypothalami compared

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L Jonsson, JO Skarphedinsson, GV Skuladottir, H Watanobe and HB Schioth

The central melanocortin system is involved in the regulation of food intake and body weight. In this study, we investigated the effect of a 4-week intracerebroventricular infusion of the melanocortin receptor agonist MT-II and the selective melanocortin-4 receptor antagonist HS024 on food intake and body weight homeostasis. The MT-II-treated rats ate less and lost considerably more weight than the control rats during the first week of treatment. During the second and third week, they gained weight and, by the end of the treatment period, the weight gain was similar to that of the control rats. The HS024 treatment caused hyperphagia and development of obesity during the entire period. Extensive accumulations of fat and a sixfold increase in leptin levels were observed in the HS024-treated rats, as compared with controls, after the 4-week period. Food conversion ratio, defined as body weight increase relative to weight of ingested food, was clearly increased in the HS024-treated rats, while it was lowered in the MT-II-treated rats compared with controls. The effect on food conversion ratio was transient, being greatest for both experimental groups during the first week and it was then attenuated to reach the level of controls at the end of the study. The results suggest that long-term injection of exogenous melanocortin receptor active substances may have an important transient effect on food conversion.

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G HUNT and A J THODY

Abstract

In animals, the coat-darkening effects of α-melanocyte stimulating hormone (α-MSH) are opposed by agouti protein. Although agouti protein has been shown to be a competitive antagonist of the melanocyte-associated MC-1 melanocortin receptor, the possibility that agouti protein can affect melanogenesis independently of its ability to antagonise melanocortin activity cannot be excluded. This study demonstrates that murine agouti protein causes both a time- and concentration-dependent suppression of melanogenesis in B16 F1 murine melanoma cells. In addition, human agouti protein decreases melanogenesis in cultured human epidermal melanocytes. However, agouti protein has little effect on the ability of α-MSH to stimulate melanogenesis. These observations raise fundamental questions about the mode of action of agouti protein in regulating melanogenesis.

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LA Noon, JM Franklin, PJ King, NJ Goulding, L Hunyady and AJ Clark

Difficulty in expressing the adrenocorticotrophin (ACTH) receptor (melanocortin 2 receptor; MC2R) after transfection of various MC2R expression vectors has been experienced by many researchers. Reproducible evidence for expression has been obtained only in the Y6/OS3 corticoadrenal cell lines or in cells expressing endogenous melanocortin receptors. In order to determine the cause of this failure of expression we have undertaken the following studies. An MC2R expression plasmid was constructed in which the green fluorescent protein (GFP) coding region had been added to the C-terminus of the mature protein. Transfection of this plasmid into Y6 cells with a cAMP-responsive reporter plasmid demonstrated normal function of this receptor. Imaging of CHO cells expressing MC2R-GFP revealed perinuclear expression, although a cholecystokinin receptor (CCKR)-GFP construct was efficiently expressed at the cell surface. Y6 cells, in contrast, showed cell surface fluorescence after transfection with MC2R-GFP. Several other cell types showed a similar pattern of GFP distribution characteristic of retention in the endoplasmic reticulum. Counterstaining with an anti-KDEL antibody confirmed this location. Co-expression of the MC2R and the CCKR-GFP did not impair CCKR trafficking to the cell surface, implying a receptor-specific impairment to trafficking in the CHO cell which was absent in the Y6 cell.

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LE Pritchard, AV Turnbull and A White

Bioactive peptides derived from the prohormone, pro-opiomelanocortin (POMC), are generated in neurons of the hypothalamus and act as endogenous ligands for the melanocortin-4 receptor (MC4R), a key molecule underlying appetite control and energy homeostasis. It is therefore important to understand many aspects of POMC gene regulation in the brain, as pharmacological manipulation of POMC expression/processing could be a potential strategy to combat obesity. Most studies that have analysed POMC gene expression in the hypothalamus have focused on gene transcription experiments. Ultimately, however, factors that regulate post-translational processing and secretion of peptides will have most bearing on melanocortin signalling. This article focuses on (a) current evidence that POMC is involved in obesity, (b) how POMC transcription is regulated in the hypothalamus, (c) the mechanism by which proteolytic processing of POMC is controlled in the hypothalamus and what peptides are produced and (d) which POMC-derived peptides are the most potent ligands at the melanocortin receptor in vitro and in vivo. It seems that post-translational cleavage of POMC in the hypothalamus may be regulated with respect to energy requirement. We predict that further research into hypothalamic POMC processing, and the proteolytic enzymes involved, may yield important new clues on how flux through the MC4R pathway is regulated.