Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The melanocortin-4 receptor (MC4R) has a vital role in the control of energy balance and the genetic basis of obesity. A polymorphism, which results in the replacement of aspartic acid with asparagine at position 298 of the porcine MC4R gene, within the seventh transmembrane domain, has previously been described. In the current study, allele frequencies for this Asp298Asn polymorphism were investigated in lines of Large White pigs which had been divergently selected for seven generations based on lean food conversion (LFC), lean growth with ad libitum feeding (LGA), lean growth with restricted feeding (LGS) and daily feed intake (DFI). The association of the Asp298Asn polymorphism with performance traits in these lines was assessed. The frequency of Asp298 was higher (P < 0.001) in the LFC high line (0.48) than the low line (0.00), while the frequency of Asn298 was higher (P < 0.01) in the LGA high line (0.22) than the low line (0.04). When analysed across all lines, the Asp298Asn polymorphism was significantly associated with ultrasonic backfat depth, average daily gain and daily feed intake (P < 0.05). Asp298 homozygous animals had mean values of 13.3 mm, 733 g and 1933 g for backfat, average daily gain and daily feed intake respectively, compared with 14.7 mm, 805 g and 2098 g for Asn298 homozygotes. Therefore, the data support a role for the MC4R Asp298Asn polymorphism in the genetic basis of economically important traits in Large White pigs.
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PMID:A melanocortin-4 receptor (MC4R) polymorphism is associated with performance traits in divergently selected Large White pig populations. 1537 42

The melanocortin-4 receptor (MC4R), a centrally expressed G protein-coupled receptor (GPCR), is essential for the maintenance of long-term energy balance in humans. Mutations in MC4R are the most common genetic cause of obesity. Since activation of this receptor leads to a decrease in food intake, MC4R is also a major therapeutic target for the treatment of obesity. Control of MC4R activity in vivo is modulated by the opposing effects of the anorexigenic agonist alpha-melanocyte-stimulating hormone (alpha-MSH) and the orexigenic antagonist agouti-related protein (AGRP). In addition, experiments in vitro have demonstrated that the human MC4R has an intrinsic constitutive activity on which AGRP also acts as an inverse agonist. The physiological role of this constitutive activity in the control of energy balance as well as the domain of the protein implicated in its maintenance are unknown. By systematically studying functional defects in naturally occurring MC4R mutations from obese patients, we defined a cluster of N-terminal mutations that selectively impair the constitutive activity of the receptor. Further characterization of this domain demonstrated that it functions as a tethered intramolecular ligand that maintains the constitutive activity of MC4R and may provide novel avenues for the design of drugs targeting this receptor. Our results also suggest that the tonic satiety signal provided by the constitutive activity of MC4R may be required for maintaining long-term energy homeostasis in humans.
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PMID:Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans. 1548 63

The identification of a highly efficacious anti-obesity agent remains an illusive goal. While many avenues of investigation have been pursued, none of the existing compounds claim much more than a 10% reduction in weight in humans (over a one year period with diet and exercise). Nonetheless, the potential reward for fulfilling this unmet medical need has kept interest levels high in the research community. The recent explosion of genetic information has identified numerous potential targets for drug screening. The melanocortin-4 receptor is a promising target and is currently being intensively investigated by many companies and academic research groups.
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PMID:Melanocortin-4 receptor agonists for the treatment of obesity. 1553 27

The melanocortin pathway consists of endogenous agonists, antagonists, G-protein coupled receptors (GPCRs), and auxiliary proteins. This pathway has been identified to participate physiologically in numerous biological pathways including energy homeostasis, pigmentation, sexual function, inflammation, cardiovascular function, adrenal function, sebaceous gland lipid production, just to list a few. During this past decade, a clear link between the melanocortin-4 receptor (MC4R) and obesity, in both mice and humans via the regulation of food intake and energy homeostasis, has made this pathway the target of many academic and industrial research endeavors in attempts to develop potent and selective MC4R small molecules as anti-obesity therapeutic agents. Herein, we attempt to summarize the known proteins that constitute the melanocortin system and discuss advances in peptide and non-peptide drug discovery.
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PMID:Progress in the development of melanocortin receptor selective ligands. 1557 46

The melanocortin system is involved in hypothalamic regulation of energy homeostasis. The melanocortin-4 receptor (MC4R) has been linked to both obesity and reproductive dysfunction. Deletion of the MC4R from the mouse genome has resulted in phenotypes including adult onset obesity, hyperphagia, and difficulty in reproducing when homozygote parents are bred. Additionally, polymorphisms of the human MC4R have been identified in morbidly obese children and adults. Herein, we have identified that voluntary exercise, provided via the presence of a running wheel, impedes the monogenetic obesity (at 20 weeks of age running wheel housed body weight=31+/-1.8 g versus conventionally housed body weight=41+/-2.3 g, a 25% decrease in body weight p<0.01), hyperphagia (average cumulative food intake is not statistically different than wild type mice housed in running wheel cages), and reproductive dysfunction phenotypes associated with the MC4R knockout mice housed by conventional means. These data demonstrate the novel finding that voluntary exercise at a young age may hinder genetically induced obesity.
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PMID:Voluntary exercise delays monogenetic obesity and overcomes reproductive dysfunction of the melanocortin-4 receptor knockout mouse. 1559 47

The agouti-related protein (AGRP) is an endogenous antagonist of the centrally expressed melanocortin receptors. The melanocortin-4 receptor (MC4R) is involved in energy homeostasis, food intake, sexual function, and obesity. The endogenous hAGRP protein is 132 amino acids in length, possesses five disulfide bridges at the C-terminus of the molecule, and is expressed in the hypothalamus of the brain. We have previously reported that a monocyclic hAGRP(103-122) peptide is an antagonist at the melanocortin receptors expressed in the brain. Stereochemical inversion from the endogenous l- to d-isomers of single or multiple amino acid modifications in this monocyclic truncated hAGRP sequence resulted in molecules that are converted from melanocortin receptor antagonists into melanocortin receptor agonists. The Asp-Pro-Ala-Ala-Thr-Ala-Tyr-cyclo[Cys-Arg-DPhe-DPhe-Asn-Ala-Phe-Cys]-Tyr-Ala-Arg-Lys-Leu peptide resulted in a 60 nM melanocortin-1 receptor agonist that is 100-fold selective versus the mMC4R, 1000-fold selective versus the mMC3R, and ca. 180-fold selective versus the mMC5R. In attempts to identify putative ligand-receptor interactions that may be participating in the agonist induced stimulation of the MC4R, selected ligands were docked into a homology molecular model of the mMC4R. These modeling studies have putatively identified hAGRP ligand DArg111-mMC4RAsn115 (TM3) and the hAGRP DPhe113-mMC4RPhe176 (TM4) interactions as important for agonist activity.
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PMID:Stereochemical studies of the monocyclic agouti-related protein (103-122) Arg-Phe-Phe residues: conversion of a melanocortin-4 receptor antagonist into an agonist and results in the discovery of a potent and selective melanocortin-1 agonist. 1561 19

Mutations of the melanocortin-4 receptor (MC4R) are associated with hyperphagia, obesity, and accelerated longitudinal growth in pig, mice and human. However, little is known about the functions of this gene in chicken. To map the MC4R gene in Chicken chromosome, we used a 6000 rads chicken-hamster radiation hybrid panel (ChikenRH6). PCR of samples from the ChikenRH6 revealed the location of the MC4R gene to be nearby markers MCW0062, BCL2 and OVY on chromosome 2q12. Five markers were placed into a single linkage group based on two-point analysis with a LOD score of greater than 5. At the same time, the MC4R gene was selected as marker to compare DNA sequence between chicken and human chromosome. The result shows there are the same homologous regions between chicken chromosome 2 (GGA2) and human chromosome 18 (HSA18), and we found that the genes BCL2 and obesity are located in the near regions of MC4R on human chromosome 18. So we can reduce that the chicken MC4R gene maybe there are the same functions with the human MC4R gene. Overall, this work reveals widespread chromosome rearrangements of MC4R between chicken and human genomes, and mappings the chicken MC4R gene on 2q12 by a RH panel.
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PMID:[Chromosomal mapping of chicken MC4R using a radiation hybrid panel and the comparative analysis of the gene homologous regions between chicken and human chromosome]. 1563 40

The melanocortin pathway consists of endogenous agonists, antagonists, G-protein coupled receptors, and ancillary proteins that mediate the function of the endogenous antagonists. The melanocortin-4 receptor (MC4R) is involved in the regulation of obesity and the melanocortin-2 receptor (MC2R) is involved in the regulation of steroidogenesis. Herein, we present the effects of voluntary exercise on the MC4R knockout mice in terms of bypassing the morbid obesity and hyperphagia phenotypes associated with this genetic obesity model. Additionally, a systematic truncation study of the adrenocorticotropin hormone (ACTH 1-24) has been performed and characterized at the cloned MC2R.
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PMID:The melanocortin pathway: effects of voluntary exercise on the melanocortin-4 receptor knockout mice and ACTH(1-24) ligand structure activity relationships at the melanocortin-2 receptor. 1566 96

To evaluate whether MTII, a melanocortin receptor 3/4 agonist, is working in hypophagic and hypothermogenic obese model, we measured food intake, body weight, oxygen consumption, and fat mass following intracerebroventricular (i.c.v.) infusion of MTII in monosodium glutamate (MSG)-induced obese rats. MTII, or artificial cerebrospinal fluid (aCSF), was infused into i.c.v. with an osmotic minipump for 1 week. MSG-obese rats were induced by neonatal injection of MSG. Five-month-old MSG rats were characterized by hypophagia, lower oxygen consumption, hyperleptinemia, and obesity compared to age-matched control rats. The infusion of MTII decreased their food intake, visceral fat, and body weight in MSG-obese rats compared with aCSF-infused rats. The oxygen consumption was increased by MTII treatment in MSG-obese rats compared with aCSF as well as pair fed (PF) rats. Interestingly, these leptin-like effects of MTII were greater in MSG-obese rats than in controls, which might be related to the increased expression of melanocortin receptor 4 (MC4R) in the hypothalamus of MSG-obese rats. Our results suggested that both anorexic and thermogenic mechanisms were activated by MTII in the MSG-obese rats and contributed to the decrease in body weight and fat mass. Moreover, there was a sensitization to MTII caused by upregulation of the melanocortin receptor in the MSG-obese rats.
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PMID:Leptin-like effects of MTII are augmented in MSG-obese rats. 1568 Apr 71

The hypothesis that the interaction of agouti-related protein (AGRP) and the melanocortin-4 receptor (MC4R) modulates feeding behavior in humans has stimulated the synthesis of conformationally constrained peptides, peptoids and small molecules in efforts to identify novel compounds that can potentially be used in the clinical treatment of obesity and related eating disorders. In addition, the availability of a high-resolution NMR structure for the MC4R-binding domain of AGRP, and studies employing site-specific murine MC4R mutants have identified key intermolecular AGRP/MC4R interactions. It is therefore surprising that only one, relatively unsophisticated, computer-based study has been reported to obtain a model for the AGRP/mMC4R complex. In this review we outline computer-based strategies for building models of the AGRP/mMC4R and related peptide/mMC4R complexes, and illustrate the strengths and limitations of sophisticated molecular dynamics methods in obtaining information that might form the basis of rational efforts to discover novel drugs that selectively interact with melanocortin receptors.
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PMID:Computer-based strategy for modeling the interaction of AGRP and related peptide ligands with the AGRP-binding site of murine melanocortin receptors. 1572 30


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