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

To assess the contribution of potential central nervous system pathways implicated in the control of appetite regulation and energy metabolism, it is essential to first identify appropriate animal models. Melanin-concentrating hormone (MCH), a conserved cyclic neuropeptide implicated in the modulation of food intake, has been shown to bind and activate two G-protein-coupled receptors, called GPR24 and MCHR2, expressed in human brain and other tissues. Here we show that several non-human species (rat, mouse, hamster, guinea pig, and rabbit) do not have functional MCHR2 receptors, or encode a nonfunctional MCHR2 pseudogene while retaining GPR24 expression. We identified three species for further evaluation that express both MCH receptor subtypes. We cloned and functionally characterized dog, ferret, and rhesus GPR24 and MCHR2 in mammalian cells and studied their brain distribution patterns by in situ hybridization. The homology, expression profile, and functional similarity of the receptors in the dog, ferret, and rhesus to that of human support the potential use of these species as preclinical animal models in the development of therapeutic agents for obesity or other MCH-mediated disorders.
 ...
PMID:Melanin-concentrating hormone receptor subtypes 1 and 2: species-specific gene expression. 1203 92

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide of nineteen amino acids in mammals. Its involvement in the feeding behaviour has been well established during the last few years. A first receptor subtype, now termed MCHIR, was discovered in 1999, following the desorphanisation of the SLCI orphan receptor, using either reverse pharmacology or systematic screening of agonist candidates. A second MCH receptor, MCH2R, has been discovered recently, by several groups working on data mining of genomic banks. The molecular pharmacology of these two receptors is only described on the basis of the action of peptides derived from MCH. The present review tentatively summarizes the knowledge on these two receptors and presents the first attempts to discover new classes of antagonists that might have major roles in the control of obesity and feeding behaviour.
 ...
PMID:Melanin-concentrating hormone and its receptors: state of the art. 1205 44

The hypothalamic neuropeptide melanin-concentrating hormone (MCH) has been implicated in a variety of physiological functions including the regulation of feeding and energy homeostasis. Two MCH receptors (MCHR1 and MCHR2) have been identified so far. To decipher the functional role of the MCH receptors, we have generated and phenotypically characterized mice rendered deficient in MCHR1 expression by homologous recombination. Inactivation of MCHR1 results in mice (MCHR1-/-) that are resistant to diet-induced obesity. With a high-fat diet, body fat mass is significantly lower in both male (4.7 +/- 0.6 g vs. 9.6 +/- 1.2 g) and female (3.9 +/- 0.2 vs. 5.8 +/- 0.5 g) MCHR1-/- mice than that of the wild-type control (P < 0.01), but the lean mass remains constant. When normalized to body weight, female mice are hyperphagic, and male mice are hyperphagic and hypermetabolic, compared with wild-type mice. Consistent with the lower fat mass, both leptin and insulin levels are significantly lower in male MCHR1-/- mice than in the wild-type controls. Our data firmly establish MCHR1 as a mediator of MCH effects on energy homeostasis and suggest that inactivation of MCHR1 alone is capable to counterbalance obesity induced by a high-fat diet.
 ...
PMID:Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. 1207 76

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide, which centrally regulates food intake and stress. MCH induces food intake in rodents and, more generally, acts as an anabolic signal in energy regulation. In addition, MCH seems to be activatory on the stress axis. Two receptors for MCH in humans have very recently been characterised, namely, MCH-R1 and MCH-R2. MCH-R1 has received considerable attention, as potent and selective antagonists acting at that receptor display anxiolytic, antidepressant and/or anorectic properties. Feeding and affective disorders are both debilitating conditions that have become serious worldwide health threats. There are as yet no efficient and/or safe cures that could contain the near-pandemia phenomen of both diseases. Thus, the discovery of MCH-R1 antagonists may lead to the development of valuable drugs to treat obesity, anxiety and depressive syndromes. In addition, it opens wide avenues to probe additional functions of the peptide, both in the brain and in the peripheral nervous system.
 ...
PMID:Melanin-concentrating hormone functions in the nervous system: food intake and stress. 1288 69

We conducted a genome-wide search for childhood obesity-associated traits, including BMI >/==" BORDER="0">95th percentile (PCT95), 97th percentile (PCT97), and 99th percentile (PCT99) as well as age of adiposity rebound (AAR), which corresponds to the beginning of the second rise in childhood adiposity. A set of 431 microsatellite markers was genotyped in 506 subjects from 115 multiplex French Caucasian families, with at least one child with a BMI >/==" BORDER="0">95th percentile. Among these 115 pedigrees, 97 had at least two sibs with a BMI >/==" BORDER="0">95th percentile. Fine-mapping was performed in the seven most positive loci. Nonparametric multipoint analyses revealed six regions of significant or suggestive linkage on chromosomes 2q33.2-q36.3, 6q22.31-q23.2, and 17p13 for PCT95, PCT97, or PCT99 and 15q12-q15.1, 16q22.1-q24.1, and 19p13.3-p13.11 for AAR. The strongest evidence of linkage was detected on chromosome 6q22.31 for PCT97 (maximum likelihood score: 4.06) at the marker D6S287. This logarithm of odds score meets genome-wide significance tested through simulation (empirical genome-wide P = 0.01 [0.0027-0.0254]). Six independent ge-nome scans in adults have reported quantitative trait loci on 6q linked to energy or glucose homeostasis-associated phenotypes. Possible candidate genes in this region include SIM1, MCHR2, and PC-1.
 ...
PMID:A genome-wide scan for childhood obesity-associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2. 1498 67

Melanin-concentrating hormone (MCH), a neuropeptide highly expressed in the lateral hypothalamus, has an important role in the regulation of energy balance and body weight in rodents. We examined whether mutations in the two known MCH receptors might be associated with obesity-related phenotypes in humans. Among 106 subjects with severe early onset obesity and a history of hyperphagia, we found two missense variants in MCHR1: Y181H and R248Q. Neither of these was found in 192 normal weight controls. R248Q cosegregated with obesity across two generations; family data were unavailable for Y181H. When expressed in HEK293 cells, R248Q showed no evidence of constitutive activation or ligand hypersensitivity for extracellular signal-regulated kinase phosphorylation. In addition, R248Q showed no enhanced suppression of cAMP generation. Two common single-nucleotide polymorphisms were found to be in linkage disequilibrium: g.-114A>G and c.39C>T. No association between either of these single-nucleotide polymorphisms and obesity-related phenotypes was found among a population cohort of 541 whites. Only two rare noncoding variants were found in MCHR2. In conclusion, mutations in the MCH receptors are not commonly found in humans with severe early onset obesity. Clarification of the relationship of these variants to obesity must await study in other populations and/or in genetically modified mice.
 ...
PMID:Melanin-concentrating hormone receptor mutations and human obesity: functional analysis. 1516 93

Melanin-concentrating hormone (MCH) is a cyclic peptide that mediates its effects by the activation of two G-protein-coupled seven transmembrane receptors (MCHR1 and MCHR2) in humans. In contrast to its primary role in regulating skin color in fish, MCH has evolved in mammals to regulate dynamic physiological functions, from food intake and energy expenditure to behavior and emotion. Chronic infusion or transgenic expression of MCH stimulates feeding and increases adipocity, whereas targeted deletion of MCH or its receptor (MCHR1) leads to resistance to diet-induced obesity with increased energy expenditure and thermogenesis. The involvement of MCH in energy homeostasis and in brain activity has also been validated in mice treated with non-peptide antagonists, suggesting that blockade of MCHR1 could provide a viable approach for treatment of obesity and certain neurological disorders. This review focuses on emerging roles of MCH in regulating central and peripheral mechanisms.
 ...
PMID:Beyond skin color: emerging roles of melanin-concentrating hormone in energy homeostasis and other physiological functions. 1547 27

Melanin-concentrating hormone (MCH) is a critical hypothalamic anabolic neuropeptide, with key central and peripheral actions on energy balance regulation. The actions of MCH are, so far, known to be transduced through two seven-transmembrane-like receptor paralogues, named MCH1R and MCH2R. MCH2R is not functional in rodents. MCH1R is an important receptor involved in mediating feeding behaviour modulation by MCH in rodents. Pharmacological antagonism at MCH1R in rodents diminishes food intake and results in significant and sustained weight loss in fat tissues, particularly in obese animals. Additionally, MCH1R antagonists have been shown to have anxiolytic and antidepressant properties. The purpose of this review is to highlight the recent numerous pieces of evidence showing that pharmacological blockade at MCH1R could be a potential treatment for obesity and its related metabolic syndrome, as well as for various psychiatric disorders.
 ...
PMID:Further insights into the neurobiology of melanin-concentrating hormone in energy and mood balances. 1654 71

Most patients with an interstitial deletion of 6q16 have Prader-Willi-like phenotype, featuring obesity, hypotonia, short hands and feet, and developmental delay. In all reported studies, the chromosome rearrangement was detected by karyotype analysis, which provides an overview of the entire genome but has limited resolution. Here we describe a detailed clinical presentation of five patients, two of whom were previously reported, with overlapping interstitial 6q16 deletions and Prader-Willi-like phenotype. Our patients share the following main features with previously reported cases: global developmental delay, hypotonia, obesity, hyperphagia, and eye/vision anomalies. All rearrangement breakpoints have been accurately defined through array-CGH at about 100 Kb resolution. We were able to narrow the shortest region of deletion overlap for the presumed gene(s) involved in the Prader-Willi-like syndrome to 4.1 Mb located at 6q16.1q16.2. Our results support the evidence that haploinsufficiency of the SIM1 gene is responsible for obesity in these patients. A possible involvement of the GRIK2 gene in autistic-like behaviour, of POPDC3 in heart development, and of MCHR2 in the control of feeding behaviour and energy metabolism is also hypothesized.
 ...
PMID:Detailed phenotype-genotype study in five patients with chromosome 6q16 deletion: narrowing the critical region for Prader-Willi-like phenotype. 1864 97

The melanin-concentrating hormone (MCH) is a cyclic peptide exerting its actions through two G-protein-coupled receptors, MCHR1 and MCHR2. MCH is implicated in the regulation of different physiological functions, including energy homeostasis and mood that is supported by the distribution of MCH and MCHR1 in the hypothalamus as well as corticolimbic structures. Genetic manipulation of MCH and MCHR1 results in a lean phenotype with increased resting energy expenditure as well as anxiolytic and antidepressant phenotypes. Similar observations have been demonstrated pharmacologically using different classes of selective MCHR1 antagonists. Here, we summarize the reported genetic and pharmacological evidence for the role played by the MCH system in the regulation of both energy homeostasis and mood disorders. We also comment on the utility of small-molecule MCHR1 antagonists for the treatment of obesity and affective disorders compared to existing therapies and provide a critical overview of the potential risks.
 ...
PMID:The role of melanin-concentrating hormone in energy homeostasis and mood disorders. 1941 62


1 2 Next >>