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)

Even among young, healthy individuals, there is more than a 10-fold variation in insulin sensitivity; however, taken in combination, all the known modifiers of insulin sensitivity - including obesity and a variety of environmental factors - explain less than one third of this variation. It is possible that genetic factors could account for the bulk of the variance observed, and hence play a major role in the development of impaired insulin sensitivity, ie insulin resistance. From the genetic point of view, insulin resistance is thought to be due to the inheritance of a number of mutations in a variety of genes. Three complementary approaches have been applied in the search for mutations: mutational analysis of candidate genes; linkage analysis of candidate genes or chromosomal regions for insulin resistance in familial type 2 diabetes; and random genome mapping with quantitative trait loci (QTL) analysis. Mutational analysis of the insulin signalling cascade has identified a glycine-arginine (Gly-Arg) substitution at codon 972 of the insulin receptor substrate-1 (IRS-1) gene with a carrier prevalence of 9% among Caucasians. Expression of this variant in 32-D cells is associated with a significant (20-30%) impairment of insulin-stimulated PI3-kinase activity, as well as reduced binding of IRS-1 to the p85 regulatory subunit of PI3-kinase. Genotype/phenotype studies stratified according to body mass index (BMI) indicate that obese subjects who are heterozygous for the mutant allele have a 50% decrease in insulin sensitivity, compared with wild-type obese subjects. This suggests that there may be an interaction between the mutant allele and obesity, such that, in the presence of obesity, the mutant variant may aggravate the obesity-associated insulin resistance. Mutational analysis has also shown that homozygous carriers of a codon Met 326 Ile mutation in the p85 subunit of phosphatidylinositol-3 (PI3)-kinase (about 2% of the Caucasian population) have lower glucose tolerance, glucose effectiveness. A further Asp to Tyr polymorphism has been identified at codon 905 of the gene encoding the regulatory subunit of glycogen-associated protein phosphatase-1 (PP1G). Individuals who are heterozygous for this polymorphism constitute 18% of the Caucasian population and appear to exhibit both tissue-specific and pathway-specific insulin resistance. It is likely that inherited insulin resistance will eventually prove to be related to subtle mutations in many such genes of the insulin signalling network and the numerous genetic components controlling energy metabolism.
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PMID:Genetics of insulin resistance. 1032 50

The three-dimensional solution structure of antiobesity drug (AOD), a 15-residue, disulfide-bonded, cyclic peptide, cyclo(6,13)-H2N-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe-OH, derived from the C-terminal domain of the human growth hormone (hGH) (residues 177-191) was determined using two-dimensional 1H NMR spectroscopy. AOD stimulates lipolysis and inhibits lipogenesis, in vitro, in rodent, porcine and human adipose tissues. These biological effects suggest that AOD is a potential therapeutic candidate for the treatment of obesity. Conformational studies of AOD were conducted in aqueous solution and in water/dimethylsulfoxide mixtures. In general, spectral quality was superior in the water/ dimethylsulfoxide mixtures. The cyclic region of AOD in water/dimethylsulfoxide adopts type I beta-turns at residues Ser8-Val9-Glu10-Gly11 and Ser12-Cys13-Gly14-Phe15, each preceded by loop-like structures. Comparison of the conformation of this peptide with residues 177-191 in the native hGH protein X-ray crystal structure indicates that the synthetic peptide retains some structural similarity to the intact protein. This study provides evidence that the C-terminal region of hGH is a specific functional domain of the multifunctional hGH protein.
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PMID:The conformational and biological analysis of a cyclic anti-obesity peptide from the C-terminal domain of human growth hormone. 1115 98

Familial genetic studies of type 2 diabetes (T2DM) of different human populations, including the French Caucasians, suggested evidence for linkage of T2DM and human chromosome 20q13, a region where maps the melanocortin 3 receptor gene (MC3R). Likewise, its homologous MC4R in human obesity, MC3R gene is also a good candidate for genetic susceptibility to glucose intolerance and T2DM. We therefore undertook a molecular study to assess the role of genetic variations of this gene in a large cohort of French families with T2DM. In these patients, we identified two missense mutations in the MC3R gene: Val(81)Ile and Lys(6)Thr. These two variants, which were in complete linkage disequilibrium, were also present in nondiabetic controls. Based on association and familial linkage disequilibrium tests results, we found that these MC3R gene-coding variants were not associated with diabetes or obesity. These variants were found, however, marginally associated with insulin and glucose levels during oral glucose tolerance testing in normoglycemic subjects. Overall, the present study provides no evidence for a major role of the MC3R coding mutations underlying the genetic linkages of T2DM and the MC3R gene region on chromosome 20q13 in T2DM families from France and other geographical origins.
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PMID:Naturally occurring mutations in the melanocortin receptor 3 gene are not associated with type 2 diabetes mellitus in French Caucasians. 1139 6

Age-related hypertrophy of adipose tissue has been associated with a significant decrease in the number of angiotensin II receptors. The aim of this study was to investigate the characteristics of angiotensin II receptors in hypertrophic adipose tissue in animal obesity model using rats postnatally treated with monosodium glutamate. Angiotensin II is known to induce hypertrophy in several tissues of the cardiovascular system and might do the same in fat tissue. The expression and binding properties of angiotensin II AT(1) receptors in epididymal fat tissue of adult rats were studied using membrane-binding, RT-PCR, and immunoblotting. The amount of AT(1) receptor mRNA did not differ significantly between obese and control rats. Despite that glutamate-treated rats displayed approximately 4-times more AT(1) receptor immunoreactive protein content in fat tissue cell membranes than the controls did. In contrast, binding experiments showed a significant (40.3 +/- 6.2 %) decrease of (125)I-Sar(1)-Ile(8)-angiotensin II-binding to fat tissue cell membranes in obese rats compared to controls. In conclusion, the present study provides evidence for the low binding properties associated with an accumulation of AT(1) receptor protein in cell membranes of the fat tissue of rats with glutamate-induced obesity. Discrepancies among angiotensin II-binding, AT(1) receptor protein, and AT(1) receptor mRNA levels indicate a possible defect in the receptor protein, which remains to be identified. The results obtained support a role of angiotensin II and AT(1) receptors in the pathogenesis of obesity.
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PMID:Elevated AT1 receptor protein but lower angiotensin II-binding in adipose tissue of rats with monosodium glutamate-induced obesity. 1175 55

Sixteen cases of necrotizing fasciitis were seen at the Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria from 1990 to 2000. Primary craniocervical involvement was recorded in seven patients (five men and two women). The clinical records of five patients were sufficiently detailed to allow us to report their age, aetiology, predisposing illness, clinical features, complications, management regimen and outcome. The patients were aged 30-75 years and in four of them odontogenic infections were the cause of the condition. Hypertension, diabetes mellitus and obesity were the underlying systemic diseases in three cases and the body/angle region of the mandible was the predominant site of the infection on the face. All five cases had involvement of the neck. Mediastinal extension was recorded in three cases. Two patients had complications: one had septicaemia and renal failure and the other developed bone necrosis. Pre-existing ill health, old age, late surgical intervention, and mediastinal and thoracic extension of infection were responsible for the only death. Treatment involved frequent and multiple surgical debridement, aggressive antimicrobial treatment and control of systemic disease. Early recognition, prompt surgical intervention, and aggressive antimicrobial treatment are essential to minimize morbidity and mortality. Rapid progression of infection, financial constraints, delayed referrals from rural clinics and distance to the tertiary hospital caused problems.
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PMID:Craniocervical necrotizing fasciitis in Ile-Ife, Nigeria. 1188 74

Loss-of-function mutations in the human melanocortin-4 receptor (MC4R) are associated with obesity. Previous work has implicated a C-terminal di-isoleucine motif at residues 316/317 in MC4R cell surface targeting. It was therefore of interest to examine function and cell surface expression of an MC4R mutation found in an obese proband in which one of these isoleucines was substituted by threonine (I317T). Single mutant (I316T or I317T) and double mutant (I316T,I317T) forms of MC4R were constructed by oligonucleotide-directed mutagenesis and tested for function and cell surface expression in transfected cells. Function was assessed using assays for agonist, [Nle(4)-d-Phe(7)]alpha-melanocyte-stimulating hormone (NDP-alpha-MSH) or forskolin-stimulated cAMP accumulation. Cell surface expression was determined by whole-cell binding of [(125)I]NDP-alpha-MSH, fluorescence immunocytochemistry and fluorescence-activated cell sorting. Maximal cAMP generation of the single mutants was reduced by 40% of wild-type receptor; the double mutant further reduced function to 40% of control, effects that were mirrored by decreases in cell-surface expression. Quantitative RT-PCR showed that, relative to wild-type receptor, transcript levels for the mutated receptors were not reduced. The results further implicate the C-terminal di-isoleucines in cell surface expression of MC4R and suggest that mutations of residues 316 or 317 would predict MC4R hypofunction.
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PMID:Cell surface expression of the melanocortin-4 receptor is dependent on a C-terminal di-isoleucine sequence at codons 316/317. 1259 26

The molecular basis of ligand recognition by the melanocortin 4 receptor (MC4R) has not been fully defined. In this study, we investigated the molecular determinants of MC4R ligand binding, employing a large array of ligands, using three approaches. First, molecular modeling of the receptor was used to identify Phe284, in transmembrane (TM) 7, as a potential site of ligand interaction. Mutation of Phe284 to alanine reduced binding affinity and potency of peptides containing L-Phe by up to 71-fold but did not appreciably affect binding of linear peptides containing D-Phe, consistent with a hydrophobic interaction between the Phe7 of alpha-melanocyte-stimulating hormone and Phe284. Second, we examined the effect of a naturally occurring mutation in TM3 (I137T) that is linked to obesity. This mutation decreased affinity and potency of cyclic, rigid peptides but not more flexible peptides, consistent with an indirect effect of the mutation on the tertiary structure of the receptor. Third, we examined the residues that support ligand selectivity for the MC4R over the MC3R. Mutation of Ile125 (TM3) of the MC4R to the equivalent residue of the MC3R (phenylalanine) selectively decreased affinity and potency of MC4R-selective ligands. This effect was mirrored by the reciprocal MC3R mutation F157I. The magnitude of this effect indicates that this locus is not of major importance. However, it is considered that an isoleucine/phenylalanine mutation may affect the orientation of Asp122, which has been identified as a major determinant of ligand binding affinity. Thus, this study provides further characterization of the MC4R binding pocket.
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PMID:Molecular determinants of melanocortin 4 receptor ligand binding and MC4/MC3 receptor selectivity. 1260 99

Mutations in the human melanocortin-4 receptor (MC4-R) gene may account for up to 5.8% of morbid nonsyndromic obesity. We have screened 120 unrelated obese patients for variants of the MC4-R gene. Four heterozygous missense variants were detected, including two polymorphisms (Val(103)Ile and Ile(251)Leu) previously described in the literature. A novel heterozygous mutation (Glu(308)Lys) was detected in a 36-yr-old female patient. Compared with the wild-type receptor, cells expressing the mutated receptor showed a reduced stimulation of cAMP production and a reduction of radioactive alpha MSH binding. No segregation of the mutation with the obese phenotype could be demonstrated. A second, potentially pathogenic mutation (Ser(30)Phe) was detected in a 31-yr-old female patient. Functional analysis of the mutated receptor showed no change in the affinity to the natural ligand alpha MSH nor limited ability to stimulate cAMP production. Sixty lean subjects were also screened, and no additional variants of the MC4-R gene were observed, except for two individuals with the Val(103)Ile polymorphism. In conclusion, we have screened a population of Italian obese subjects for MC4-R variants, demonstrating a 1.7% prevalence of potentially pathogenic mutations. A novel heterozygous missense mutation (Glu(308)Lys) that impairs MC4-R functional activity in vitro was characterized.
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PMID:Genetic screening for melanocortin-4 receptor mutations in a cohort of Italian obese patients: description and functional characterization of a novel mutation. 1476 12

Inhibition of fatty acid synthase (FAS) induces a rapid decline in fat stores in mice, suggesting a role for this enzyme in energy homeostasis. The human FAS gene (FAS) maps to chromosome 17q25, a region previously shown to have suggestive linkage to adiposity in a genome-wide linkage scan for genetic determinants of obesity in Pima Indians. To investigate the potential role of FAS in the pathophysiology of human obesity, the FAS gene was sequenced and 13 single nucleotide polymorphisms (SNPs) were identified. Five representative SNPs were genotyped in 216 full-blooded, nondiabetic Pima Indians for association analyses. A Val1483Ile polymorphism (GTC to ATC; allele frequency of A = 0.10) was associated with percentage of body fat and 24-h substrate oxidation rates measured in a respiratory chamber. Compared with homozygotes for the Val variant, subjects with Ile/x had a lower mean percentage of body fat (30 +/- 1 vs. 33 +/- 1%, P = 0.002; adjusted for age, sex, and family membership) and a lower mean carbohydrate oxidation rate (983 +/- 41 vs. 1,094 +/- 19 kcal/day, P = 0.03), which resulted in a lower mean 24-h respiratory quotient (0.845 +/- 0.01 vs. 0.850 +/- 0.01 kcal/day, P = 0.04; both adjusted for age, sex, family membership, percentage of body fat, and energy balance). Our findings indicate that the Val1483Ile substitution in FAS is protective against obesity in Pima Indians, an effect possibly explained by the role of this gene in the regulation of substrate oxidation.
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PMID:A novel missense substitution (Val1483Ile) in the fatty acid synthase gene (FAS) is associated with percentage of body fat and substrate oxidation rates in nondiabetic Pima Indians. 1522 Feb 20

Obesity is a prominent feature of the Bardet-Biedl syndrome (BBS), one subset of which, BBS6, is due to mutations in the chaperonin-like gene termed the McKusick-Kaufman syndrome (MKKS) gene. We tested whether variation in MKKS contributes to common and probably polygenic forms of obesity by performing mutation analysis of the coding region in 60 Danish white men with juvenile-onset obesity. Five variants were identified, including two synonymous mutations (Pro(39)Pro and Ile(178)Ile) and three nonsynonymous variants (Ala(242)Ser, Arg(517)Cys, and Gly(532)Val). Furthermore, the rare Ala(242)Ser was identified in two families and showed partial cosegregation with obesity. The Pro(39)Pro, Ile(178)Ile, and Arg(517)Cys variants are in complete linkage disequilibrium and defined a prevalent haplotype. In a case-control study, the Arg(517)Cys polymorphism allele prevalence was 11.4% [95% confidence interval (CI), 9.7-13.0] among 744 men with juvenile-onset obesity and 9.3% (CI, 7.9-10.7) among 867 control subjects (P = 0.048). However, among middle-aged men the allelic prevalence was 9.7% (CI, 7.9-11.4) among 523 obese men and 12.2% (CI, 10.8-13.6) among 1051 lean men (P = 0.037). In conclusion, it is unlikely that MKKS variants play a major role in the pathogenesis of nonsyndromic obesity, although in rare cases the A242S allele may contribute to obesity.
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PMID:Variation of the McKusick-Kaufman gene and studies of relationships with common forms of obesity. 1548 80


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