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)

L-Methionine (0.1 g/kg body wt) was administered to young white [n = 18; mean (+/- SD) age 20.0 +/- 1.0 y] and black [n = 12; mean (+/- SD) age 22.0 +/- 1.3 y] volunteers who had a similar lifestyle and who did not differ significantly from each other with respect to plasma folate or vitamin B-12 concentrations. Blacks, however, had significantly lower plasma pyridoxal-5'-phosphate concentrations compared with whites (P < 0.001). Fasting plasma homocysteine concentrations in blacks and whites were not significantly different. The mean (+/- SD) maximum increase in plasma homocysteine concentration measured after methionine loading was significantly lower (P < 0.01) in blacks (11.0 +/- 3.6 mumol/L) than in whites (18.0 +/- 6.2 mumol/L). Six weeks of vitamin supplementation (1.0 mg folic acid, 400 micrograms vitamin B-12, and 10 mg pyridoxine/d) reduced the mean (+/- SD) fasting plasma homocysteine concentration from 9.6 +/- 3.5 to 7.2 +/- 1.6 mumol/L in whites (P < 0.05) and from 8.4 +/- 2.4 to 5.6 +/- 1.4 mumol/L in blacks (P < 0.01). The mean (+/- SD) maximum increase in plasma homocysteine concentration after methionine loading declined from 18.0 +/- 6.2 to 11.1 +/- 2.3 mumol/L (P < 0.01) in whites, but vitamin supplementation did not have a significant effect on the methionine-load test in black volunteers. A significant race-by-time interaction shows that blacks metabolized homocysteine more effectively than did whites, which may partly explain their relative resistance against coronary heart disease despite a high prevalence of obesity, hypertension, and smoking.
 ...
PMID:Effective homocysteine metabolism may protect South African blacks against coronary heart disease. 757 13

In the present study mRNA from the subcutaneous adipose tissue of 68 obese (defined as a body mass index > or = 27.3 for men and > or = 27.8 for women) and 38 lean subjects was screened for mutations in the ob gene coding region. No mutations in the coding region of the human ob gene were detected using Conformation Sensitive Gel Electrophoresis in 105 subjects. A first base substitution (G to A) was detected in one individual, which changed a valine to a methionine at position 94. The mRNA of all subjects contained the codon for glutamine-49, ruling out the possibility of a splice defect occurring during the removal of intron 2. These observations suggest that defects in the ob gene sequence itself are not the primary cause of obesity in humans.
 ...
PMID:Mutation screening and identification of a sequence variation in the human ob gene coding region. 860 34

The relationship between physical inactivity, body mass index (BMI) (wt[kg]/ht[m]2), and pattern of adipose distribution with risk of colorectal adenomas (precursors of cancer) was examined in 13,057 female nurses in the United States, 40 to 65 years of age in 1986, who had an endoscopy between 1986 and 1992. From 1986 to 1992, 439 participants were newly diagnosed with adenomas of the distal colorectum. After controlling for age, prior endoscopy, parental history of colorectal cancer, smoking, aspirin, and intakes of animal fat, dietary fiber, folate, methionine, and alcohol, physical activity was associated inversely with risk of large (> or = 1 cm) adenomas in the distal colon (relative risk [RR] = 0.57, 95 percent confidence interval [CI] = 0.30-1.08, comparing high and low quintiles of average weekly energy expenditure from leisure-time activities; P trend = 0.05). Much of the benefit came from activities of moderate intensity such as brisk walking. In addition, BMI was associated directly with risk of large adenomas in the distal colon (multivariate RR = 2.21 [CI = 1.18-4.16], P trend = 0.0001, for BMI > or = 29 cf < 21 kg/m2). Waist circumference and the waist-to-hip ratio (WHR) were not related significantly to adenoma independently of BMI, but women with both a high BMI and high WHR were at greater risk of large colon adenoma (multivariate RR = 1.99, CI = 0.98-4.05) than women with high BMI but relatively low WHR (multivariate RR = 1.35, CI = 0.61-2.97). BMI was not related to small (< 1 cm) adenoma risk but physical activity had an inverse association with small adenomas in the distal colon (multivariate RR = 0.68, CI = 0.40-1.15, P trend = 0.03). The relationships between BMI or physical activity were considerably weaker and inconsistent for rectal adenomas. These results, in women, support an inverse association between physical activity and occurrence or progression of adenomas in the distal colon; obesity is associated with an elevated risk of large adenomas.
 ...
PMID:Physical activity, obesity, and risk of colorectal adenoma in women (United States). 874 Jul 38

Methionine metabolism and transmethylation are central to the metabolism and differentiation of all known cells. In enkaryotic organisms, methionine metabolism and transmethylation are of paramount importance in modification and regulation of proteins, lipids, and nucleic acids. The differential methylation of genes regulates their expression in the myriad of cells in eukaryotic organisms. Disruption and abnormalities in methionine metabolism and transmethylation seems to be associated with the major diseases of mankind, including cancer, heart disease, aging, obesity, and Parkinson's disease. In this review, we describe how aberrant and abnormal methionine metabolism and transmethylation are related to these major diseases. Most importantly, we review and hypothesize how the developing therapeutic recombination methioninase (rMETase) can be utilized to cure or prevent all of these diseases.
 ...
PMID:Methioninase: a therapeutic for diseases related to altered methionine metabolism and transmethylation: cancer, heart disease, obesity, aging, and Parkinson's disease. 923 67

It has been suggested that television watching and physical activity are related to obesity. This association, however, has been investigated mainly in children. This study provided the opportunity to examine the relationship between television watching, physical activity, and body mass index in adult Pima Indians, a population with a high prevalence of obesity. Hours per day of television watched, past-year physical levels (MET-h/wk; leisure and occupational combined) and BMI (kg.m-2) were measured in 2452 men and women subjects 21-59 yr old. In adults between the ages of 21 and 39 yr, TV and physical activity levels were negatively correlated (r = -0.11 for men and -0.10 for women). Weaker associations were found between TV and BMI (r = 0.08 for men and 0.04 for women). There were no significant relationships among these variables in older adults (49-59 yr), possibly because of low reported levels of physical activity and TV. Multiple linear regression analysis revealed that physical activity and television watching in men and activity in women were significantly related to BMI. These data suggest that increasing activity levels and decreasing the time spent in sedentary behavior such as watching television should both be considered as potential intervention strategies in obesity prevention programs.
 ...
PMID:Associations among physical activity, television watching, and obesity in adult Pima Indians. 924 90

Our objective was to investigate whether genetic variants of the uncoupling protein 1 (UCP1) gene are associated with juvenile-onset obesity or alterations in weight gain and insulin sensitivity in young healthy Caucasians. Single-strand conformation polymorphism and heteroduplex analysis of the coding region of the UCP1 gene was performed in 56 subjects randomly selected at the draft board examination from a cohort of 156 males with juvenile-onset obesity. Association studies of amino acid variants were undertaken in the cohort of males with juvenile-onset obesity, a cohort of 205 randomly selected control males, and a subgroup of this cohort comprising 76 lean subjects. Genetic variants of the coding region as well as a previously described a-->g nucleotide polymorphism of the 5'-flanking region of the UCP1 gene were examined for associations with accelerated weight gain or reduced sensitivity to insulin in a cohort of 380 young healthy Caucasians. The mutational analysis revealed five nucleotide substitutions that changed the sequence of UCP1, Arg/Trp40, Ala/Thr64, Val/Met137, Met/Leu229, and Lys/Asn257 and two nucleotide substitutions in the nontranslated region of exon 1. Among subjects with juvenile-onset obesity, the allelic frequencies of Ala/Thr64 and Met/Leu229 were both 8.2% (95% confidence interval: 5.1-11.3%) vs. 8.8% (6.0-11.6%) and 8.1% (5.3-10.9%), respectively, in the cohort of randomly selected control subjects. Among lean control subjects, the allelic frequencies of the polymorphisms were 8.2% (3.7-12.7%) and 5.6% (1.9-9.3%), respectively. In the cohort of young healthy subjects, measurements of obesity and insulin sensitivity did not differ between carriers of the Ala/Thr64 and Met/Leu229 variants and wild-type carriers. The Val/Met137 and Lys/Asn257 mutations were each found in one subject with juvenile-onset obesity, and the Arg/Trp40 mutation was found in two obese subjects and in one control subject. The allelic frequency of the nucleotide polymorphism of the 5'-flanking region of the UCP1 gene was 25.3% (22.2-28.4%) in the cohort of 380 young Danes. There were no differences in body mass index, fat mass, waist-to-hip ratio, or weight gain during childhood or adolescence between carriers and noncarriers of this nucleotide variant. Although we cannot exclude an effect of the rare mutations in the UCP1 gene on susceptibility to juvenile-onset obesity, genetic variation of the coding region of the UCP1 gene is not a common factor contributing to obesity in Caucasian subjects of Danish ancestry.
 ...
PMID:Studies of genetic variability of the uncoupling protein 1 gene in Caucasian subjects with juvenile-onset obesity. 939 15

Melanocortins, which are involved in melanocyte pigmentation control and glucocorticoid stimulation, have functional roles in various physiological mechanisms and have been shown to participate in higher cortical functions. Recently, it has also been reported that melanocyte-stimulating hormone (MSH) and melanocortin 4 receptor (MC4R) are the key components of the hypothalamic response to obesity. The solution structures of both melanocyte-stimulating hormone alpha-MSH (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) and its analog alpha-MSH-ND (Ac-Ahx-Asp-His-DPhe-Arg-Trp-Lys-NH2) (Ahx, 2-aminohexanoic acid) have been determined by two-dimensional NMR spectroscopy and simulated-annealing calculations. The NMR data revealed that alpha-MSH forms a hairpin loop conformation which includes conserved message sequences, whereas alpha-MSH-ND prefers a type I beta-turn comprising residues of Asp2-His3-DPhe4-Arg5. Final simulated-annealing structures of both alpha-MSH-ND and alpha-MSH peptides converged with rmsd of 0.07 nm for alpha-MSH-ND and 0.1 nm for alpha-MSH between backbone atoms, respectively. This result will provide the structural bases of melanocortin functions as well as valuable information for structure-based drug design involving the regulation of obesity and feeding.
 ...
PMID:Solution structures of the melanocyte-stimulating hormones by two-dimensional NMR spectroscopy and dynamical simulated-annealing calculations. 979 99

The melanocortin-4 receptor gene (MC4-R) has been implicated in weight regulation. Recently, two independent groups reported frameshift mutations associated with a dominant form of obesity (1, 2). We screened the coding region of the MC4-R in 306 extremely obese children and adolescents (mean body mass index: BMI 34.4 +/- 6.6 kg/m2), 25 healthy underweight students (mean BMI 17.1 +/- 0.8 kg/m2), 52 normal weight individuals (mean BMI 22.0 +/- 1.0 kg/m2), 51 inpatients with anorexia nervosa (AN, DSM IV criteria, mean BMI 14.3 +/- 1.5 kg/m2) and 27 patients with bulimia nervosa (BN, DSM IV criteria, mean BMI 21.7 +/- 5.8 kg/m2) by single strand conformation polymorphism analysis (SSCP). Several mutations were identified, including the frameshift mutation described (1). The mutations were as follows: a) The deletion of 4 bp (delta of CTCT at codon 211) results in a frameshift, thus rendering a truncated protein. This mutation has been assumed to be associated with dominantly-inherited morbid obesity in humans (1). Both the index patient (BMI 42.06 kg/m2, height 171 cm, age 19.6 years) and her mother (BMI 37.55 kg/m2, height 164 cm, age 42.5 years) were heterozygous for the deletion. b) A nonsense mutation at position 35 of the MC4-R was detected in two obese probands (BMI 31.29 kg/m2 and BMI 45.91 kg/m2). This mutation leads to a truncated protein that encompasses the N-terminal extracellular domain. Both carriers additionally showed (c) a missense mutation (Asp-37-Val). In both of these cases Tyr-35-Stop and Asp-37-Val were maternally transmitted, thus these variations form a haplotype. d) e) A male obese proband harbored two missense mutations (Ser-30-Phe, Gly-252-Ser). f)-i) Four different missense mutations (Pro-78-Leu, Thr-112-Met, Arg-165-Trp, Ile-317-Thr) were detected in four different male probands, respectively. All of these mutations (a to i) were found solely in extremely obese individuals whose BMIs were all above the 99th percentile. j) A silent mutation (C-579-T, Val-193-Val) was detected in a male underweight individual. k) A previously described polymorphism (Val-103-Ile; 3) was detected with similar frequencies in all different study groups. 1) We identified a novel polymorphism (Ile-251-Leu) with similar allele frequencies in all groups under study. In conclusion, our data indicate that mutations in the MC4-R are not uncommon. Whereas our data support the evidence for dominantly inherited obesity as revealed by the three obese probands with haplo-insufficiency, the functional significance of the missense mutations remains to be determined.
 ...
PMID:Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans. 1019

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.
 ...
PMID:Genetics of insulin resistance. 1032 50

Thanks to progress in zinc research, it is now possible to describe in more detail how zinc ions (Zn++) and nitrogen monoxide (NO), together with glutathione (GSH) and its oxidized form, GSSG, help to regulate immune responses to antigens. NO appears to be able to liberate Zn++ from metallothionein (MT), an intracellular storage molecule for metal ions such as zinc (Zn++) and copper (Cu++). Both Zn++ and Cu++ show a concentration-dependent inactivation of a protease essential for the proliferation of the AIDS virus HIV-1, while zinc can help prevent diabetes complications through its intracellular activation of the enzyme sorbitol dehydrogenase (SDH). A Zn++ deficiency can lead to a premature transition from efficient Th1-dependent cellular antiviral immune functions to Th2-dependent humoral immune functions. Deficiencies of Zn++, NO and/or GSH shift the Th1/Th2 balance towards Th2, as do deficiencies of any of the essential nutrients (ENs) - a group that includes methionine, cysteine, arginine, vitamins A, B, C and E, zinc and selenium (Se) - because these are necessary for the synthesis and maintenance of sufficient amounts of GSH, MT and NO. Via the Th1/Th2 balance, Zn++, NO, MT and GSH collectively determine the progress and outcome of many diseases. Disregulation of the Th1/Th2 balance is responsible for autoimmune disorders such as diabetes mellitus. Under Th2, levels of interleukin-4 (II-4), II-6, II-10, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) are raised, while levels of II-2, Zn++, NO and other substances are lowered. This makes things easier for viruses like HIV-1 which multiply in Th2 cells but rarely, if ever, in Th1 cells. AIDS viruses (HIVs) enter immune cells with the aid of the CD4 cell surface receptor in combination with a number of co-receptors which include CCR3, CCR5 and CXCR4. Remarkably, the cell surface receptor for LTB4 (BLTR) also seems to act as a co-receptor for CD4, which helps HIVs to infect immune cells. The Th2 cytokine II-4 increases the number of CXCR4 and BLTR co-receptors, as a result of which, under Th2, the HIV strains that infect immune cells are precisely those that are best able to accelerate the AIDS disease process. The II-4 released under Th2 therefore not only promotes the production of more HIVs and the rate at which they infect immune cells, it also stimulates selection for the more virulent strains. Zn++ inhibit LTB4 production and numbers of LTB4 receptors (BLTRs) in a concentration-dependent way. Zn++ help cells to keep their LTB4 'doors' shut against the more virulent strains of HIV. Moreover, a sufficiency of Zn++ and NO prevents a shift of the Th1/Th2 balance towards Th2 and thereby slows the proliferation of HIV, which it also does by inactivating the HIV protease. Research makes it look likely that deficiencies of ENs such as zinc promote the proliferation of Th2 cells at the expense of Th1 cells. Zinc deficiency also promotes cancer. Under the influence of Th1 cells, zinc inhibits the growth of tumours by activating the endogenous tumour-suppressor endostatin, which inhibits angiogenesis. The modern Western diet, with its excess of refined products such as sugar, alcohol and fats, often contains, per calorie, a deficiency of ENs such as zinc, selenium and vitamins A, B, C and E, which results in disturbed immune functions, a shifted Th1/Th2 balance, chronic (viral) infections, obesity, atherosclerosis, autoimmunity, allergies and cancer. In view of this, an optimization of dietary composition would seem to give the best chance of beating (viral) epidemics and common (chronic) diseases at a realistic price.
 ...
PMID:Modern diets and diseases: NO-zinc balance. Under Th1, zinc and nitrogen monoxide (NO) collectively protect against viruses, AIDS, autoimmunity, diabetes, allergies, asthma, infectious diseases, atherosclerosis and cancer. 1049 17


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>