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)

Recently, a missense mutation replacing tryptophan with arginine at codon 64 of the beta 3-adrenergic receptor gene was shown to be associated with insulin resistance in nondiabetic subjects and to an earlier onset of NIDDM in Pima Indians. We studied whether the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene in a cohort of young healthy Danes was associated with high birth weight, accelerated weight gain during childhood and adolescence, present obesity, or impaired insulin sensitivity. The protocol included 380 unrelated white subjects in whom insulin sensitivity and secretion were measured during a combined intravenous glucose and tolbutamide tolerance test. A number of biochemical and anthropometric characteristics were determined for each subject. The subjects were genotyped for the codon 64 polymorphism by applying polymerase chain reaction restriction fragment-length polymorphism screening with the use of endonuclease BstN1. The allelic frequency of the mutated allele was 7% (95% CI: 5-10%), and it was similar in obese and nonobese subjects. The beta 3-adrenergic receptor gene variant was not related to birth weight or weight gain during childhood or adolescence. In its heterozygous form, the gene variant was not associated with an altered insulin sensitivity index (SI) or other features of the insulin resistance syndrome (BMI, blood pressure, fasting serum lipid levels, or fasting serum fibrinolytic variables). Three homozygous carriers of the polymorphism were identified, and each had a significantly higher BMI (27.4 +/- 1.3 vs. 23.5 +/- 3.7 kg/m2 [mean +/- SD]; P = 0.032), lower SI [4.9 +/- 2.9 vs. 15.4 +/- 9.0 10(-5) x (min x pmol/l)-1; P = 0.013], and higher fasting serum C-peptide (730 +/- 155 vs. 471 +/- 158 pmol/l; P = 0.016) than the wild-type carriers. The homozygous carriers also had significantly higher levels of fasting serum triglyceride (P = 0.042) and serum LDL cholesterol (P = 0.013). When adjustments were made for age, sex, BMI, and VO2max in a multiple regression analysis, a significantly negative association was found between homozygosity for the codon 64 variant and the SI (P = 0.009). We conclude that in young healthy Danes, the homozygous form but not the heterozygous form of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor may be associated with obesity and, independent of BMI, with a low SI. Since only three homozygous carriers were identified among 380 subjects, the results must be interpreted with caution, and studies of larger population samples are needed.
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PMID:Insulin sensitivity and body weight changes in young white carriers of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene. 869 Jan 60

The beta 3-adrenergic receptor, located mainly in fat cells of visceral adipose tissue, is involved in the regulation of lipolysis and thermogenesis. Recently, a mutation in the corresponding gene resulting in the replacement of tryptophan by arginine in position 64 (Trp64Arg) has been demonstrated, which associated with obesity and metabolic complications of obesity. We have investigated whether this polymorphism is associated with changes in beta 3-adrenergic receptor function or clinical characteristics in 40 non-obese and 43 obese non-diabetic subjects who underwent elective abdominal surgery. The beta-adrenergic receptor gene polymorphism was examined by restriction-enzyme cleavage conformation. Beta 3-adrenergic receptor function was investigated by measuring lipolysis in isolated visceral white fat cells incubated with noradrenaline (natural ligand) or (CGP) 12,177 (selective beta 3-agonist). No homozygotes for the mutation were found. The allelic frequency of Trp64Arg was similar in obese and non-obese subjects (9.4 and 12.5%, respectively). In obese and non-obese subjects there was no change in body mass index, body fat distribution, fat cell size, fasting circulating levels of insulin, glucose or lipids, blood pressure or adipocyte lipolysis induced by noradrenaline or CGP 12,177 when Trp64Arg heterozygotes were compared with Trp64A homozygotes. Our results suggest that the Trp64Arg mutation in its heterozygous form is not a major determinant of beta 3-adrenergic receptor function (when assessed by lipolysis in white adipose tissue) or of the pathophysiology of obesity.
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PMID:Phenotypic characterization of the Trp64Arg polymorphism in the beta 3-adrenergic receptor gene in normal weight and obese subjects. 881 12

A tryptophan to arginine (Trp64Arg) mutation in the beta 3-adrenergic receptor (beta 3-AR) gene has been implicated in diabetes and obesity. We investigated the relationship of the beta 3-AR gene mutation with total body weight, BMI, central abdominal fat, blood pressure (BP), and reproductive history in 686 elderly subjects (429 women, 257 men; mean age 69.8 +/- 6.9 [+/-SD] years) from a cross section of a normal population in Australia. About 14% of the test population were heterozygote carriers of the Trp64Arg mutation; however, significant effects on clinical parameters were only observed in women. The frequency of the mutation was significantly increased in obese women compared with lean women (BMI > or = 27: 20% compared with BMI < 27: 11%, P = 0.02). Significantly higher total body weight (67.5 +/- 12.9 vs. 64.1 +/- 12.2 kg, P = 0.03) and BMI (26.3 +/- 4.7 vs. 25.1 +/- 4.5 kg/m2, P = 0.03) was observed in heterozygote women compared with normal subjects (homozygous for tryptophan). Central abdominal fat was not significantly different, except in women under 70 years, where heterozygotes had 16% higher abdominal fat compared with normal subjects. Female heterozygotes had significantly higher diastolic BP, even after adjustment for age and BMI (88.9 +/- 11.1 vs. 84.2 +/- 10.8 mmHg, P = 0.003) and a longer reproductive life, with an earlier menarche (12.8 +/- 1.3 vs. 13.4 +/- 1.5 years, P = 0.006), a higher gravidity (4.4 +/- 2.4 vs. 3.5 +/- 2.1, P = 0.01), and higher parity (3.8 +/- 2.0 vs. 3.0 +/- 1.9, P = 0.005). Clearly, the beta 3-AR mutation has pleiotrophic effects on a number of physiological systems, including BMI, BP, and reproductive history, perhaps suggesting evolutionary reasons for its maintenance in the population.
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PMID:The beta 3-adrenergic receptor gene Trp64Arg mutation is overrepresented in obese women. Effects on weight, BMI, abdominal fat, blood pressure, and reproductive history in an elderly Australian population. 882 71

We recently identified a mutation in the human beta 3-adrenergic receptor (beta 3AR) gene (codon 64 TGGTrp -> CGGArg; TRP64ARG) that associates with features of the insulin resistance syndrome and an earlier onset of noninsulin-dependent diabetes mellitus (NIDDM). We scanned the beta 3AR gene for mutations by single stranded conformational polymorphism analysis in 20 Nauruans with obesity and NIDDM. No mutations were identified. Sixty-five Nauruan subjects were genotyped for the TRP64ARG beta 3AR. All subjects were homozygous for the normal allele. We genotyped Samoans and Asians for the TRP64ARG beta 3AR. Seven of 52 Samoans were heterozygous for the mutant arginine allele (allele frequency, 0.07). Of these, 5 were diabetic and 2 were nondiabetic (by Fisher's exact test, P = 0.4). There were trends toward increased body mass indices, waist to hip ratios, and 2-h insulin levels during oral glucose tolerance tests in Samoans with the mutation; however, the limited number of subjects available for study precluded rigorous statistical analysis. The TRP64ARG beta 3AR was also detected in Chinese, Chinese Americans, and subjects from the Indian subcontinent. In conclusion, the TRP64ARG beta 3AR mutation or any other mutation in the beta 3AR gene is not a major contributor to genetic susceptibility to NIDDM and obesity likely in Nauruans.
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PMID:Molecular scanning for mutations in the beta 3-adrenergic receptor gene in Nauruans with obesity and noninsulin-dependent diabetes mellitus. 892 75

Obesity and insulin resistance are important risk factors for the development of noninsulin-dependent diabetes (NIDDM) and are prevalent among predisposed first degree relatives of diabetic individuals. Recent molecular screening and analysis of a common missense mutation of the beta 3-adrenergic receptor gene suggested this locus as a strong candidate for increased obesity, earlier age of diabetes onset, and insulin resistance. To test the hypothesis that the beta 3-adrenergic receptor locus affects diabetes susceptibility, obesity as measured by body mass index, and components of the insulin resistance syndrome, we examined the role of this region in families ascertained for two or more NIDDM siblings. Linkage analysis was conducted using both parametric and nonparametric analyses, including multipoint sibling pair analysis. We found no evidence for linkage to NIDDM as a dichotomous trait and no evidence for linkage to body mass index, waist/hip ratio, insulin levels, or glucose levels as quantitative traits or to reported age of onset among NIDDM individuals. The Trp64 Arg missense mutation was present in 11% of the population. The mutation was not associated with NIDDM, and Arg64 carriers did not have earlier NIDDM onset, higher body mass index, or higher waist/hip ratio than Trp64 homozygotes. Among relatives, Arg64 carriers had significantly lower fasting glucose levels and lower waist/hip ratios than Trp64 homozygotes, but no characteristics of the insulin resistance syndrome. We conclude that the beta 3-adrenergic receptor locus does not play an important role in NIDDM susceptibility or in the insulin resistance syndrome among members of families with a strong predisposition to NIDDM.
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PMID:Role of the beta 3-adrenergic receptor locus in obesity and noninsulin-dependent diabetes among members of Caucasian families with a diabetic sibling pair. 895 53

The metabolic response of adipose tissue to stimuli leading to lipid mobilization is important in determining the direction of metabolism and the degree to which adipose tissue can store lipids and release fatty acids in times of need. The lipolytic machinery is controlled by the activity of hormone-sensitive lipase, which in turn is controlled by the cellular levels of cAMP. The production of cAMP is abnormal in the adipose tissue of some animal models of obesity. In the ob/ob mouse, the defective cAMP production has been associated with deficient levels of some of the isoforms of the guanine nucleotide transducing G-proteins and also with the low expression and functionality of the beta 3-adrenergic receptor (beta 3-AR). The recent discovery of the ob gene product leptin calls into question the role of the ob gene in the regulation of the cAMP cascade in adipose tissue. The importance of the beta 3-AR and leptin in regulating human adipose tissue metabolism remains to be clarified.
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PMID:Of mice and women: the beta 3-adrenergic receptor leptin and obesity. 901 68

We investigated whether the polymorphism of the beta 3-adrenergic receptor (beta 3-AR) gene, which is associated with insulin resistance in non-diabetic subjects and an earlier onset of non-insulin-dependent diabetes mellitus in Pima Indians, was associated with visceral fat obesity and features of the insulin resistance syndrome in Japanese premenopausal obese women. There was no difference between 131 obese women and 256 control subjects (0.23 vs 0.17, p = 0.112) in the frequency of the Arg64 allele. The visceral fat area measured by computerised tomography scan was greater in homozygous Arg64Arg (172 +/- 17 cm2, n = 6) and heterozygous Trp64Arg (178 +/- 47 cm2, n = 48) women than in women homozygous for the Trp64Trp (121 +/- 46 cm2, n = 77) genotype (p < 0.01). This was also reflected by increased total body fat but not by increased body mass index. The association between the Trp64 allele and visceral fat mass by multiple regression analysis, was independent of age, body mass index and total fat mass (p < 0.004). Moreover, homozygous carriers of the Arg64 allele had higher systolic blood pressure, higher fasting and post-load glucose and insulin concentrations, higher cholesterol, and triglyceride and lower HDL-cholesterol concentrations than homozygous carriers of the Trp64 allele. Some of these differences were also observed between heterozygous Trp64Arg and homozygous Trp64Trp genotypes (glucose tolerance, insulin and cholesterol concentration). We conclude that in obese women the beta 3-AR polymorphism may be used as a genetic marker for visceral fat obesity and the insulin resistance syndrome.
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PMID:Beta 3-adrenergic-receptor polymorphism: a genetic marker for visceral fat obesity and the insulin resistance syndrome. 904 81

The beta 3-adrenergic receptor (beta 3AR) is implicated in the regulation of thermogenesis and lipolysis, and it is suggested that the Trp64 Arg mutation in this receptor may contribute to the development of obesity. To examine whether the Trp64 Arg mutation had any effect on body weight during adult life, the beta 3AR genotype was determined in 186 unselected Japanese men, most of whom had records of body weight measured yearly from 25-53 yr of age. Of them, 26 subjects were diagnosed as having noninsulin-dependent diabetes mellitus (NIDDM) and 41 as having impaired glucose tolerance. There were 6 subjects (3%) with homozygous mutation, 67 (36%) with heterozygous mutation, and 113 (61%) with normal allele. Among the 3 genotypes, there were no significant differences in body mass index (BMI) at any age between 25-53 yr and the prevalence of NIDDM at the age of 53 yr. When longitudinal changes in body weight were compared between subjects with and without mutation, the former were less prone to gain weight than the latter. The frequency of the mutant allele was 1) not different among obese (BMI, > 26.4), intermediate (BMI, 22-26.4), and nonobese (BMI, < 22.0) subjects (0.21, 0.22, and 0.26, respectively; P = 0.77); 2) lower in subjects with NIDDM than in those without it, but the difference was insignificant (0.12 vs. 0.23; P = 0.07); and 3) similar between 186 unselected men and another group of 100 patients with NIDDM that were randomly selected for comparison (0.21 vs. 0.23). These results suggest that the beta 3AR is not a major contributing factor to obesity or NIDDM in Japanese men.
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PMID:Lack of association between the Trp64 Arg mutation in the beta 3-adrenergic receptor gene and obesity in Japanese men: a longitudinal analysis. 910 Jun 8

The Trp64Arg mutation of the beta 3-adrenergic receptor (beta 3AR) is prevalent in several ethnic groups and is associated with weight gain, and some features of syndrome X such as insulin resistance and dyslipidaemia. Nevertheless, it is not known at present whether this mutation is associated with visceral obesity, which is an important risk factor for the development of hypertension, dyslipidaemia, insulin resistance, non-insulin-dependent diabetes mellitus, and atherosclerosis. To investigate whether this mutation may contribute to visceral obesity, we studied the relationships between beta 3AR genotypes and clinical phenotypes. The Trp64Arg allele of beta 3AR was examined in 278 Japanese men with respect to variables relating to visceral obesity assessed by computerised tomography. To detect the Trp64Arg mutation, polymerase chain reaction-restriction fragment length polymorphism analysis using Bst NI digestion was performed. This mutation was more frequently observed in subjects with higher body mass index (BMI) (p = 0.02). Moreover, in 120 subjects with a moderate degree of obesity (22 < or = BMI < 26.4 kg/m2), the mutation (homozygotes and heterozygotes) was associated with visceral obesity (higher ratio of visceral to subcutaneous fat area; V/S) (p = 0.03). Furthermore, the Trp64Arg allele was more frequent in subjects with lower serum triglyceride levels (p = 0.02) and the Trp64Arg homozygotes, but not heterozygotes, exhibited lower triglyceride levels. Thus, this mutation appears to be associated with visceral obesity but with lower serum triglyceride. It is suggested that those with the mutation may describe a subset of subjects characterized by decreased lipolysis in visceral adipose tissue.
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PMID:A mutation of the beta 3-adrenergic receptor is associated with visceral obesity but decreased serum triglyceride. 911 25

Mutation frequencies in the beta 3-adrenergic receptor gene were measured in 83 CAD patients and 107 controls (all Japanese nationals) and the mutation incidence in the two groups was compared. The relationship between characteristics of lipid and glucose metabolism and presence or absence of the mutation was examined in CAD patients. The frequency of this mutant allele in CAD patients was significantly higher than that of controls. The presence of this mutation was significantly associated with higher body mass index, but not with other plasma lipid and glucose levels in CAD patients. This mutation was associated with coronary heart disease and obesity but was not with glucose and lipid metabolism disorders in Japanese nationals.
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PMID:Association of a genetic variation in the beta 3-adrenergic receptor gene with coronary heart disease among Japanese. 912 44


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