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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The beta 3 subtype of adrenaline and noradrenaline receptors has now been extensively characterized at the structural and functional levels. Ligand binding and adenylyl cyclase activation studies helped define a beta-adrenergic profile that is quite distinct from that of the beta 1- and beta 2-adrenergic receptors, but strongly reminiscent of most of the "atypical" responses reported in earlier pharmacologic studies. Human, other large mammal, and rodent receptors share most of the characteristic beta 3 properties, although obvious species-specific differences have been identified. Recently, the incidence of a naturally occurring variant of the human beta 3-adrenergic receptor was shown to be correlated with hereditary obesity in Pima Indians and in Japanese individuals, and in Western obese patients with increased dynamic capacity to add on weight and develop non-insulin-dependent diabetes mellitus (NIDDM). A mild weight increase was also shown to develop in female, but not male, mice in which the beta 3 receptor gene was disrupted. Taken together, these results now provide a consistent picture of an important role of the beta 3-adrenoceptor in the regulation of lipid metabolism and as an obvious target for drugs to treat some forms of obesity.
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PMID:Structure and function of the beta 3-adrenergic receptor. 913 Dec 60

Obesity is a major risk factor for morbidity and mortality, and a series of pharmacologic approaches are available for helping to manage the problem. Obesity is caused by an imbalance between caloric intake and energy expenditure, which is influenced by both environmental and genetic factors. Pharmacologic treatments include anorexigenic agents, which fall into two broad categories: those that act via brain catecholamine pathways and those that act via serotonin pathways. The most recent oral agents approved are dexfenfluramine, which is currently being marketed, and sibutramine. Both agents inhibit the control reuptake of serotonin but in addition may have effects on thermogenesis. Under investigation are agents that increase energy expenditure: the beta 3-adrenergic receptor agonists and drugs that prevent the intestinal absorption of free fatty acids and cholesterol. In development are innovative approaches to influence leptin and its receptors, various obesity genes, and biologic substances thought to influence satiety (neuropeptide Y, enterostatin, cholecystokinin, bombesin, and amylin). Obesity has now become a major target for drug development not only for affecting obesity per se but also for managing and preventing comorbid conditions such as diabetes and cardiovascular disease.
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PMID:The pharmacologic approach to the treatment of obesity. 920 52

To assess the contribution of a replacement of Trp at codon 64 of beta 3-adrenergic receptor by Arg to fat distribution and metabolic disturbances in Japanese general population, we examined the missense mutation in 1122 persons consisting of 817 men aged 50.0 +/- 8.9 years and 305 women aged 50.8 +/- 8.5 years in Kyushu, Japan. The incidence of Arg64 allele was 0.21; no age-dependent decrease of the allele frequency was observed, suggesting that the mutation was not associated with early mortality. The genotype was not significantly correlated with body mass index or the thickness of visceral fat estimated by ultrasonography. Glucose tolerance and glucose-induced insulin secretion were not significantly different among subjects with Trp/Trp, Trp/Arg and Arg/Arg at codon 64. Although in obese persons the ratio of heterozygotes for the mutation tended to be higher in subjects with impaired glucose tolerance than in subjects with normal glucose tolerance, the tendency was not observed in non-obese persons. Furthermore none of 39 non-obese individuals homozygous for the mutation was diabetic, whereas two out of six obese homozygous persons were diabetic. These observations suggest that the missense mutation may not be a main determinant of obesity in populations taking low fat/low energy Japanese-style diet and it may not be deleterious at least in non-obese individuals.
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PMID:Beta 3-adrenergic receptor gene polymorphism is not a major genetic determinant of obesity and diabetes in Japanese general population. 927 71

We have investigated the W64R (Trp64Arg) mutation in the beta-3-adrenergic receptor in 2270 healthy British males aged 50-61 y. The frequency of the rare R allele was 0.07 (95% confidence interval (CI) 0.06-0.08). The men showed an absence of association between W64R genotype and weight or height, both in the whole sample and in each quintile of the body mass index (BMI), and there was no association with tendency to gain weight. The W64R heterozygous state appears not to be a major contributing factor to obesity in the general population.
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PMID:W64R mutation in beta-3-adrenergic receptor gene and weight in a large population sample. 957 46

Clinical receptology encompasses broad areas, including receptor or postreceptor defects due to mutations of receptor or other genes, abnormalities due to receptor antibodies and secondary changes of receptors under various pathological conditions. Recent progress in molecular biology has succeeded in cloning genes of receptors, G-proteins and other cellular proteins that are involved in the signal transduction and clarified their germ-line and somatic mutations. It is of importance that mutations of receptors and G-proteins do not necessarily cause loss of function but sometimes cause gain of function of receptors or G-proteins, thus leading to hyperfunction. Molecular basis that causes either loss or gain of function has been studied but is not completely understood. Some examples of gain of function mutatious of G-protein coupled receptors, tyrosin kinase-type receptors and G alpha protein are shown. Another important aspect in receptor research is that mutation of a single receptor gene sometimes result in different phenotypes and even different modes of inheritance. For example, mutations of rhodopsin (a G-protein coupled receptor) gene cause retinitis pigmentosa of autosomal dominant type and autosomal recessive type and also cause congenital stationary night blindness. Exact mechanisms responsible for such differences are not completely understood. There are polymorphisms in some genes that may be involved in some diseases. An example is a polymorphism in beta 3-adrenergic receptor that is claimed but not clearly demonstrated to be a cause of obesity or type II diabetes. Such polymorphism is possibly a gene in polygenic diseases. Receptology is important for elucidating pathogenesis of complex diseases.
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PMID:[Recent progress in clinical aspects of receptor research]. 970 34

Structure and essential motifs of beta 3-adrenergic receptor (known previously as atypical beta-AR), which plays a central role in regulation of lipid metabolism have been described. Obesity results from an imbalance between caloric intake and energy expenditure. The consequence of catecholamine activation of beta 3-AR is increased mobilization of fatty acids from triglyceride stores (lipolysis) in brown and white adipose tissue as well as increased fatty acid beta-oxidation and heat-production via UCP-1 (thermogenesis) in brown adipose tissue. A pharmacokinetic effects of beta 3-agonists and putative involvement of Trp/Arg mutation in beta 3-AR gene in obesity and another metabolic disorders have been discussed.
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PMID:[Beta-3 adrenergic receptor--structure and role in obesity and metabolic disorders]. 1064 45

Beta 3-adrenergic receptors are expressed predominantly on white and brown adipocytes. Activation of the receptor stimulates lipolysis in adipose tissues and increases energy expenditure by thermogenesis in brown adipocytes. It is proposed that dysfunction of beta 3-adrenergic receptor result to obesity and insulin resistance. Trp64Arg mutation of human beta 3-adrenergic receptor gene is found frequently in Pima Indians and Japanese, and rare in Caucasians. Although the mutation have little, if any, functional disturbance especially in acute phase in vivo, it is reported to associate to obesity and earlier onset of type 2 diabetes. The role of beta 3-adrenergic receptor in insulin resistance is still unknown in detail. Further studies and clinical applications are expected.
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PMID:[Insulin resistance and beta 3-adrenergic receptor function]. 1070 54

The beta 3 subtype of adrenaline and noradrenaline receptors has been extensively characterized at structural and functional levels. Ligand binding and adenyl cyclase activation studies have helped to define their unique beta-adrenergic profile. Humans, other larger mammals, and rodents share most of the characteristic beta 3-adrenergic receptor properties, although obvious species-specific differences have been identified. Most studies in animal models have shown a distinct beta 3-adrenergic receptor activity that results in an increase in energy expenditure, decrease of fat mass (especially of intra-abdominal fat), and increased glucose disposal efficiency. It is of interest that mild weight increase was shown to develop in female but not male mice, in whom the beta 3-adrenergic receptor gene was disrupted. Recently, the incidence of a naturally occurring variant of the human beta 3-adrenergic receptor was shown to correlate with hereditary obesity in Pima Indians and Japanese individuals. In Western obese patients, this phenotype increased the capacity to gain weight and develop type 2 diabetes mellitus. Studies of humans with the Trp64Arg variant have shown controversial results. Many studies have failed to show any effect in heterozygous male subjects, and only modest effects in homozygous male subjects. In women, several studies have shown modest-to-significant effects regarding weight gain, intra-abdominal fat, and decreased insulin sensitivity in heterozygous and homozygous women. Other studies have failed to show any effect in heterozygous females. Disruptions in the activity of the beta 3-adrenergic receptor in the homozygous male and the heterozygous or homozygous female appear to have a profound effect in animal models, but a limited consequence in human physiology. Association with obesity or diabetes in humans is still controversial. This difference between animal and human models may be explained by the different quantity and distribution of metabolically active brown adipose tissue in the two.
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PMID:Insulin resistance and type 2 diabetes mellitus: its relationship with the beta 3-adrenergic receptor. 1071 58

The regulation of resistin, a new adipose-derived circulating factor, is the subject of controversy. In particular, the question of its modulation in obesity led to opposite results reported by two different groups. In the current study, we assayed adipocyte resistin mRNA using fluorescent real-time RT-PCR. We studied the expression of resistin in mice which are differently sensitive to diet-induced obesity: the FVB/n strain, which poorly responds to high-fat diet and transgenic mice that express human alpha 2A-AR in adipose tissue in the absence of beta 3-adrenergic receptor (AR) under the FVB genetic background which are highly sensitive to high-fat diet and develop hyperplastic obesity. We observed that FVB mice, which have no significant increased body weight after an 8-week high-fat diet period, exhibited no alteration of resistin expression. In contrast, the transgenic mice developing high-fat diet-induced obesity exhibited markedly downregulated adipocyte resistin mRNA. We also showed that obesity induced by gold thioglucose injection in FVB/n mice reduces the expression of resistin in isolated adipocytes. This argues for decreased expression of resistin as a hallmark of obesity. Moreover, our data show that feeding a high-fat diet is not a primary determinant of resistin regulation.
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PMID:Decreased resistin expression in mice with different sensitivities to a high-fat diet. 1171 11

As the white adipose tissue, especially abdominal fat is an endocrine organ secreting adipocytokines, which induce insulin resistance, hypertension, and arteriosclerotic diseases, reduction of the abdominal fat is important. But effect of the diet therapy differs in each individual, because of the difference of energy expenditure. Since the relationship between the missense mutation (Trp64Arg) of the beta 3-adrenergic receptor (beta 3-AR) gene and low energy expenditure in the obese Pima Indians was made clear, gene polymorphisms that mediate body weight are reported one after another. We also reported that one third of Japanese have the Trp64Arg mutation of beta 3-AR gene, which may produce obesity or difficulties in weight loss. Here we introduce the obesity-related genes, and report the importance of Tailor-made diet therapy based on molecular genetics to improve obesity.
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PMID:[The tailor-made diet therapy to improve obesity]. 1180 27


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