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)

Anorectic drugs are increasingly being used in obesity to induce and/or maintain weight loss. We have focused on the development of metabolic enhancers. These compounds increase energy expenditure, which is important because weight loss is associated with metabolic re-adjustment to reduce energy output. Thus, metabolic enhancers ensure that energy expenditure is maintained when food intake is reduced. Beta3-adrenoceptor agonists are thermogenic agents that increase energy output by stimulating heat generation. Early selective beta3-agonists were effective in producing weight loss in obese rats, but were largely ineffective in humans. In addition, many interacted with other types of beta receptor to produce side-effects. The development of a Chinese hamster ovary cell (CHO) transfection system, using the human beta3-adrenoceptor gene, resulted in potential new selective human beta3-agonists being identified. However, the in vitro activity of these agents does not necessarily reflect their action in vivo, due to the presence of other receptor types and G proteins in the target cells, and interactions between them. The characterization of a selective beta3-antagonist, SR59230A, has allowed us to examine beta3-agonist activity in different experimental systems. The CHO transfection system has been used to show that SR59230A is effective in blocking agonist activity against both the rat adrenoceptor, and three human beta3-receptor isoforms. In addition, SR59230A shows competitive inhibition of agonist activity in both rat and human model systems. This antagonist may therefore provide a pharmacological tool for the functional study of by newly identified beta3-receptor agonists.
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PMID:Advances in pharmacotherapy for obesity. 975 39

With age, there are increases in adiposity, leptin mRNA in white adipose tissue (WAT), and serum leptin levels in rats. Beta3-adrenergic agonists are anti-obesity agents in rodents, and activation of beta3-adrenergic receptors (beta3AR) mediates an acute decrease in food consumption, increased thermogenesis in brown adipose tissue (BAT), increased lipolysis in WAT, and suppression of leptin gene expression and serum leptin levels. Because beta3AR signal transduction is impaired with age in BAT and WAT, beta3AR-mediated regulation of leptin, feeding behavior, and adiposity may also be impaired with age. To test this hypothesis, we infused young (6 month) and old (24 month) F344 x BN rats with the beta3AR agonist CL316,243 (1 mg kg(-1) day(-1)) using osmotic minipumps for 7 days. Food intake, body mass, adiposity, and serum leptin, as well as leptin, uncoupling protein 1 (UCP1), and lipoprotein lipase (LPL) mRNA in BAT or WAT were determined. In young rats, CL316,243 infusion reduced body mass and adiposity, suppressed serum leptin and leptin mRNA levels in WAT, induced UCP1 in WAT, and increased UCP1 and LPL mRNA levels in BAT. Moreover, treatment with CL316,243 was associated with a marked but transient suppression of food intake. Most of the responses elicited in the old rats with CL316,243 treatment were qualitatively similar to those in the young rats, but blunted in magnitude. Beta3AR activation of adenylyl cyclase was also reduced in the aged rats. These data suggest that, although CL316,243 is an effective agent in aged rats, the maximum responses are reduced, suggesting that the impaired beta3AR signal transduction with age is a major determining factor in the reduced effectiveness of CL316,243 in older rats.
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PMID:Beta3-adrenergic regulation of leptin, food intake, and adiposity is impaired with age. 1055 66

Cross-talk between insulin and the adrenergic system is important in the regulation of energy homeostasis. In cultured, differentiated mouse brown adipocytes, beta3-adrenergic stimulation induced a 4.5-fold increase in uncoupling protein-1 (UCP-1) expression, which was diminished by 25% in the presence of insulin. Beta3-adrenergic stimulation also activated mitogen-activated protein (MAP) kinase by 3.5-fold and caused a decrease in basal phosphoinositide (PI) 3-kinase activity detected in p110gamma- and Gbeta-subunit-immunoprecipitates in a time-dependent manner, whereas insulin stimulated p110alpha- and phosphotyrosine-associated PI 3-kinase activity. Inhibition of MAP kinase or PI 3-kinase potentiated the beta3-adrenergic effect on UCP-1 expression, both alone and in the presence of insulin. Thus, insulin inhibits beta3-adrenergic stimulation of UCP-1, and both MAP kinase and PI 3-kinase are negative regulatory elements in the beta3-adrenergic control of UCP-1 expression. Cross-talk between the adrenergic and insulin signaling systems and impaired regulation of UCP-1 might contribute to the development of a reduced energy balance, resulting in obesity and insulin resistance.
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PMID:Insulin and the beta3-adrenoceptor differentially regulate uncoupling protein-1 expression. 1084 79

Beta3-adrenergic receptors (AR) are nearly exclusively expressed in brown and white adipose tissues, and chronic activation of these receptors by selective agonists has profound anti-diabetes and anti-obesity effects. This study examined metabolic responses to acute and chronic beta3-AR activation in wild-type C57Bl/6 mice and congenic mice lacking functional uncoupling protein (UCP)1, the molecular effector of brown adipose tissue (BAT) thermogenesis. Acute activation of beta3-AR doubled metabolic rate in wild-type mice and sharply elevated body temperature and BAT blood flow, as determined by laser Doppler flowmetry. In contrast, beta3-AR activation did not increase BAT blood flow in mice lacking UCP1 (UCP1 KO). Nonetheless, beta3-AR activation significantly increased metabolic rate and body temperature in UCP1 KO mice, demonstrating the presence of UCP1-independent thermogenesis. Daily treatment with the beta3-AR agonist CL-316243 (CL) for 6 days increased basal and CL-induced thermogenesis compared with naive mice. This expansion of basal and CL-induced metabolic rate did not require UCP1 expression. Chronic CL treatment of UCP1 KO mice increased basal and CL-stimulated metabolic rate of epididymal white adipose tissue (EWAT) fourfold but did not alter BAT thermogenesis. After chronic CL treatment, CL-stimulated thermogenesis of EWAT equaled that of interscapular BAT per tissue mass. The elevation of EWAT metabolism was accompanied by mitochondrial biogenesis and the induction of genes involved in lipid oxidation. These observations indicate that chronic beta3-AR activation induces metabolic adaptation in WAT that contributes to beta3-AR-mediated thermogenesis. This adaptation involves lipid oxidation in situ and does not require UCP1 expression.
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PMID:White adipose tissue contributes to UCP1-independent thermogenesis. 1295 94

Beta3-adrenergic receptor (beta3AR) stimulates lipolysis in human fat cells, so its gene can constitute a candidate to explain a part of genetic predisposition to human obesity and related disorders. The Trp64Arg polymorphism in the beta3AR gene has been reported to be associated with insulin resistance, obesity and type 2 diabetes; little is known about its possible association with cancer. To check this association we determined the distribution of its genotypes and frequency of alleles in endometrial cancer patients with or without overweight/obesity as compared to appropriate controls. The Trp64Arg polymorphism was determined by PCR-based MspI restriction fragment length polymorphism in DNA of peripheral blood leukocytes. The study population consisted of 169 subjects, among them were 79 endometrial cancer patients and 90 controls without cancer. There were 34 obese (BMI > or = 30 kg/m2) and 22 overweight (30 BMI > or = BMI > or = 27 kg/m2) individuals among endometrial cancer patients. There was a significant (p < 0.001) difference in genotype distribution and allele frequency between endometrial cancer patients and controls without cancer. The odds ratios for the Trp/Arg and Arg/Arg genotypes as well as for the Arg allele were considerably higher than 1. Analysis of the polymorphism in the cancer group patients due to BMI revealed that the distribution of genotypes and the frequency of alleles in obese/overweight patients differed significantly from those in patients with normal weight with an odds ratio for the Trp/Arg genotype and the Arg allele of about 4. The prevalence of the Arg allele of the Trp64Arg polymorphism in the beta3-adrenergic receptor gene may contribute to the susceptibility to endometrial cancer among obese/overweight individuals.
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PMID:An association between the Trp64Arg polymorphism in the beta3-adrenergic receptor gene and endometrial cancer and obesity. 1574 38

Beta3-adrenergic receptor (ADRB3) is a mediator of catecholamine-stimulated lipolysis in humans. The Trp64Arg polymorphism with T/C transition in the ADRB3 gene has been considered to reduce lipolysis and metabolic expenditure. Here, we investigated the hitherto unknown role of the Trp64Arg substitution on food preference among healthy young adults (mean age, 24.3; n = 53, including 25 men). Preference toward four food types (bitter, sour, salty, or sweet) and greasy (high-fat) foods was examined using a self-reported questionnaire. There was no noticeable sex-difference in food preference. Incidentally, only among female subjects, the genotype frequencies of the Trp64Arg polymorphism were in accordance with the Hardy-Weinberg equilibrium. Consequently, female subjects were divided into two groups for further analyses: 18 subjects with TT genotype (Trp64Trp) (wild-type group) and 10 subjects with TC genotype (Trp64Arg) (heterozygous group). No significant difference was observed in preference for four food types between the groups. However, when sweet foods were divided into high-fat and low-fat subgroups, food preference for high-fat sweet foods in heterozygous group was significantly higher than that in wild-type group. Moreover, when subjects were divided into two classes based on preference for greasy foods (like, n = 16 or dislike, n = 12), the preference degree in heterozygous group who liked high-fat foods (n = 5) was significantly higher than that in wild-type group (n = 11), suggesting that the Trp64Arg substitution might genetically enhance high-fat food preference. Thus, understanding the relationship between ADRB3 Trp64Arg substitution and fat preference will be valuable for obesity prevention.
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PMID:Association between Beta3-Adrenergic Receptor Trp64Arg Polymorphism and Fat Preference in Healthy Young Japanese Women. 3135 27