Disease relevance of ADRB3

• These findings do not support the view that there is an association between the Trp64Arg mutation in the ADRB3 gene and obesity [1].
• We conclude that the Trp(64)Arg mutation of ADRB3 has little or no influence on either body weight or body mass index in the general Japanese population [2].
• Stimulation of the ADRB3 adrenergic receptor induces relaxation of human placental arteries: influence of preeclampsia [3].
• The Trp64Arg polymorphism of beta(3)-adrenergic receptor (ADRB3) has been reported to be associated with insulin resistance and gestational diabetes mellitus (GDM) [4].
• CONCLUSION: A potential association may exist between risk of breast cancer and polymorphisms in the ADRB2 and ADRB3 genes; further studies in larger samples and/or in different ethnic groups are warranted to investigate this potential association [5].

Psychiatry related information on ADRB3

• Beta 3-adrenergic-receptor allele distributions in children, adolescents and young adults with obesity, underweight or anorexia nervosa [6].

High impact information on ADRB3

• The beta 3-adrenergic receptor, located mainly in adipose tissue, is involved in the regulation of lipolysis and thermogenesis [7].
• Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity [7].
• We used the polymerase chain reaction to amplify a region of the gene for the beta 3-adrenergic receptor encoding amino acid residues 27 to 110 in genomic DNA extracted from leukocytes from 185 patients with morbid obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], > 40) and 94 normal subjects [7].
• The Trp64Arg allele of the beta 3-adrenergic receptor is associated with abdominal obesity and resistance to insulin and may contribute to the early onset of NIDDM [8].
• Association of a polymorphism in the beta 3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns [8].

Chemical compound and disease context of ADRB3

• This result suggests the involvement of cystic fibrosis transmembrane conductance regulator (CFTR) chloride current in the electrophysiological effects of beta3-adrenoceptor stimulation in non-cystic fibrosis tissues [9].
• A possible pathogenic mutation in the beta 3-adrenergic-receptor gene (Trp64Arg) has been reported to be associated with an earlier age of onset of non-insulin-dependent diabetes mellitus (NIDDM) and clinical features of the insulin resistance syndrome in Pima Indian, Finnish and French subjects [10].
• Further, thermogenesis in adipocytes was stimulated by CL316243, a beta3-adrenoceptor agonist being developed to treat obesity [11].
• The thermogenic beta 3-adrenoceptor agonist BRL 26830A has been shown to increase weight loss in dieting subjects but tremor was a frequent adverse effect [12].
• Different regulation of free fatty acid levels and glucose oxidation by the Trp64Arg polymorphism of the beta3-adrenergic receptor gene and the promoter variant (A-3826G) of the uncoupling protein 1 gene in familial combined hyperlipidemia [13].

Biological context of ADRB3

• Recent studies have suggested that a missense Trp64Arg mutation in the beta3 adrenergic receptor (ADRB3) gene was involved in obesity and insulin resistance [1].
• The beta(3)-adrenergic receptor (ADRB3) is expressed mainly in visceral adipose tissue and is thought to contribute to lipolysis and the delivery of free fatty acids to the portal vein [2].
• However, there were no remarkable differences of IL-4 receptor or ADRB3 genotype prevalences [14].
• The beta(3) adrenergic receptor (ADRB3) is expressed in adipose tissue and plays a role in energy metabolism [15].
• SR 59119A, salbutamol, and isoproterenol (ADRB3, ADRB2, and nonselective ADRB agonists, respectively) induced a concentration-dependent relaxation of placental artery rings obtained from women with uncomplicated or preeclamptic pregnancies [3].

Anatomical context of ADRB3

• We have constructed a 2.8 Mb YAC contig of this region, centered on the human Fibroblast Growth Factor Receptor 1 (FGFR1) locus and encompassing the Adrenergic beta 3 Receptor (ADRB3) locus [16].
• Whereas beta-actin and the beta 2AR were detected in virtually all tissues, RT-PCR using beta 3AR primers gave products from 13 tissues, including skeletal muscle, lung, adipose tissue, kidney, small intestine, pancreas, spleen, and adrenal gland [17].
• 5. beta 3-Adrenoceptor mRNA expression, investigated with a polymerase chain reaction assay, was demonstrated in both types of adipocytes in the same cell preparations that had a lipolytic response to CGP 12177 [18].
• 1. The existence of a functional beta 3-adrenoceptor in man was investigated by studying the lipolytic action of selective beta-adrenoceptor agents in isolated white omental and subcutaneous fat cells [18].
• The selective beta3-adrenoceptor agonist BRL-37344 failed to affect anti-IgE-induced histamine release from cultured mast cells [19].

Associations of ADRB3 with chemical compounds

• METHODS: In a cross-sectional study, adult Aymara subjects (n = 152) living in the Andean regions of northern Chile were characterized with respect to their ADRB2 and ADRB3 genotypes, body mass index, plasma leptin and insulin levels, fasting glucose concentration, blood pressure, and plasma lipid profile [20].
• RT-PCR performed on as little as 20 ng of total RNA from 3T3-F442A cells, which expressed beta 3AR at very low levels (approximately 20 fmol/mg of protein), provided an easily detectable signal by ethidium bromide staining and Southern blotting of electrophoresed products [17].
• Furthermore, the obese subjects demonstrated a sixfold lower alpha 2-adrenoceptor sensitivity (P = 0.04). beta 3-Adrenoceptor sensitivity, but not alpha 2-, beta 1-, or beta 2-adrenoceptor sensitivity, correlated with norepinephrine-induced lipolysis (r = -0.67, P = 0.0001) and fat cell volume (r = -0.71, P = 0.0001) [21].
• Rat adipose tissue has been previously shown to express the beta 3-adrenoreceptor and lipolysis was increased in rat adipose tissue in the presence of alprenolol 10(-4) M and 10(-5) M [22].
• Beta 3-adrenoceptor agonists, BRL 37344 and SR 58611A, do not induce relaxation of human, sheep and guinea-pig airway smooth muscle in vitro [23].
• Insulin resistance, blood pressures and serum levels of lipids and glucose were not associated with the presence of the Arg variant of the ADRB3 gene [24].
• The beta3-AR agonists also increased contractility but with a much lower efficacy (approximately 10%) than isoprenaline [25].

Physical interactions of ADRB3

• Determination of structural domains for G protein coupling and ligand binding in beta 3-adrenergic receptor [26].

Regulatory relationships of ADRB3

• Patch-clamp experiments confirmed that CFTR channels were permanently activated in cells co-expressing CFTR and a high level of beta3-adrenoceptor [9].
• Trp64Arg mutation of the beta3-adrenergic receptor (AR) gene and C161T substitution of the peroxisome proliferator-activated receptor (PPAR) gamma gene have been reported to be associated with obesity or lipid metabolism in adults [27].
• CONCLUSIONS: These results indicate that in cerebral infarcted rats detrusor hyperreflexia can be suppressed by the selective beta3-adrenoceptor agonist CL316243 without increasing post-void residual volume and without significant cardiovascular side effects [28].
• Mechanisms of beta 3-adrenoceptor-induced eNOS activation in right atrial and left ventricular human myocardium [29].

Other interactions of ADRB3

• Association analysis of the entire group showed significant evidence for a synergistic effect between the Thr92Ala DIO2 and Trp64Arg ADRB3 variants on BMI (both variants 34.3 plus minus 0.9 kg/m(2) vs. neither variant 33.1 plus minus 0.4 kg/m(2), P = 0.04 for interaction) [30].
• RT-PCR was performed on RNA obtained from 23 different human tissues, using primers for the beta 3AR, the beta 2AR, and beta-actin, which acted as a control [17].
• Moreover, in women, a statistically significant interaction (P=0.026) between the LPL and the ADRB3 gene loci in determining BMI was found [31].
• No statistically significant relationship was demonstrated for the investigated ADRB3 Trp64Arg and the GNB3 C825T polymorphisms in terms of BWC post-treatment, suggesting these two polymorphisms do not play a significant role in clozapine-induced BWC [32].
• Three SNPs (803T>C of AGT, 677CT of MTHFR, 190T>C of ADRB3) showed weak differences in allelic frequency [33].

Analytical, diagnostic and therapeutic context of ADRB3

• Western blot analysis, however, revealed a decreased expression of the ADRB3 immunoreactive protein in arteries from preeclamptic compared to normotensive women [3].
• ADRB2 and ADRB3 genotypes were determined by polymerase chain reaction (PCR) restriction fragment length polymorphism assessment [5].
• Northern blots of selected tissues failed to reveal any beta 3AR mRNA, suggesting little or no expression [17].
• beta 3-Adrenoceptor (beta 3-AR) agonists were first identified more than twelve years ago and were found to be remarkably effective in animal models of obesity and Type II (non-insulin dependent) diabetes [34].
• We examined the association between mutations of the IRS-1 gene at codon 972, mutations of the beta-3-AR gene at codon 64, and the combination of both mutations with the degree of weight loss, waist to hip ratio and the prevalence of hypertension, dyslipidemia and type 2 diabetes mellitus [35].

References