• Preventive Nutrition and Food Science
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• 제9권1호
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• pp.71-78
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• 2004

Adrenergic receptors play a major role in thermogenesis and lipolysis in brown and visceral adipose tissues, and have been implicated in the pathogenesis of obesity and metabolic disorders. The purpose of this study was to estimate the effects of $\beta$2-adrenergic receptor ($\beta$2AR) and $\beta$3-adrenergic receptor ($\beta$3AR) genotypes on hyperglycemia and obesity in the Korean population. A representative sample consisting of 530 Korean men and women were measured for height, weight, BMI, WHR, obesity index and body composition. The genotypes of $\beta$2AR polymorphism in codon 27 and $\beta$3AR polymorphism in codon 64 were analyzed by the PCR RFLP method. Serum concentrations of fasting glucose, total cholesterol, HDL cholesterol and triglyceride were determined. The frequencies of $\beta$2AR and $\beta$3AR genotype were: both wild type, 62.5% ; only $\beta$2AR variant type, 12.8% ; only $\beta$3AR variant type, 18.8% ; and both variant type, 5.8% ; the frequency of E and R alleles were 0.098 and 0.137, respectively. Among the physiological parameters, fasting glucose level was significantly higher in subjects with both variant type compared with the three other types (p <0.05), Subjects with both variant type had 12%, 12% and 9.3% increases in serum glucose levels compared with wild type, only $\beta$2AR variant type, and only $\beta$3AR variant type, respectively. When logistic regression analysis was conducted to estimate the risk for hyperglycemia, the subjects were selected for fasting blood glucose concentrations of more than 6.105 m㏖/L (110 mg/dL), and the odds ratios were 1.215 (p=0.636) for only $\beta$2AR variant type,1.659 (p=0.089) for only $\beta$3AR variant type, and 3.078 (p=0.011) for both variant type. These results suggest that the interaction of $\beta$2AR and $\beta$3AR variant genotypes has a strong association with increased glucose levels, and might be a significant risk factor for hyperglycemia among Korean subjects.

• 한국환경성돌연변이발암원학회지
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• 제21권2호
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• pp.95-98
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• 2001

$\beta$$_2$-Adrenergic receptors($\beta$$_2$-AR) contribute to cardiovascular regulation by influencing several functions and a several studies suggest that a decreased function of the $\beta$$_2$-AR may be involved in essential hypertension. We investigated the Arg16Gly mutation of $\beta$$_2$-AR gene, which show enhanced agonist-promoted downregulation of the receptor and yielded different results in terms of association with essential hypertension. We studied the relationship between genetic variation in the $\beta$$_2$-adrenergic receptor gene and hypertension in a Korean population using Nde I restriction fragment length polymorphism (RFLP) analysis. There were significant differences in allele and genotype frequencies between essential hypertensive and normotensive group (Odds ratio(CI) = 1.71 (1.09-2.70)). Therefore, our result suggests that the Nde I RELP of the $\beta$$_2$-adrenergic receptor gene may be useful as a genetic marker in hypertension diagnostics in Korean population.

• The Korean Journal of Physiology and Pharmacology
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• 제1권2호
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• pp.161-167
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• 1997

This study compares the subtypes of central beta adrenergic receptors (ARs) of brains of untreated rats with those of imipramine-treated rats. Beta adrenergic receptors were measured by quantitative autoradiography of the binding of $^3H$-dihydroalprenolol ($^3H$-DHA) in coronal sections of rat brain. Repeated treatment of rats with imipramine significantly reduced the binding of $^3H$-DHA to beta-1 AR in many brain areas, especially throughout the cerebral cortex, hippocampus, thalamus, and amygdala. Significant reductions of the binding of $^3H$-DHA to beta-2 AR were not found in any area of the brain. These data suggests that a selective down-regulation of beta-1 AR may be involved in the adaptive changes occurring after prolonged imipramine treatment.

• Asian-Australasian Journal of Animal Sciences
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• 제14권1호
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• pp.13-16
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• 2001

Bovine ${\beta}1$-adrenergic receptor (AR) cDNA was cloned using degenerative primers. Bovine ${\beta}1$-AR coded for 467 amino acids and the comparison of the deduced amino acid sequence with that of sheep showed 93.4% identity. Northern blot analysis indicated that transcript size for the bovine ${\beta}1$-AR was 3.6 kb in the adipose tissue. The expression level of three $\beta$-ARs (1, 2, and 3) in bovine abdominal, subcutaneous, and perirenal adipose tissues were examined using reverse transcription-polymerase chain reaction (RT-PCR), and the levels of ${\beta}1$- and ${\beta}3$-AR mRNA were found to be lower in the subcutaneous adipose tissue than in the abdominal and perirenal adipose tissues. These results suggest that the expression of $\beta$-ARs mRNA are differentially regulated among the adipose tissues.

• Molecules and Cells
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• 제38권2호
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• pp.105-111
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• 2015

The beta2-adrenergic receptor (${\beta}2AR$) belongs to the G protein coupled receptor (GPCR) family, which is the largest family of cell surface receptors in humans. Extra attention has been focused on the human GPCRs because they have been studied as important protein targets for pharmaceutical drug development. In fact, approximately 40% of marketed drugs directly work on GPCRs. GPCRs respond to various extracellular stimuli, such as sensory signals, neurotransmitters, chemokines, and hormones, to induce structural changes at the cytoplasmic surface, activating downstream signaling pathways, primarily through interactions with heterotrimeric G proteins or through G-protein independent pathways, such as arrestin. Most GPCRs, except for rhodhopsin, which contains covalently linked 11 cis-retinal, bind to diffusible ligands, having various conformational states between inactive and active structures. The first human GPCR structure was determined using an inverse agonist bound ${\beta}2AR$ in 2007 and since then, more than 20 distinct GPCR structures have been solved. However, most GPCR structures were solved as inactive forms, and an agonist bound fully active structure is still hard to obtain. In a structural point of view, ${\beta}2AR$ is relatively well studied since its fully active structure as a complex with G protein as well as several inactive structures are available. The structural comparison of inactive and active states gives an important clue in understanding the activation mechanism of ${\beta}2AR$. In this review, structural features of inactive and active states of ${\beta}2AR$, the interaction of ${\beta}2AR$ with heterotrimeric G protein, and the comparison with ${\beta}1AR$ will be discussed.

• Biomolecules & Therapeutics
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• 제25권1호
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• pp.44-56
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• 2017

Insulin resistance is characterized by the reduced ability of insulin to stimulate tissue uptake and disposal of glucose including cardiac muscle. These conditions accelerate the progression of heart failure and increase cardiovascular morbidity and mortality in patients with cardiovascular diseases. It is noteworthy that some conditions of insulin resistance are characterized by up-regulation of the sympathetic nervous system, resulting in enhanced stimulation of ${\beta}$-adrenergic receptor (${\beta}$AR). Overstimulation of ${\beta}$ARs leads to the development of heart failure and is associated with the pathogenesis of insulin resistance in the heart. However, pathological consequences of the cross-talk between the ${\beta}$AR and the insulin sensitivity and the mechanism by which ${\beta}$AR overstimulation promotes insulin resistance remain unclear. This review article examines the hypothesis that ${\beta}$ARs overstimulation leads to induction of insulin resistance in the heart.

• Clinical and Experimental Emergency Medicine
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• 제3권3호
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• pp.175-180
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• 2016

Objective Combination of ${\beta}_1-adrenergic$ receptor (AR) blockade and ${\beta}_2-AR$ activation might be a potential novel therapy for treating heart failure. However, use of ${\beta}-AR$ agonists and/or antagonists in the clinical setting is controversial because of the lack of information on cardiac inotropic or chronotropic regulation by AR signaling. Methods In this study, we performed hemodynamic evaluation by examining force frequency response (FFR), Frank-Starling relationship, and response to a non-selective ${\beta}-AR$ agonist (isoproterenol) in hearts isolated from 6-month-old transgenic (TG) mice overexpressing ${\beta}_1-$ and ${\beta}_2-ARs$ (${\beta}_1-$ and ${\beta}_2-AR$ TG mice, respectively). Results Cardiac physiologic consequences of ${\beta}_1-$ and ${\beta}_2-AR$ overexpression resulted in similar maximal response to isoproterenol and faster temporary decline of positive inotropic response in ${\beta}_2-AR$ TG mice. ${\beta}_1-AR$ TG mice showed a pronounced negative limb of FFR, whereas ${\beta}_2-AR$ TG mice showed high stimulation frequencies with low contractile depression during FFR. In contrast, Frank-Starling relationship was equally enhanced in both ${\beta}_1-$ and ${\beta}_2-AR$ TG mice. Conclusion Hemodynamic evaluation performed in the present showed a difference in ${\beta}_1-$ and ${\beta}_2-AR$ signaling, which may be due to the difference in the desensitization of ${\beta}_1-$ and ${\beta}_2-ARs$.

• Journal of Nutrition and Health
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• 제35권8호
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• pp.870-879
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• 2002

The purpose of this study was to investigate the obesity and state of dietary intake of 216 young Korean females, and the influence of $\beta$-II, III Adrenergic receptor (AR) gene polymorphism upon obesity and dietary intake. The average weight, height and BMI of the subjects were 160 cm, 54 kg, and 20.9 kg/$m^2$, respectively. The average triceps skinfold thickness, waist circumference, hip circumference and WHR were 21.7mm, 73.1cm, 93.3cm and 0.78, respectively. The results of body composition measurement using bioimpedance method, average body fluid, body protein, mineral mass and body fat were 29.271, 7.22 kg, 6.79 kg and 19.16 kg, respectively. A dietary survey was conducted using 24-hour recall method. Average calorie intake was 1621 ㎉, which is 81% of Korean RDA. We detected 182 (84.3%) Gln27 (QQ) homozygotes and 34 (15.7%) Gln27Glu (QE) heterozygotes for $\beta$-II AR polymorphism. For $\beta$-III AR polymorphism, we detected 163 (75.5%) Trp64 (WW) and 53 (24.5%) Trp 64Arg (WR). The results of comparing of obesity by $\beta$-II AR gene polymorphism, obesity index and BMI of QE type were slightly higher than those of the QQ type. For $\beta$-III AR gene polymorphism, the mean BMI, obesity index, fat mass and percent body fat (%) of the WR type were significantly higher than those of the WW type (p < 0.05). These findings suggest that genetic variability in the human $\beta$-III AR is associated with obesity among young Korean females. We also evaluated the effect of the simultaneous presence of the $\beta$-II AR and $\beta$-III AR polymorphism on obesity. We found that the BMI and obesity index of the mutant type in both $\beta$-II AR and $\beta$-III AR were significantly higher than those of the type that has only one gene mutation or has no mutation (p < 0.05), indicating a synergistic effect of $\beta$-II AR and $\beta$-III AR polymorphism on obesity. No association was found between $\beta$-II Ad or $\beta$-III AR polymorphism and dietary intake.

• 방사선산업학회지
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• 제10권4호
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• pp.181-187
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• 2016

Selective ${\beta}_1$-agonist and antagonists are used for the treatment of cardiac diseases including congestive heart failure, angina pectoris and arrhythmia. Selective ${\beta}_1$-antagonists including nebivolol have high binding affinity on ${\beta}_1$-adrenergic receptor, not ${\beta}_2$-receptor mainly expressed in smooth muscle. Nebivolol is one of most selective ${\beta}_1$-blockers in clinically used ${\beta}_1$-blockers including atenolol and bisoprolol. We tried to develop clinically useful cardiac PET tracers using a selective ${\beta}_1$-blocker. Nebivolol is $C_2$-symmetric and has two chromane moiety with a secondary amino alcohol and aromatic fluorine. We adopted the general synthetic strategy using epoxide ring opening reaction. Unlike formal synthesis of nebivolol, we prepared two chromane building blocks with fluorine and iodine which was transformed to diaryliodonium salt for labelling of $^{18}F$. Two epoxide building blocks were readily prepared from commercially available chromene carboxylic acids (1, 8). Then, the amino alcohol building block (15) was prepared by ammonolysis of epoxide (14) followed by coupling reaction with the other building block, epoxide (7). Diaryliodonium salt, a precursor for $^{18}F$-aromatic substitution, was synthesized in moderate yield which was readily subjected to $^{18}F$-aromatic substitution to give $^{18}F$-labelled nebivolol.

• International Journal of Oral Biology
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• 제36권4호
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• pp.173-178
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• 2011

Tumor necrosis factor alpha ($TNF{\alpha}$) is a multifunctional cytokine that is elevated in inflammatory diseases such as atherosclerosis, diabetes and rheumatoid arthritis. Recent evidence has suggested that ${\beta}2$ adrenergic receptor (${\beta}2AR$) activation in osteoblasts suppresses osteogenic activity. In the present study, we explored whether $TNF{\alpha}$ modulates ${\beta}AR$ expression in osteoblastic cells and whether this regulation is associated with the inhibition of osteoblast differentiation by $TNF{\alpha}$. In the experiments, we used C2C12 cells, MC3T3-E1 cells and primary cultured mouse bone marrow stromal cells. Among the three subtypes of ${\beta}AR$, ${\beta}2$ and ${\beta}3AR$ were found in our analysis to be upregulated by $TNF{\alpha}$. Moreover, isoproterenol-induced cAMP production was observed to be significantly enhanced in $TNF{\alpha}$-primed C2C12 cells, indicating that $TNF{\alpha}$ enhances ${\beta}2AR$ signaling in osteoblasts. $TNF{\alpha}$ was further found in C2C12 cells to suppress bone morphogenetic protein 2-induced alkaline phosphatase (ALP) activity and the expression of osteogenic marker genes including Runx2, ALP and osteocalcin. Propranolol, a ${\beta}2AR$ antagonist, attenuated this $TNF{\alpha}$ suppression of osteogenic differentiation. $TNF{\alpha}$ increased the expression of receptor activator of NF-${\kappa}B$ ligand (RANKL), an essential osteoclastogenic factor, in C2C12 cells which was again blocked by propranolol. In summary, our data show that $TNF{\alpha}$ increases ${\beta}2AR$ expression in osteoblasts and that a blockade of ${\beta}2AR$ attenuates the suppression of osteogenic differentiation and stimulation of RANKL expression by $TNF{\alpha}$. These findings imply that a crosstalk between $TNF{\alpha}$ and ${\beta}2AR$ signaling pathways might occur in osteoblasts to modulate their function.