Roles of Beta2- and Beta3-Adrenoceptor Polymorphisms in Hypertension and Metabolic Syndrome

Masuo, Kazuko

doi:https://doi.org/10.4061/2010/832821

International Journal of Hypertension

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Volume 2010 | Article ID 832821 | https://doi.org/10.4061/2010/832821

Roles of Beta2- and Beta3-Adrenoceptor Polymorphisms in Hypertension and Metabolic Syndrome

Kazuko Masuo¹

Academic Editor: Toshio Ogihara

Received19 Jul 2010

Accepted02 Sept 2010

Published21 Oct 2010

Abstract

Hypertension, diabetes mellitus (especially type 2 diabetes mellitus), metabolic syndrome and obesity are rapidly growing public health problems. Sympathetic nerve activation is observed in obesity, hypertension and diabetes mellitus, which have strong genetic as well as environmental determinants. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of catecholamines in obesity have been mainly mediated via the 2- and 3-adrenergic receptors in humans. Further, 2-adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. Genetic polymorphistns of the -adrenoceptor gene have been shown to alter the function of several adrenoceptor subtypes and thus to modify the response to catecholamine. 2-adrenoceptor polymorphisms (Arg16Gly, Gln27Glu, and Thr164Ile) have been studied in relation to hypertension. Genetic variations in the 3-adrenoceptor (i.e. Try64Arg variant) are also associated with both obesity and hypertension. However, the precise relationships of the polymorphisms of 2- and 3-adrenoceptor genes with sympathetic nervous system activity, hypertension, and metabolic syndrome have not been fully clarified. This paper will discuss the current topics involving the influence of the sympathetic nervous system and 2- and 3- adrenoceptor polymorphisms in hypertension and metabolic syndrome.

1. Introduction

Obesity, hypertension, and metabolic syndrome (type 2 diabetes mellitus) are major and growing health problems and are known as high-risk factors for subsequent cardiovascular and renal complications [1–3]. Obesity, hypertension, diabetes, and metabolic syndrome are intimately associated [4–6], and sympathetic nervous activation is frequently observed in those conditions. Thus, sympathetic nerve activation may play a major role in the onset and development of hypertension, obesity, and metabolic syndrome (diabetes mellitus) as well as cardiovascular complications in patients with hypertension, diabetes and obesity [2, 7].

The sympathetic nervous system plays an important role in the regulation of energy expenditure. Reduced energy expenditure and resting metabolic rate are predictive of weight gain (obesity). The sympathetic nervous system participates in regulating energy balance through thermogenesis [8]. A large part of the sympathetic nervous system-mediated energy expenditure takes place in skeletal muscle, via the coupling of catecholamines with β2-adrenoceptors. Catecholamines are also powerful regulators of lipolysis and act via 1-, 2-, 3- (stimulatory), and 2- (inhibitory) adrenoceptor subtypes in adipose tissue, where their role becomes especially important during both exercise and energy restriction, when increased need for fat as a fuel exists. Thus, -adrenoceptors play important roles in energy expenditure and control body weight [9–13].

Recently, there is evidence that human hypertension and obesity have strong genetic backgrounds [14–16]. Harrap et al. reported that about 46% of the phenotype of systolic blood pressure are determined genetically for hypertension [17, 18]. Masuo et al. [18–22] have reported close relationships between 2- and 3-adrenoceptor polymorphisms accompanying elevated sympathetic nervous activity, blood pressure elevation (hypertension), weight gain (obesity), and insulin resistance in a series of longitudinal study. Many epidemiological studies on the relationships between -adrenoceptor polymorphisms, hypertension, obesity, and diabetes (metabolic syndrome) have still been discordant.

This paper will discuss the current topics involving the contribution of the sympathetic nervous system and 2- and 3-adrenoceptor polymorphisms in the onset and the development of hypertension and metabolic syndrome (type 2 diabetes mellitus).

2. Subtypes of Adrenoceptors (Table 1)

The adrenoceptors (or adrenergic receptors) are a class of G protein-coupled receptors which specifically bind their endogenous ligands, the catecholamines (epinephrine and norepinephrine). Many tissues possess these adrenoceptors, and the binding of an agonist generally elicits a “typical” sympathetic response (i.e., the fight-or-flight response). Table 1 shows the effects of catecholamines bound to adrenoceptors (Table 1) and these effects on sympathetic nervous activity are through - and -adrenergic receptors.

There are several types of adrenergic receptors, but there are two main groups: -adrenoceptors (1- and 2-adrenoceptors) and -adrenoceptors (1-, 2-, and 3-adrenoceptors). Table 1 also summaries the distributions and functions of the 1-, 2-, 1-, 2-, and 3-adrenoceptors [24, 25]. The -receptors bind norepinephrine and epinephrine, though norepinephrine has higher affinity. Phenylephrine is a selective agonist of the -adrenoceptors (both 1- and 2-receptors), thus phenylephrine is usually used to investigate the -adrenoceptors function. -adrenoceptors are linked to G proteins, which are linked to adenyl cyclase. -adrenoceptor agonists cause the intracellular elevation of the second messenger cyclic AMP. Downstream effects of cyclic AMP include cyclic AMP dependent protein kinase, which mediates the intracellular events following hormone binding.

3. Sympathetic Nervous Activity and Insulin Resistance in Hypertension (Figure 1)

Insulin resistance in hypertension has been well documented in many epidemiological and clinical studies [8, 26, 27]. Several investigators have reported that chronic insulin administration elevates blood pressure in rats and in humans [28], although insulin also has effects on vasodilation. In addition, many clinical and epidemiological studies have demonstrated the close relationships between sympathetic nerve activity, insulin resistance and hypertension [19, 29–32].

Landsberg and other investigators examined the effect of feeding and starvation on sympathetic nerve activity in the cardiac tissue of animals, noting that feeding raised sympathetic nerve activity, and starvation had the opposite effect [33–35]. Energy intake stimulates hyperinsulinemia and sympathetic nerve activity resulting in blood pressure elevations in a cycle to inhibit thermogenesis. Insulin-mediated sympathetic nerve stimulation in obese subjects is a compensatory mechanism aimed at restoring the energy balance by increasing the metabolic rate [33]. Therefore, hyperinsulinemia and insulin resistance in obese subjects are all part of a response to limit further weight gain via stimulating sympathetic nerve activity and thermogenesis [28].

On the other hand, Julius et al. [36] have hypothesized that increased sympathetic nerve activity in skeletal muscle causes neurogenic vasoconstriction, thereby reducing blood flow to muscle and consequently inducing a state of insulin resistance by lowering glucose delivery and uptake in hypertension and obesity. Both blood pressure elevation and weight gain may reflect a primary increase in sympathetic nervous tone. Masuo et al. [30, 37] supported Julius’s hypothesis. They described that high plasma norepinephrine might predict future blood pressure elevations and weight gain accompanying deterioration in insulin resistance observed in HOMA-IR (homeostasis model assessments of insulin resistance) [30, 37]. Rocchini et al. [38] reported that clonidine prevented insulin resistance in obese dogs over a 6-week period. Their results suggest that sympathetic nerve activity might play a major role in the development of insulin resistance accompanying blood pressure elevations. Valentini et al. [39] reported attenuation of hemodynamic and energy expenditure responses to isoproterenol infusion in hypertensive patients, suggesting that sympathetic nerve activity-induced hypertension may subsequently lead to the development of obesity.

Many epidemiological studies showed close linkages of beta2- and beta3-adrenoceptor polymorphisms with obesity, hypertension, and the metabolic syndrome shown in Tables 2, 3, and 4. Sympathetic nervous activity is related to body weight or blood pressure through β-adrenoceptors. Thus, close linkages between sympathetic nerve activity and insulin resistance might depend on the β-adrenoceptor polymorphisms. Thus, one could speculate that the strong associations between β-adrenoceptor polymorphisms and insulin resistance might provide evidence that heightened sympathetic nerve activity followed by insulin resistance might play a major role in hypertension and obesity, because β-adrenoceptor polymorphisms might relate to insulin resistance through heightened sympathetic nerve activity (Figure 1).

4. Role of β-Adrenoceptor Polymorphisms in Hypertension, Obesity, and Diabetes

The sympathetic nervous system plays an important role in the regulation of energy expenditure and blood pressure regulation. A large part of the sympathetic nervous system-mediated energy expenditure takes place in skeletal muscle, via the coupling of catecholamines with 2-adrenoceptors. Catecholamines are also powerful regulators of lipolysis and act via 1-, 2-, 3- (stimulatory), and 2- (inhibitory) adrenoceptor subtypes in adipose tissue, where their role becomes especially important during both exercise and energy restriction, when increased need for fat as a fuel exists. Stimulation of -adrenergic receptors by the sympathetic nervous system is a significant physiological modulator of pre- and postprandial energy expenditure [11–13] and total daily energy expenditure [9, 10].

Recent studies show that -adrenoceptors are polymorphic. Single nucleotide polymorphisms might have functional consequences in terms of receptor activity and regulation and hence may contribute to the pathophysiology of hypertension and obesity. On the other hand, there are few studies on the relationships between -adrenoceptor polymorphisms, hypertension, obesity, and metabolic syndrome.

4.1. 1-Adrenoceptor Polymorphisms

The 1-adrenoceptor is predominantly expressed in cardiac myocytes and adipose tissue, where its activation leads to increased heart rate and contractility and stimulation of lipolysis, respectively. The two most common 1-adrenoceptor polymorphisms are Ser49Gly and Arg389Gly, with relative allele frequencies of 0.85/0.15 and 0.70/0.30 in the Caucasian population, respectively. The 1-adrenoceptor is a candidate gene for obesity because of its role in catecholamine-mediated energy homeostasis [72, 73]. For example, in obese individuals, the degree of weight loss during a very low calorie diet has been shown to correlate with changes in 1-adrenoceptor protein concentration in adipose tissue [72]. A population cohort of 761 women showed that women carrying the Gly49 genotype had greater increases in BMI over15 years compared to those with the Ser49 genotype [73]. Conversely, the distribution of the Arg389Gly polymorphism is similar in lean and obese subjects [74] and in a large cohort study including 3981 normotensive and 2518 hypertensive subjects [75]. The factors which might explain the discrepancy of published data are shown in the later section.

4.2. 2-Adrenoceptor Polymorphisms

The 2-adrenoceptor is the dominant lipolytic receptor in white human adipose tissue [13] and in skeletal muscle [12]. It also plays an important regulatory role in the peripheral vasculature. Genetic polymorphisms of the 2-adrenoceptor have been associated with hypertension, obesity, and metabolic syndrome (diabetes mellitus). The most common polymorphisms are Arg16Gly, with an allele frequency of 0.40/0.60, and Gln27Glu, with an allele frequency of 0.55/0.45, in the Caucasian population. The Thr164Ile polymorphism is rare, occurring in only 3 to 5% of the general Caucasians population.

Studies of agonist stimulation in cultured cells demonstrate that Gly16 receptors have a greater reduction in numbers or enhanced downregulation when compared with Arg16 whereas the Glu27 receptor is resistant to down regulation when compared with the Gln27 variant [108]. A number of clinical studies have investigated the impact of these polymorphisms on vascular responsiveness [40, 109]. Gratze et al. [110] found that young normotensive white men homozygous for the Gly16 allele had higher blood pressure and lower peripheral vasodilation after infusion of the 2-agonist salbutamol. Similar results were obtained by Hoit et al. [111] using the agonist terbutaline. On the other hand, three studies investigating isoprenaline induced increase in the limb blood flow Thus, volunteers homozygous for Gly16 exhibited larger vasodilatory responses than did volunteers homozygous for Arg16 [23]. Conflicting results have also been published with regard to the effects of genetic variants on the sympathetic nervous system modulation of energy expenditure. Bell et al. [112] reported that the response of resting energy expenditure to nonspecific -adrenoceptor stimulation (with isoproterenol infusion) was not different between the 3 genotypes of Arg16Gly. Stob et al. [41] showed that individuals carrying the Arg16Arg variant of the 2-adrenoceptor gene have a reduced thermogenic response to selective 2-adrenoceptor activation.

Associations of 2-adrenoceptor polymorphisms with hypertension and metabolic syndrome have been reported in many epidemiological studies but results are also discordant (summarised in Tables 2 and 3).

4.3. 3-Adrenoceptor Polymorphisms

The 3-adrenoceptor, which is mainly expressed in adipose tissue, differs from the 2-adrenoceptor in two ways: it has a lower affinity for catecholamines, and it resists desensitisation (i.e., downregulation). These characteristic differences might lead to the different effects of catecholamine on 2-adrenoceptors and 3-adrenoceptors. 3-adrenoceptors stimulate the mobilization of lipids from the white fat cell and increase thermogenesis in brown fat cell. Decreased function of 3-adrenoceptor in white adipose tissue could slow lipolysis and thereby cause the retention of lipids in fat cells. Slow lipolysis may contribute strongly to visceral obesity in human, and treatment of obese animal models with selective 3-adrenergic agonists reduces fat stores most effectively [94, 113, 114]. Many epidemiological studies have shown the strong relationships between 3-adrenoceptor polymorphisms (mainly Trp54Arg), hypertension, metabolic syndrome, and obesity [78, 94, 113–117] (Table 4).

4.4. Confounding Variables Affecting the Relationships of -Adrenoceptor Polymorphisms with Obesity, Hypertension, and Diabetes (Table 5)

Tables 2, 3, 4, and 5 show the discordant contributions of -adrenoceptor polymorphisms to hypertension, metabolic syndrome (type 2 diabetes), and obesity. Table 5 summarizes factors which might explain the discrepancy of published data. Further, haplotypes of polymorphisms have strong influence on -adrenoceptor function in each polymorphism [20, 58, 59, 105–107].

5. Conclusions

The role of the sympathetic nervous system 2- and 3-adrenoceptor polymorphisms in hypertension, metabolic syndrome (diabetes mellitus), and obesity is discussed through a literature review. Sympathetic nervous system activity and -adrenoceptor polymorphisms (mainly 2- and 3-adrenoceptor polymorphisms) might contribute to the onset and maintenance of hypertension, metabolic syndrome, and obesity; however, the findings have been discordant. Further, few studies have been performed to evaluate the relationship between 2- and 3-adrenoceptor polymorphisms and sympathetic nervous system activity in the same study. A better understanding for the relationships of genetic background (polymorphisms) with sympathetic nervous system activity as the cause for hypertension (blood pressure elevation), metabolic syndrome (insulin resistance), and obesity (weight gain) might help for clinical treatment for obesity-related hypertension and metabolic syndrome. In fact, a number of studies have investigated genetic polymorphisms as determinants of cardiovascular response to antihypertensive drug therapy [103, 104]. But further research on gene-drug interactions is necessary. In addition, to clarify the pathogenesis and mechanisms may lead to the prevention of hypertension and metabolic syndrome in obesity.

References

A. H. Mokdad, B. A. Bowman, E. S. Ford, F. Vinicor, J. S. Marks, and J. P. Koplan, “The continuing epidemics of obesity and diabetes in the United States,” Journal of the American Medical Association, vol. 286, no. 10, pp. 1195–1200, 2001.
View at: Google Scholar
C. Heidemann, H. Boeing, T. Pischon, U. Nöthlings, H.-G. Joost, and M. B. Schulze, “Association of a diabetes risk score with risk of myocardial infarction, stroke, specific types of cancer, and mortality: a prospective study in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort,” European Journal of Epidemiology, vol. 24, no. 6, pp. 281–288, 2009.
View at: Publisher Site | Google Scholar
K. M. Flegal, B. I. Graubard, D. F. Williamson, and M. H. Gail, “Cause-specific excess deaths associated with underweight, overweight, and obesity,” Journal of the American Medical Association, vol. 298, no. 17, pp. 2028–2037, 2007.
View at: Publisher Site | Google Scholar
F. Ramsey, A. Ussery-Hall, D. Garcia et al., “Centers for disease control and prevention (CDC),” MMWR Surveillance Summaries, vol. 57, pp. 1–20, 2008.
View at: Google Scholar
C. L. Ogden, C. D. Fryar, M. D. Carroll, and K. M. Flegal, “Advance data from vital and health statics,” CDC, vol. 347, pp. 1–20, 2004.
View at: Google Scholar
A. H. Mokdad, M. K. Serdula, W. H. Dietz, B. A. Bowman, J. S. Marks, and J. P. Koplan, “The spread of the obesity epidemic in the United States, 1991–1998,” Journal of the American Medical Association, vol. 282, no. 16, pp. 1519–1522, 1999.
View at: Publisher Site | Google Scholar
S. R. Preis, S.-J. Hwang, S. Coady et al., “Trends in all-cause and cardiovascular disease mortality among women and men with and without diabetes mellitus in the Framingham heart study, 1950 to 2005,” Circulation, vol. 119, no. 13, pp. 1728–1735, 2009.
View at: Publisher Site | Google Scholar
M. Spraul, E. Ravussin, A. M. Fontvieille, R. Rising, D. E. Larson, and E. A. Anderson, “Reduced sympathetic nervous activity. A potential mechanism predisposing to body weight gain,” Journal of Clinical Investigation, vol. 92, no. 4, pp. 1730–1735, 1993.
View at: Google Scholar
S. Iwashita, M. Tanida, N. Terui et al., “Direct measurement of renal sympathetic nervous activity in high-fat diet-related hypertensive rats,” Life Sciences, vol. 71, no. 5, pp. 537–546, 2002.
View at: Publisher Site | Google Scholar
M. B. Monroe, D. R. Seals, L. F. Shapiro, C. Bell, D. Johnson, and P. P. Jones, “Direct evidence for tonic sympathetic support of resting metabolic rate in healthy adult humans,” American Journal of Physiology, vol. 280, no. 5, pp. E740–E744, 2001.
View at: Google Scholar
E. E. Blaak, M. A. van Baak, K. P. G. Kempen, and W. H. M. Saris, “Role of α- and β-adrenoceptors in sympathetically mediated thermogenesis,” American Journal of Physiology, vol. 264, no. 1, pp. E11–E17, 1993.
View at: Google Scholar
E. Hagström-Toft, S. Enoksson, E. Moberg, J. Bolinder, and P. Arner, “β-adrenergic regulation of lipolysis and blood flow in human skeletal muscle in vivo,” American Journal of Physiology, vol. 275, no. 6, pp. E909–E916, 1998.
View at: Google Scholar
S. Enoksson, M. Talbot, F. Rife, W. V. Tamborlane, R. S. Sherwin, and S. Caprio, “Impaired in vivo stimulation of lipolysis in adipose tissue by selective β2-adrenergic agonist in obese adolescent girls,” Diabetes, vol. 49, no. 12, pp. 2149–2153, 2000.
View at: Google Scholar
K. Masuo, H. Mikami, T. Ogihara, and M. L. Tuck, “Familial hypertension, insulin, sympathetic activity, and blood pressure elevation,” Hypertension, vol. 32, no. 1, pp. 96–100, 1998.
View at: Google Scholar
K. Masuo, H. Mikami, T. Ogihara, and M. L. Tuck, “Familial obesity, sympathetic activation and blood pressure level,” Blood Pressure, vol. 10, no. 4, pp. 199–204, 2001.
View at: Publisher Site | Google Scholar
J. Cui, J. L. Hopper, and S. B. Harrap, “Genes and family environment explain correlations between blood pressure and body mass index,” Hypertension, vol. 40, no. 1, pp. 7–12, 2002.
View at: Publisher Site | Google Scholar
J. Cui, J. L. Hopper, and S. B. Harrap, “Genes and family environment explain correlations between blood pressure and body mass index,” Hypertension, vol. 40, no. 1, pp. 7–12, 2002.
View at: Publisher Site | Google Scholar
K. J. Scurrah, S. G. Zaloumis, J. L. Hopper, and S. B. Harrap, “Contribution of genes and environment to variation in postural changes in mean arterial and pulse pressure,” Journal of Hypertension, vol. 26, no. 12, pp. 2319–2325, 2008.
View at: Publisher Site | Google Scholar
K. Masuo, H. Mikami, T. Ogihara, and M. L. Tuck, “Differences in insulin and sympathetic responses to glucose ingestion due to family history of hypertension,” American Journal of Hypertension, vol. 9, no. 8, pp. 739–745, 1996.
View at: Publisher Site | Google Scholar
A. C. Pereira, M. S. Floriano, G. F. A. Mota et al., “β2 adrenoceptor functional gene variants, obesity, and blood pressure level interactions in the general population,” Hypertension, vol. 42, no. 4, pp. 685–692, 2003.
View at: Publisher Site | Google Scholar
K. Masuo, T. Katsuya, Y. Fu, H. Rakugi, T. Ogihara, and M. L. Tuck, “β2- and β3-adrenergic receptor polymorphisms are related to the onset of weight gain and blood pressure elevation over 5 years,” Circulation, vol. 111, no. 25, pp. 3429–3434, 2005.
View at: Publisher Site | Google Scholar
K. Masuo, T. Katsuya, H. Kawaguchi et al., “Rebound weight gain as associated with high plasma norepinephrine levels that are mediated through polymorphisms in the β2-adrenoceptor,” American Journal of Hypertension, vol. 18, no. 11, pp. 1508–1516, 2005.
View at: Publisher Site | Google Scholar
K. Leineweber, “Beta-adrenergic receptor polymorphism in human cardiovascular disease,” Annals of Medicine, vol. 36, no. 1, pp. 64–69, 2004.
View at: Publisher Site | Google Scholar
L. T. Jablonskis and P. R. C. Howe, “Lack of influence of circulating adrenaline on blood pressure in normotensive and hypertensive rats,” Blood Pressure, vol. 3, no. 1-2, pp. 112–119, 1994.
View at: Google Scholar
M. Dóda, “Role of different subtypes of adrenoceptors in pressor responses to catecholamines released from sympathetic nerve endings,” Brain Research Bulletin, vol. 42, no. 1, pp. 51–57, 1996.
View at: Publisher Site | Google Scholar
E. Ferrannini, G. Buzzigoli, and R. Bonadonna, “Insulin resistance in essential hypertension,” The New England Journal of Medicine, vol. 317, no. 6, pp. 350–357, 1987.
View at: Google Scholar
K. Masuo, H. Mikami, T. Ogihara, and M. L. Tuck, “Prevalence of hyperinsulinemia in young, nonobese Japanese men,” Journal of Hypertension, vol. 15, no. 2, pp. 157–165, 1997.
View at: Publisher Site | Google Scholar
L. Landsberg, “Insulin-mediated sympathetic stimulation: role in the pathogenesis of obesity-related hypertension (or, how insulin affects blood pressure, and why),” Journal of Hypertension, vol. 19, no. 3, pp. 523–528, 2001.
View at: Publisher Site | Google Scholar
K. D. Ward, D. Sparrow, L. Landsberg, J. B. Young, P. S. Vokonas, and S. T. Weiss, “Influence of insulin, sympathetic nervous system activity, and obesity on blood pressure: the Normative Aging Study,” Journal of Hypertension, vol. 14, no. 3, pp. 301–308, 1996.
View at: Publisher Site | Google Scholar
K. Masuo, H. Kawaguchi, H. Mikami, T. Ogihara, and M. L. Tuck, “Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation,” Hypertension, vol. 42, no. 4, pp. 474–480, 2003.
View at: Publisher Site | Google Scholar
K. Masuo, “Obesity-related hypertension: role of the sympathetic nervous system, insulin, and leptin,” Current Hypertension Reports, vol. 4, no. 2, pp. 112–118, 2002.
View at: Google Scholar
N. E. Straznicky, E. A. Lambert, G. W. Lambert, K. Masuo, M. D. Esler, and P. J. Nestel, “Effects of dietary weight loss on sympathetic activity and cardiac risk factors associated with the metabolic syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 11, pp. 5998–6005, 2005.
View at: Publisher Site | Google Scholar
L. Landsberg, “Diet, obesity and hypertension: an hypothesis involving insulin, the sympathetic nervous system, and adaptive thermogenesis,” Quarterly Journal of Medicine, vol. 61, no. 236, pp. 1081–1090, 1986.
View at: Google Scholar
L. Landsberg and J. B. Young, “Fasting, feeding and regulation of the sympathetic nervous system,” The New England Journal of Medicine, vol. 298, no. 23, pp. 1295–1301, 1978.
View at: Google Scholar
K. O'Dea, M. Esler, and P. Leonard, “Noradrenaline turnover during under- and over-eating in normal weight subjects,” Metabolism, vol. 31, no. 9, pp. 896–899, 1982.
View at: Google Scholar
S. Julius, M. Valentini, and P. Palatini, “Overweight and hypertension: a 2-way street?” Hypertension, vol. 35, no. 3, pp. 807–813, 2000.
View at: Google Scholar
K. Masuo, H. Mikami, M. Itoh, T. Ogihara, and M. L. Tuck, “Sympathetic activity and body mass index contribute to blood pressure levels,” Hypertension Research, vol. 23, no. 4, pp. 303–310, 2000.
View at: Google Scholar
A. P. Rocchini, H. Z. Mao, K. Babu, P. Marker, and A. J. Rocchini, “Clonidine prevents insulin resistance and hypertension in obese dogs,” Hypertension, vol. 33, no. 1, pp. 548–553, 1999.
View at: Google Scholar
M. Valentini, S. Julius, P. Palatini et al., “Attenuation of haemodynamic, metabolic and energy expenditure responses to isoproterenol in patients with hypertension,” Journal of Hypertension, vol. 22, no. 10, pp. 1999–2006, 2004.
View at: Publisher Site | Google Scholar
V. Large, L. Hellström, S. Reynisdottir et al., “Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function,” Journal of Clinical Investigation, vol. 100, no. 12, pp. 3005–3013, 1997.
View at: Google Scholar
N. R. Stob, C. Bell, M. A. van Baak, and D. R. Seals, “Thermic effect of food and β-adrenergic thermogenic responsiveness in habitually exercising and sedentary healthy adult humans,” Journal of Applied Physiology, vol. 103, no. 2, pp. 616–622, 2007.
View at: Publisher Site | Google Scholar
T. Hayakawa, Y. Nagai, T. Kahara et al., “Gln27Glu and Arg16Gly polymorphisms of the β2-adrenergic receptor gene are not associated with obesity in Japanese men,” Metabolism, vol. 49, no. 9, pp. 1215–1218, 2000.
View at: Publisher Site | Google Scholar
H. Jia, P. Sharma, R. Hopper, C. Dickerson, D. D. Lloyd, and M. J. Brown, “β2-adrenoceptor gene polymorphisms and blood pressure variations in East Anglian Caucasians,” Journal of Hypertension, vol. 18, no. 6, pp. 687–693, 2000.
View at: Google Scholar
H.-G. Xie, C. M. Stein, R. B. Kim et al., “Human β2-adrenergic receptor polymorphisms: no association with essential hypertension in black or white Americans,” Clinical Pharmacology and Therapeutics, vol. 67, no. 6, pp. 670–675, 2000.
View at: Google Scholar
G. Candy, N. Samani, G. Norton et al., “Association analysis of β2 adrenoceptor polymorphisms with hypertension in a Black African population,” Journal of Hypertension, vol. 18, no. 2, pp. 167–172, 2000.
View at: Google Scholar
J. R. Cockcroft, A. G. Gazis, D. J. Cross et al., “β2-adrenoceptor polymorphism determines vascular reactivity in humans,” Hypertension, vol. 36, no. 3, pp. 371–375, 2000.
View at: Google Scholar
A. Meirhaeghe, N. Helbecque, D. Cottel, and P. Amouyel, “Impact of polymorphisms of the human β2-adrenoceptor gene on obesity in a French population,” International Journal of Obesity, vol. 24, no. 3, pp. 382–387, 2000.
View at: Google Scholar
N. Kato, T. Sugiyama, H. Morita et al., “Association analysis of β2-adrenergic receptor polymorphisms with hypertension in Japanese,” Hypertension, vol. 37, no. 2, pp. 286–292, 2001.
View at: Google Scholar
K. Bengtsson, M. Orho-Melander, O. Melander et al., “β2-adrenergic receptor gene variation and hypertension in subjects with type 2 diabetes,” Hypertension, vol. 37, no. 5, pp. 1303–1308, 2001.
View at: Google Scholar
D. L. Ellsworth, S. A. Coady, W. Chen et al., “Influence of the β2-adrenergic receptor Arg16Gly polymorphism on longitudinal changes in obesity from childhood through young adulthood in a biracial cohort: the Bogalusa heart study,” International Journal of Obesity, vol. 26, no. 7, pp. 928–937, 2002.
View at: Publisher Site | Google Scholar
S.-H. Kim, D.-J. Kim, I. A. Seo et al., “Significance of β2-adrenergic receptor gene polymorphism in obesity and type 2 diabetes mellitus in Korean subjects,” Metabolism, vol. 51, no. 7, pp. 833–837, 2002.
View at: Publisher Site | Google Scholar
T.-J. Chang, M.-H. Tsai, Y.-D. Jiang et al., “The Arg16Gly polymorphism of human β2-adrenoreceptor is associated with type 2 diabetes in Taiwanese people,” Clinical Endocrinology, vol. 57, no. 5, pp. 685–690, 2002.
View at: Publisher Site | Google Scholar
C. T. M. Van Rossum, B. Hoebee, J. C. Seidell et al., “Genetic factors as predictors of weight gain in young adult Dutch men and women,” International Journal of Obesity, vol. 26, no. 4, pp. 517–528, 2002.
View at: Publisher Site | Google Scholar
C. Garenc, L. Pérusse, Y. C. Chagnon et al., “Effects of β2-adrenergic receptor gene variants on adiposity: the HERITAGE Family Study,” Obesity Research, vol. 11, no. 5, pp. 612–618, 2003.
View at: Google Scholar
F. Galletti, R. Iacone, E. Ragone et al., “Lack of association between polymorphism in the β2- adrenergic receptor gene, hypertension, and obesity in the Olivetti heart study,” American Journal of Hypertension, vol. 17, no. 8, pp. 718–720, 2004.
View at: Publisher Site | Google Scholar
T. Ikarashi, O. Hanyu, S. Maruyama et al., “Genotype Gly/Gly of the Arg16Gly polymorphism of the β 2-adrenergic receptor is associated with elevated fasting serum insulin concentrations, but not with acute insulin response to glucose, in type 2 diabetic patients,” Diabetes Research and Clinical Practice, vol. 63, no. 1, pp. 11–18, 2004.
View at: Publisher Site | Google Scholar
J. Tafel, I. Branscheid, B. Skwarna et al., “Variants in the human β1-, β2- and β 3-adrenergic receptor genes are not associated with morbid obesity in children and adolescents,” Diabetes, Obesity and Metabolism, vol. 6, no. 6, pp. 452–455, 2004.
View at: Publisher Site | Google Scholar
D. L. Ellsworth, S. A. Coady, W. Chen, S. R. Srinivasan, E. Boerwinkle, and G. S. Berenson, “Interactive effects between polymorphisms in the β-adrenergic receptors and longitudinal changes in obesity,” Obesity Research, vol. 13, no. 3, pp. 519–526, 2005.
View at: Google Scholar
I. C. Trombetta, L. T. Batalha, M. U. P. B. Rondon et al., “Gly16 + Glu27 β2-adrenoceptor polymorphisms cause increased forearm blood flow responses to mental stress and handgrip in humans,” Journal of Applied Physiology, vol. 98, no. 3, pp. 787–794, 2005.
View at: Publisher Site | Google Scholar
K. Masuo, T. Katsuya, Y. Fu, H. Rakugi, T. Ogihara, and M. L. Tuck, “β2-adrenoceptor polymorphisms relate to insulin resistance and sympathetic overactivity as early markers of metabolic disease in nonobese, normotensive individuals,” American Journal of Hypertension, vol. 18, no. 7, pp. 1009–1014, 2005.
View at: Publisher Site | Google Scholar
K. Masuo, T. Katsuya, H. Kawaguchi et al., “β2-adrenoceptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic activation,” American Journal of Hypertension, vol. 19, no. 10, pp. 1084–1091, 2006.
View at: Publisher Site | Google Scholar
H. Kawaguchi, K. Masuo, T. Katsuya et al., “β2- and β3-adrenoceptor polymorphisms relate to subsequent weight gain and blood pressure elevation in obese normotensive individuals,” Hypertension Research, vol. 29, no. 12, pp. 951–959, 2006.
View at: Publisher Site | Google Scholar
T. Kurabayashi, T. Yahata, J. Quan, and K. Tanaka, “Association of polymorphisms in the β2 and β3 adrenoceptor gene with polycystic ovary syndrome,” Journal of Reproductive Medicine, vol. 51, no. 5, pp. 389–393, 2006.
View at: Google Scholar
A. P. Gjesing, G. Andersen, K. S. Burgdorf et al., “Studies of the associations between functional β2- adrenergic receptor variants and obesity, hypertension and type 2 diabetes in 7,808 white subjects,” Diabetologia, vol. 50, no. 3, pp. 563–568, 2007.
View at: Publisher Site | Google Scholar
K. Masuo, T. Katsuya, K. Sugimoto et al., “High plasma norepinephrine levels associated with β2-adrenoceptor polymorphisms predict future renal damage in nonobese normotensive individuals,” Hypertension Research, vol. 30, no. 6, pp. 503–511, 2007.
View at: Publisher Site | Google Scholar
S. M. Echwald, T. I. A. Sørensen, A. Tybjærg-Hansen, T. Andersen, and O. Pedersen, “Gln27Glu variant of the human β2-adrenoreceptor gene is not associated with early-onset obesity in Danish men,” Diabetes, vol. 47, no. 10, pp. 1657–1658, 1998.
View at: Publisher Site | Google Scholar
L. Hellström, V. Large, S. Reynisdottir, H. Wahrenberg, and P. Arner, “The different effects of a Gln27Glu β2-adrenoceptor gene polymorphism on obesity in males and in females,” Journal of Internal Medicine, vol. 245, no. 3, pp. 253–259, 1999.
View at: Publisher Site | Google Scholar
B. Kortner, A. Wolf, D. Wendt, U. Beisiegel, and D. Evans, “Lack of association between a human β-2 adrenoceptor gene polymorphism (Gln27Glu) and morbid obesity,” International Journal of Obesity, vol. 23, no. 10, pp. 1099–1100, 1999.
View at: Google Scholar
T. Kawamura, G. Egusa, R. Fujikawa, and M. Okubo, “Gln27Glu variant of the β2-adrenergic receptor gene is not associated with obesity and diabetes in Japanese-Americans,” Metabolism, vol. 50, no. 4, pp. 443–446, 2001.
View at: Publisher Site | Google Scholar
O. Ukkola, A. Tremblay, and C. Bouchard, “Beta-2 adrenergic receptor variants are associated with subcutaneous fat accumulation in response to long-term overfeeding,” International Journal of Obesity, vol. 25, no. 11, pp. 1604–1608, 2001.
View at: Publisher Site | Google Scholar
J. L. González Sánchez, A. M. Proenza, M. T. Martínez Larrad et al., “The glutamine 27 glutamic acid polymorphism of the β 2-adrenoceptor gene is associated with abdominal obesity and greater risk of impaired glucose tolerance in men but not in women: a population-based study in Spain,” Clinical Endocrinology, vol. 59, no. 4, pp. 476–481, 2003.
View at: Publisher Site | Google Scholar
M. Rasmussen, A. Belza, T. Almdal et al., “Change in β1-adrenergic receptor protein concentration in adipose tissue correlates with diet-induced weight loss,” Clinical Science, vol. 108, no. 4, pp. 323–329, 2005.
View at: Publisher Site | Google Scholar
Y. Linné, I. Dahlman, and J. Hoffstedt, “β1-adrenoceptor gene polymorphism predicts long-term changes in body weight,” International Journal of Obesity, vol. 29, no. 5, pp. 458–462, 2005.
View at: Publisher Site | Google Scholar
M. Rydén, J. Hoffstedt, P. Eriksson, S. Bringman, and P. Arner, “The Arg389gly β1-adrenergic receptor gene polymorphism and human fat cell lipolysis,” International Journal of Obesity, vol. 25, no. 11, pp. 1599–1603, 2001.
View at: Publisher Site | Google Scholar
A. P. Gjesing, G. Andersen, A. Albrechtsen et al., “Studies of associations between the Arg389Gly polymorphism of the β1-adrenergic receptor gene (ADRB1) and hypertension and obesity in 7677 Danish white subjects,” Diabetic Medicine, vol. 24, no. 4, pp. 392–397, 2007.
View at: Publisher Site | Google Scholar
K. Clement, C. Vaisse, B. S. J. Manning et al., “Genetic variation in the β3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity,” The New England Journal of Medicine, vol. 333, no. 6, pp. 352–354, 1995.
View at: Publisher Site | Google Scholar
E. Widen, M. Lehto, T. Kanninen, J. Walston, A. R. Shuldiner, and L. C. Groop, “Association of a polymorphism in the β3-adrenergic-receptor gene with features of the insulin resistance syndrome in finns,” The New England Journal of Medicine, vol. 333, no. 6, pp. 348–351, 1995.
View at: Publisher Site | Google Scholar
J. Walston, K. Silver, C. Bogardus et al., “Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the β3-adrenergic-receptor gene,” The New England Journal of Medicine, vol. 333, no. 6, pp. 343–347, 1995.
View at: Publisher Site | Google Scholar
T. Fujisawa, H. Ikegami, E. Yamato et al., “Association of Trp64Arg mutation of the β3-adrenergic-receptor with NIDDM and body weight gain,” Diabetologia, vol. 39, no. 3, pp. 349–352, 1996.
View at: Publisher Site | Google Scholar
K. Silver, J. Walston, Y. Wang, G. Dowse, P. Zimmet, and A. R. Shuldiner, “Molecular scanning for mutations in the β3-adrenergic receptor gene in nauruans with obesity and noninsulin-dependent diabetes mellitus,” Journal of Clinical Endocrinology and Metabolism, vol. 81, no. 11, pp. 4155–4158, 1996.
View at: Publisher Site | Google Scholar
T. Fujisawa, H. Ikegami, E. Yamato et al., “Trp64Arg mutation of β3-adrenergic receptor in essential hypertension. Insulin resistance and the adrenergic system,” American Journal of Hypertension, vol. 10, no. 1, pp. 101–105, 1997.
View at: Publisher Site | Google Scholar
N. Sakane, T. Yoshida, T. Umekawa, M. Kondo, Y. Sakai, and T. Takahashi, “β3-adrenergic-receptor polymorphism: a genetic marker for visceral fat obesity and the insulin resistance syndrome,” Diabetologia, vol. 40, no. 2, pp. 200–204, 1997.
View at: Publisher Site | Google Scholar
J. Rissanen, M. Kuopusjärvi, J. Pihlajamäki et al., “The Trp64Arg polymorphism of the β3-adrenergic receptor gene: lack of association with NIDDM and features of insulin resistance syndrome,” Diabetes Care, vol. 20, no. 8, pp. 1319–1323, 1997.
View at: Google Scholar
N. McFarlane-Anderson, F. Bennett, R. Wilks et al., “The Trp64Arg mutation of the β3-adrenergic receptor is associated with hyperglycemia and current body mass index in Jamaican women,” Metabolism, vol. 47, no. 5, pp. 617–621, 1998.
View at: Publisher Site | Google Scholar
E. García-Rubi, R. D. Starling, A. Tchernof et al., “Trp64Arg variant of the β3-adrenoceptor and insulin resistance in obese postmenopausal women,” Journal of Clinical Endocrinology and Metabolism, vol. 83, no. 11, pp. 4002–4005, 1998.
View at: Google Scholar
J. A. M. J. L. Janssen, J. W. Koper, R. P. Stolk et al., “Lack of associations between serum leptin, a polymorphism in the gene for the β3-adrenergic receptor and glucose tolerance in the Dutch population,” Clinical Endocrinology, vol. 49, no. 2, pp. 229–234, 1998.
View at: Publisher Site | Google Scholar
K. Shiwaku, T. Q. Gao, A. Isobe, T. Fukushima, and Y. Yamane, “A Trp64Arg mutation in the β3-adrenergic receptor gene is not associated with moderate overweight in Japanese workers,” Metabolism, vol. 47, no. 12, pp. 1528–1530, 1998.
View at: Google Scholar
B. Ongphiphadhanakul, R. Rajatanavin, S. Chanprasertyothin et al., “Relation of β3-adrenergic receptor gene mutation to total body fat but not percent body fat and insulin levels in Thais,” Metabolism, vol. 48, no. 5, pp. 564–567, 1999.
View at: Publisher Site | Google Scholar
A. Pulkkinen, A. Kareinen, L. Saarinen, S. Heikkinen, S. Lehto, and M. Laakso, “The codon 64 polymorphism of the β3-adrenergic receptor gene is not associated with coronary heart disease or insulin resistance in nondiabetic subjects and non-insulin-dependent diabetic patients,” Metabolism, vol. 48, no. 7, pp. 853–856, 1999.
View at: Publisher Site | Google Scholar
C. Christiansen, P. Poulsen, and H. Beck-Nielsen, “The Trp64Arg mutation of the adrenergic β-3 receptor gene impairs insulin secretion: a twin study,” Diabetic Medicine, vol. 16, no. 10, pp. 835–840, 1999.
View at: Publisher Site | Google Scholar
K. Stangl, I. Cascorbi, M. Laule et al., “The β3-adrenergic receptor Trp64Arg mutation is not associated with coronary artery disease,” Metabolism, vol. 50, no. 2, pp. 184–188, 2001.
View at: Publisher Site | Google Scholar
P. Strazzullo, R. Iacone, A. Siani et al., “Relationship of the Trp64Arg polymorphism of the beta3-adrenoceptor gene to central adiposity and high blood pressure: interaction with age. Cross-sectional and longitudinal findings of the Olivetti prospective heart study,” Journal of Hypertension, vol. 19, no. 3, pp. 399–406, 2001.
View at: Publisher Site | Google Scholar
T. Ishii, H. Hirose, T. Kawai et al., “Effects of intestinal fatty acid-binding protein gene Ala54Thr polymorphism and β3-adrenergic receptor gene Trp64Arg polymorphism on insulin resistance and fasting plasma glucose in young to older Japanese men,” Metabolism, vol. 50, no. 11, pp. 1301–1307, 2001.
View at: Publisher Site | Google Scholar
N. Kurokawa, K. Nakai, S. Kameo, Z.-M. Liu, and H. Satoh, “Association of BMI with the β3-adrenergic receptor gene polymorphism in Japanese: meta-analysis,” Obesity Research, vol. 9, no. 12, pp. 741–745, 2001.
View at: Google Scholar
M. C. Ochoa, A. Marti, C. Azcona et al., “Gene-gene interaction between PPARγ2 and ADRβ3 increases obesity risk in children and adolescents,” International Journal of Obesity, vol. 28, supplement 3, pp. S37–S41, 2004.
View at: Publisher Site | Google Scholar
P. I. Porto, S. I. García, G. Dieuzeide, C. González, M. S. Landa, and C. J. Pirola, “Clinical features of the metabolic syndrome in adolescents: minor role of the Trp64Arg β3-adrenergic receptor gene variant,” Pediatric Research, vol. 55, no. 5, pp. 836–841, 2004.
View at: Publisher Site | Google Scholar
P.-J. Tsai, L.-P. Tsai, Y.-H. Lee et al., “Lack of relationship between β3-adrenergic receptor gene polymorphism and gestational diabetes mellitus in a Taiwanese population,” Metabolism, vol. 53, no. 9, pp. 1136–1139, 2004.
View at: Publisher Site | Google Scholar
K. Højlund, C. Christiansen, K. S. Bjørnsbo et al., “Energy body composition and insulin response to glucose in male twins discordant for the Trp64Arg polymorphism of the β3 -adrenergic receptor gene,” Diabetes, Obesity and Metabolism, vol. 8, no. 3, pp. 322–330, 2006.
View at: Publisher Site | Google Scholar
S. Tamaki, Y. Nakamura, Y. Tabara et al., “Relationship between metabolic syndrome and Trp64Arg polymorphism of the β3-adrenergic receptor gene in a general sample: the Shigaraki study,” Hypertension Research, vol. 29, no. 11, pp. 891–896, 2006.
View at: Publisher Site | Google Scholar
S. Morcillo, F. Cardona, G. Rojo-Martínez et al., “Effect of the combination of the variants -75G/A APOA1 and Trp64Arg ADRB3 on the risk of type 2 diabetes (DM2),” Clinical Endocrinology, vol. 68, no. 1, pp. 102–107, 2008.
View at: Publisher Site | Google Scholar
A. P. Gjesing, G. Andersen, K. Borch-Johnsen, T. Jørgensen, T. Hansen, and O. Pedersen, “Association of the β3-adrenergic receptor Trp64Arg polymorphism with common metabolic traits: studies of 7605 middle-aged white people,” Molecular Genetics and Metabolism, vol. 94, no. 1, pp. 90–97, 2008.
View at: Publisher Site | Google Scholar
K. Dunajska, F. Lwow, A. Milewicz et al., “β3-adrenergic receptor polymorphism and metabolic syndrome in postmenopausal women,” Gynecological Endocrinology, vol. 24, no. 3, pp. 133–138, 2008.
View at: Publisher Site | Google Scholar
T. J. Maxwell, M. M. Ameyaw, S. Pritchard et al., “Beta-2 adrenergic receptor genotypes and haplotypes in different ethnic groups,” International Journal of Molecular Medicine, vol. 16, no. 4, pp. 573–580, 2005.
View at: Google Scholar
H. Schelleman, B. H. Stricker, A. De Boer et al., “Drug-gene interactions between genetic polymorphisms and antihypertensive therapy,” Drugs, vol. 64, no. 16, pp. 1801–1816, 2004.
View at: Publisher Site | Google Scholar
J. Hoffstedt, O. Poirier, A. Thörne et al., “Polymorphism of the human β3-adrenoceptor gene forms a well-conserved haplotype that is associated with moderate obesity and altered receptor function,” Diabetes, vol. 48, no. 1, pp. 203–205, 1999.
View at: Publisher Site | Google Scholar
A. Sandilands, G. Yeo, M. J. Brown, and K. M. O'Shaughnessy, “Functional responses of human β1 adrenoceptors with defined haplotypes for the common 389R>G and 49S>G polymorphisms,” Pharmacogenetics, vol. 14, no. 6, pp. 343–349, 2004.
View at: Publisher Site | Google Scholar
M. Tomaszewski, N. J. R. Brain, F. J. Charchar et al., “Essential hypertension and β2-adrenergic receptor gene: linkage and association analysis,” Hypertension, vol. 40, no. 3, pp. 286–291, 2002.
View at: Publisher Site | Google Scholar
S. A. Green, J. Turki, M. Innis, and S. B. Liggett, “Amino-terminal polymorphisms of the human β2-adrenergic receptor impart distinct agonist-promoted regulatory properties,” Biochemistry, vol. 33, no. 32, pp. 9414–9419, 1994.
View at: Google Scholar
V. Dishy, G. G. Sofowora, H.-G. Xie et al., “The effect of common polymorphisms of the β2-adrenergic receptor on agonist-mediated vascular desensitization,” The New England Journal of Medicine, vol. 345, no. 14, pp. 1030–1035, 2001.
View at: Publisher Site | Google Scholar
G. Gratze, J. Fortin, R. Labugger et al., “β-2 adrenergic receptor variants affect resting blood pressure and agonist-induced vasodilation in young adult Caucasians,” Hypertension, vol. 33, no. 6, pp. 1425–1430, 1999.
View at: Google Scholar
B. D. Hoit, D. P. Suresh, L. Craft, R. A. Walsh, and S. B. Liggett, “β2-adrenergic receptor polymorphisms at amino acid 16 differentially influence agonist-stimulated blood pressure and peripheral blood flow in normal individuals,” American Heart Journal, vol. 139, no. 3, pp. 537–542, 2000.
View at: Google Scholar
C. Bell, N. R. Stob, and D. R. Seals, “Thermogenic responsiveness to nonspecific β-adrenergic stimulation is not related to genetic variation in codon 16 of the β2-adrenergic receptor,” American Journal of Physiology, vol. 290, no. 4, pp. E703–E707, 2006.
View at: Publisher Site | Google Scholar
A. P. Gjesing, G. Andersen, K. S. Burgdorf et al., “Studies of the associations between functional β2- adrenergic receptor variants and obesity, hypertension and type 2 diabetes in 7,808 white subjects,” Diabetologia, vol. 50, no. 3, pp. 563–568, 2007.
View at: Publisher Site | Google Scholar
P. Arner, “The β3-adrenergic receptor—a cause and cure of obesity?” The New England Journal of Medicine, vol. 333, no. 6, pp. 382–383, 1995.
View at: Publisher Site | Google Scholar
S. Enocksson, M. Shimizu, F. Lonnqvist, J. Nordenstrom, and P. Arner, “Demonstration of an in vivo functional β3-adrenoceptor in man,” Journal of Clinical Investigation, vol. 95, no. 5, pp. 2239–2245, 1995.
View at: Google Scholar
Y. T. Yang and M. A. McElligott, “Multiple actions of β-adrenergic agonists on skeletal muscle and adipose tissue,” Biochemical Journal, vol. 261, no. 1, pp. 1–10, 1989.
View at: Google Scholar
T. Oizumi, M. Daimon, T. Saitoh et al., “Genotype Arg/Arg, but not Trp/Arg, of the Trp64Arg polymorphism of the β3-adrenergic receptor is associated with type 2 diabetes and obesity in a large Japanese sample,” Diabetes Care, vol. 24, no. 9, pp. 1579–1583, 2001.
View at: Google Scholar

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Copyright © 2010 Kazuko Masuo. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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