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Am J Physiol Endocrinol Metab 290: E703-E707, 2006. First published November 8, 2005; doi:10.1152/ajpendo.00411.2005
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Thermogenic responsiveness to nonspecific beta-adrenergic stimulation is not related to genetic variation in codon 16 of the beta2-adrenergic receptor

Christopher Bell, Nicole R. Stob, and Douglas R. Seals

Department of Integrative Physiology, University of Colorado, Boulder, Colorado

Submitted 30 August 2005 ; accepted in final form 7 November 2005


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
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Stimulation of beta-adrenergic receptors (beta-AR) by the sympathetic nervous system (SNS) modulates energy expenditure (EE), but substantial interindividual variability is observed. We determined whether the thermogenic response to beta-AR stimulation is related to genetic variation in codon 16 of the beta2-AR, a biologically important beta-AR polymorphism, and whether differences in SNS activity (i.e., the stimulus for agonist-promoted downregulation) are involved. The increase in EE ({Delta}EE, indirect calorimetry, ventilated hood) above resting EE in response to nonspecific beta-AR stimulation [iv isoproterenol: 6, 12, and 24 ng/kg fat-free mass (FFM)/min] was measured in 46 healthy adult humans [Arg16Arg: 9 male, 7 female, 48 ± 5 yr; Arg16Gly: 11 male, 4 female, 53 ± 5 yr; Gly16Gly: 3 male, 12 female, 48 ± 5 yr (means ± SE)]. Neither FFM-adjusted baseline resting EE (P = 0.83) nor the dose of isoproterenol required to increase EE 10% above resting (P = 0.87) differed among the three groups (Arg16Arg: 5,409 ± 209 kJ/day, 11.2 ± 2.1 ng·kg FFM–1·min–1; Arg16Gly: 5,367 ± 272 kJ/day, 11.1 ± 2.1 ng·kg FFM–1·min–1; Gly16Gly: 5,305 ± 159 kJ/day, 10.5 ± 1.4 ng·kg FFM–1·min–1). Consistent with this, muscle sympathetic nerve activity and plasma norepinephrine concentrations were not different among the groups. Group differences in sex composition did not influence the results. Our findings indicate that the thermogenic response to nonspecific beta-AR stimulation, an important mechanistic component of overall beta-AR modulation of EE, is not related to this beta2-AR polymorphism in healthy humans. This may be explained in part by a lack of association between this gene variant and tonic SNS activity.

sympathetic activity; energy expenditure; genomics

IN HUMANS, stimulation of beta-adrenergic receptors (beta-AR) by the sympathoadrenal system is a significant physiological modulator of pre- and postprandial energy expenditure (EE) (4, 7, 17, 20, 24, 28, 30, 31, 33). beta-AR thermogenesis is also a critical physiological determinant of total daily EE and resistance to obesity in transgenic mice, particularly during high-fat feeding (2).

In healthy adult humans, individual and group differences in beta-AR thermogenesis are related primarily to tissue responsiveness to beta-AR stimulation (17, 18). However, beta-AR responsiveness varies considerably among individuals (18, 27). We (6) recently found that the coefficient of variation for the increase in EE above resting metabolic rate (RMR) in response to nonselective beta-AR stimulation with isoproterenol was ~50%.

The mechanisms underlying this variation have not been established. Recent evidence in humans suggests that a single nucleotide polymorphism in codon 16 of the beta2-AR gene influences regulation of multiple physiological systems and responses (11, 13–15, 21) including the increase in EE in response to selective beta2-AR activation (25). However, with respect to the latter observation (25), in vivo physiological activation of the peripheral beta-AR system and consequent increases in EE occur as a result of activation of all three beta-AR subtypes (30, 31). It is unknown whether this beta2-AR gene variant modulates the increase in EE in response to nonspecific beta-AR activation. If so, it is possible that differences in tonic sympathetic nervous system activity and norepinephrine release are involved because beta-AR signaling is sensitive to agonist-promoted downregulation (16, 23).

Accordingly, our primary aim was to determine whether the increase in EE in response to nonspecific beta-AR stimulation is associated with genetic variation in codon 16 of the beta2-AR. On the basis of the recent work using selective beta2-AR activation (25), we hypothesized that adults with the Arg16Arg polymorphism would demonstrate reduced responsiveness to nonspecific beta-AR stimulation. A secondary goal was to determine whether any group differences observed in nonselective beta-AR responsiveness were related to differences in tonic peripheral sympathetic nervous system activity.


   MATERIALS AND METHODS
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 MATERIALS AND METHODS
RESULTS
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Experimental Subjects

We studied 46 healthy adult males and females (18–74 yr). Subjects were recruited via standard methods (posters and newspaper and radio advertisements). Neither training status nor subject sex were considered as selection criteria. To minimize the risk of an adverse event associated with beta-AR stimulation, we specified in advance that all subjects must be healthy as assessed by medical history, physical examination, and metabolic-cardiovascular status. In addition, older subjects (≥35 years) had normal resting electrocardiograms (ECG) as well as ECG and blood pressure assessments during graded treadmill exercise to exhaustion. Subjects were nonsmokers and were not regularly taking any medications or vitamin/antioxidant supplements. The nature, purpose, and risks of the study were explained to each subject before written informed consent was obtained. The Human Research Committee at the University of Colorado-Boulder approved the experimental protocol.

Experimental Procedures

After screening, all primary outcome measurements were made during two visits to the University of Colorado-Boulder General Clinical Research Center (GCRC) on separate mornings, each after a 12-h fast, 2-h abstention from water, and 24-h abstention from vigorous physical exercise. Subjects were studied under quiet resting conditions in the semirecumbent position. Measurements were performed between 0700 and 0900 in a dimly lit room at a comfortable temperature (~23°C). Premenopausal females were studied during the early follicular phase of the menstrual cycle.

Thermogenic response to nonspecific beta-AR stimulation. Subjects were instrumented for measurement of heart rate (ECG) and blood pressure. A catheter was placed in an antecubital vein and was kept patent with heparin. After instrumentation and a 30-min rest period, baseline RMR was measured as previously described (7, 24). The first 15 min were considered a habituation period, after which oxygen consumption and carbon dioxide production were averaged each minute for 30 min using a ventilated hood indirect calorimetry system (DeltaTrac II Metabolic Monitor; SensorMedics, Yorba Linda, CA). This measurement was then repeated over three consecutive 30-min periods during incremental intravenous administration of the nonselective beta-AR agonist isoproterenol [6, 12, and 24 ng·kg fat free mass–1 (FFM)·min–1]. EE was calculated from the average of the final 25 min of each 30-min collection using the Weir formula (32). Steady-state conditions for oxygen uptake and carbon dioxide production during these sampling periods were confirmed by comparing the first and last minute of each sampling period (all P < 0.05). These data were then used to calculate the dose of isoproterenol required to increase EE 15% above RMR.

Microneurography. During a separate visit to the laboratory, recordings of multiunit skeletal muscle sympathetic nerve activity (MSNA) were obtained from the peroneal nerve by use of microneurography as previously described (4, 5) and expressed as bursts of integrated activity per minute. The same investigator (C. Bell) analyzed all neurograms and was blind to the group identity of the subjects.

DNA was isolated from 10 ml of whole blood (Puregene; Gentra Systems, Minneapolis, MN) and analyzed for genetic variation in beta2-ARs at codon 16 by the Genotyping & Mutation Core Laboratory at the University of Colorado Health Sciences Center, as previously described (1).

Dietary intake and composition were estimated from food diaries maintained for 3 consecutive days (2 weekdays and 1 weekend day). Subjects kept accurate and complete diet records and were provided with a diet scale (Scaleman; Target, Minneapolis, MN) to weigh all food. A GCRC registered dietician subsequently analyzed all of the food diaries by using standard computer-assisted procedures (ESHA-The Food Processor, version 7.6, Salem, OR).

Body composition was determined using dual-energy X-ray absorptiometry (DXA-IQ, software v. 4.1; Lunar Radiation, Madison, WI). Maximal oxygen uptake (VO2 max) was assessed during the screening visit via incremental treadmill exercise as previously described (3).

Statistical Analysis

RMR was adjusted for differences in FFM using analysis of covariance (relation between RMR and FFM: r = 0.78, P < 0.001). One-way analysis of variance (ANOVA) was used to examine differences in the dose of isoproterenol required to increase EE 10% above RMR in Arg16Arg, Arg16Gly, and Gly16Gly groups. Two-way ANOVA with repeated measures on one factor was used to examine differences in the percent increase in EE above RMR between the polymorphic groups. Multiple comparisons of factor means were performed using the Neuman-Keuls test. Relations between variables of interest were determined by simple correlation analysis. The level of statistical significance was set at P < 0.05. Data are expressed as means ± SE.


   RESULTS
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Subject Characteristics

Age, body mass, body mass index, body composition, VO2 max, resting heart rate and blood pressure, and RMR adjusted for FFM were not different among the groups (Table 1). Arg16Gly subjects were taller than those in the Gly16Gly group, and waist-to-hip ratio was lower in Gly16Gly compared with the other two groups. These differences could be explained by group sex composition.


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  		Table 1. Subject demographics, body composition, and cardiorespiratory parameters

 
Plasma concentrations of insulin, total cholesterol, and low-density lipoprotein cholesterol were not different among the groups (Table 2). Plasma high-density lipoprotein cholesterol concentration was lower in Gly16Gly subjects, and plasma triglyceride concentration was greater in Arg16Arg compared with the other two groups. Plasma glucose concentration was lower in Arg16Gly compared with Arg16Arg subjects. The difference in high-density lipoprotein concentration could be explained by group sex composition. Dietary intake (total energy intake and macronutrient composition) was unremarkable (i.e., not fad or macronutrient extreme) and was not different among groups (P > 0.05).


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  		Table 2. Baseline blood parameters

 
Thermogenic Responsiveness to Nonselective beta-AR Stimulation is Not Associated with Genetic Variation in Codon 16 of the beta2-AR

Neither absolute RMR [Arg16Arg, 5,447 ± 208; Arg16Gly, 5,640 ± 272; Gly16Gly, 4,991 ± 157 kJ/day (3.78 ± 0.14, 3.92 ± 0.19, 3.47 ± 0.11 kJ/min)] nor RMR adjusted for FFM (Table 1) were different among the groups (P > 0.05). EE increased above RMR in a dose-dependent manner in response to incremental beta-AR stimulation in all groups (P < 0.001; Table 3), but there was no interaction with genetic variation in codon 16 of the beta2-AR (P > 0.05; Fig. 1). The lack of association between the thermogenic response and this gene variant remained when the data were expressed as absolute EE, EE adjusted for FFM, change in absolute EE, and change in EE adjusted for FFM (all P > 0.05; data not shown). Respiratory exchange ratio was 0.82–0.85 at baseline and was not consistently affected by isoproterenol dose or genetic variation in codon 16 of the beta2-AR (P > 0.05). There were no significant interactions between isoproterenol dose and genetic variation in codon 16 of the beta2-AR for heart rate or blood pressure (all P > 0.05; Table 3).


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  		Table 3. Cardiovascular and metabolic responses to incremental nonspecific beta-adrenergic receptor stimulation (isoproterenol)

 

Figure 1
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  		Fig. 1. Thermogenic responsiveness to nonspecific beta-adrenergic receptor (beta-AR) stimulation is not associated with genetic variation in codon 16 of the beta2-AR. Energy expenditure (EE) was increased above resting metabolic rate in response to incremental beta-AR stimulation with iv isoproterenol in all subjects (P < 0.001), but there was no interaction with genetic variation in codon 16 of the beta2-AR (P > 0.05). Iso EE10%, dose of isoproterenol required to increase EE 15% above resting metabolic rate. Data are means ± SE.

 
Sympathetic Nervous System Activity Is Not Associated with Genetic Variation in Codon 16 of the beta2-AR

Baseline MSNA (Fig. 2) and plasma norepinephrine concentration were related to each other (r = 0.74, P < 0.001), but neither was associated with genetic variation in codon 16 of the beta2-AR (plasma norepinephrine: Arg16Arg 1.4 ± 0.2; Arg16Gly 1.6 ± 0.3; Gly16Gly 1.3 ± 0.3 nmol/l, P > 0.05).


Figure 2
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  		Fig. 2. Baseline skeletal muscle sympathetic nerve activity (MSNA) is not associated with genetic variation in codon 16 of the beta2-AR (P > 0.05). Data are means ± SE.

 
Lack of Influence of Within-Group Sex Composition on Primary Outcome Variables

All statistical comparisons were reanalyzed with sex as a covariable and also as an additional independent variable. None of the observations with respect to the primary outcome variables (thermogenic response to beta-AR stimulation and sympathetic nervous system activity) was influenced by group differences in group sex composition.

Correlates of beta-AR Thermogenesis

Among the pooled subjects there were no relations between the increase in EE in response to nonselective beta-AR stimulation and tonic peripheral sympathetic nervous system activity as described by MSNA (r = –0.10, P > 0.05) or plasma norepinephrine concentration (r = 0.01, P > 0.05). Similarly, beta-AR-mediated thermogenesis was not related to age (r = –0.17, P = 0.25), body mass index (r = –0.02, P = 0.87), or training status [as described by VO2 max (r = 0.11, P = 0.44)].


   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
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The results of the present study provide experimental support for the idea that thermogenic responsiveness to nonselective beta-AR stimulation is not associated with genetic variation in codon 16 of the beta2-AR. This investigation extends and clarifies the physiological significance of recent findings that adults with the Arg16Arg variant of the beta2-AR demonstrate a reduced thermogenic response to selective beta2-AR activation (iv salbutamol) (25). Because beta-AR modulation of EE occurs as a result of stimulation of all three beta-AR subtypes (30, 31), our findings are consistent with the concept that this polymorphism likely does not play an important role in determining metabolic responsiveness to endogenous physiological activation of the peripheral beta-AR system. Our results also fail to show any relation between this gene variant and either absolute RMR or RMR normalized for FFM.

The secondary goal of the present investigation was to determine whether measurements of peripheral sympathetic nervous system activity were associated with genetic variation in codon 16 of the beta2-AR, perhaps explaining any group differences observed in the thermogenic response to nonspecific beta-AR activation. On the basis of recent observations that the Arg16Arg beta2-AR polymorphism is associated with reduced sensitivity to selective beta2-AR stimulation (25), it could have been hypothesized that tonic peripheral sympathetic nervous system activity is greater in adults with that gene variant, causing greater norepinephrine release and agonist-promoted downregulation. Thus an additional novel finding of the present investigation is that genetic variation in codon 16 of the beta2-AR is not associated with basal MSNA. In agreement with this observation, there was no relation between this polymorphism and plasma norepinephrine concentration. Indeed, peripheral sympathetic activity was not related to metabolic responsiveness to nonspecific beta-AR stimulation in the present study. This observation has important implications given that beta-ARs are known to downregulate in the presence of tonically high sympathetic stimulation (16, 23). These findings in the present study may explain the lack of relation between basal sympathetic nervous system activity and tonic beta-AR support of RMR that we have reported previously (24).

Consistent with the thermogenic response, in the present investigation the increases in heart rate to isoproterenol were similar in the polymorphic groups. However, this cannot be interpreted as evidence for a lack of association between genetic variation in codon 16 and cardiac chronotropic responsiveness to beta-AR activation. Cardiovascular responsiveness to beta-AR stimulation cannot be assessed under the conditions of the present study because the hemodynamic effects of systemic isoproterenol administration activate baroreflexes, which in turn actively buffer heart rate via reflex cardiac autonomic adjustments (8). This effect can mask group differences in cardiovascular responsiveness to isoproterenol that are apparent when baroreflex counterregulation is abolished with ganglionic blockade (34).

There are at least four additional experimental considerations that should be mentioned. First, other single-nucleotide polymorphisms exist that influence beta2-AR modulation of physiological function and thus could have affected our results. In the present investigation, however, additional post hoc analysis revealed that neither genetic variation at codon 27 nor at 164 of the beta2-AR influenced thermogenic response to nonspecific beta-AR stimulation. Similarly, the decreased thermogenic response of Arg16Arg to specific beta2-AR stimulation could not be explained by variation at codon 27 (25). An alternative approach to understanding the collective influence and potential interaction of these two gene variants is to consider haplotype combinations: combinations of genetic variation at codon 16 and 27 (9). Statistical analyses of these various combinations did not reveal a main effect of any of these potential combinations with respect to the thermogenic response to beta-AR stimulation; however, due to our sample size, we were unable to match for potential confounding variables that might have influenced beta-AR function (such as age, sex, and VO2 max). Clearly, future studies of beta2-AR gene variants will benefit from sufficiently large sample sizes so as to be able to consider haplotype groups consisting of appropriately matched subjects.

Second, as a logical follow-up to the previous point, our codon 16 beta2-AR results are based on relatively small sample sizes and thus could have been influenced by this factor. However, the recent study of Oomen et al. (25) observed a significant association between this gene variant on codon 16 and metabolic responsiveness to selective beta2-AR stimulation with even smaller samples sizes than the present study. Moreover, power calculations indicated that, if the variability of the present data remained constant, a sample size of over 250 subjects per polymorphism (i.e., per group) would be required to detect a statistically significant association between this gene variant and the increase in EE in response to isoproterenol in the present study.

Third, we deliberately chose to use a nonselective beta-AR agonist to mimic in vivo physiological stimulation of the peripheral beta-AR system and attempted to determine the influence of a specific beta2-AR gene variant. However, we cannot ignore that in addition to other variants in the beta2-AR gene the remaining beta-AR subtypes (beta1-AR and beta3-AR) also have functionally significant single-nucleotide polymorphisms (19, 22) that may influence the increase in EE during isoproteternol administration. Unfortunately, a thorough analysis of the influence of each of these beta-ARs and their associated polymorphisms is beyond the scope of the present study. Furthermore, to our knowledge, no data have been presented to suggest a possible distribution linkage between the various polymorphisms of the three receptor subtypes.

Finally, it is possible that our results were influenced by the group differences in sex composition in the present study. However, our extensive statistical analyses aimed at determining any such effect indicated that this was not the case. Furthermore, preliminary evidence from our laboratory shows that metabolic responsiveness to nonselective beta-AR stimulation, determined as in the present study, is not influenced by subject sex (6).

In the largely Caucasian cohort studied in the present investigation, we found approximately equal numbers of subjects with the three polymorphisms (Table 1). The majority of previous studies have reported that the Arg16Arg variant is less common in Caucasians (10–12, 25, 29). However, some investigations have observed distributions more similar to that observed in our study (13, 26).

In summary, the results of the present investigation support the conclusion that the thermogenic response to nonspecific beta-AR stimulation, the most physiologically relevant expression of beta-AR modulation of EE in healthy humans, is not related to genetic variation in codon 16 of the beta2-AR gene. Furthermore, we have shown for the first time that peripheral sympathetic nervous system activity, as described by MSNA and plasma norepinephrine concentrations, is not associated with this polymorphism. The latter finding may, at least in part, provide a mechanistic explanation for the lack of relation between nonspecific beta-AR stimulation of EE and this beta2-AR gene variant.


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
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This study was supported by the following National Institutes of Health awards: AG-06537, AG-13038, AG-15897, AG-022053, and 2 M01-RR-00051. C. Bell is currently affiliated with the Department of Health and Exercise Science, Colorado State University.


   ACKNOWLEDGMENTS
 
We thank Angela R. Moquin for technical and administrative assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. Bell, Dept. of Health and Exercise Science, 205E Moby-B Complex/1582 Campus Delivery, Colorado State University, Fort Collins, CO 80523-1582 (e-mail: cbell{at}cahs.colostate.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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  1. Aynacioglu AS, Cascorbi I, Gungor K, Ozkur M, Bekir N, Roots I, and Brockmoller J. Population frequency, mutation linkage and analytical methodology for the Arg16Gly, Gln27Glu and Thr164Ile polymorphisms in the beta2-adrenergic receptor among Turks. Br J Clin Pharmacol 48: 761–764, 1999.[CrossRef][ISI][Medline]
  2. Bachman ES, Dhillon H, Zhang CY, Cinti S, Bianco AC, Kobilka BK, and Lowell BB. BetaAR signaling required for diet-induced thermogenesis and obesity resistance. Science 297: 843–845, 2002.[Abstract/Free Full Text]
  3. Bell C, Carson JM, Motte NW, and Seals DR. Ascorbic acid does not affect the age-associated reduction in maximal cardiac output and oxygen consumption in healthy adults. J Appl Physiol 98: 845–849, 2005.[Abstract/Free Full Text]
  4. Bell C, Day DS, Jones PP, Christou DD, Petitt DS, Osterberg K, Melby CL, and Seals DR. High energy flux mediates the tonically augmented beta-adrenergic support of resting metabolic rate in habitually exercising older adults. J Clin Endocrinol Metab 89: 3573–3578, 2004.[Abstract/Free Full Text]
  5. Bell C, Jones PP, and Seals DR. Oxidative stress does not modulate metabolic rate or skeletal muscle sympathetic activity with primary aging in adult humans. J Clin Endocrinol Metab 88: 4950–4954, 2003.[Abstract/Free Full Text]
  6. Bell C, Petitt DS, and Seals DR. Differences in beta-adrenergic responsiveness do not explain the attenuated tonic beta-adrenergic support of resting metabolism in women compared with men (Abstract). Obesity Res 12: A105, 2004.
  7. Bell C, Seals DR, Monroe MB, Day DS, Shapiro LF, Johnson DG, and Jones PP. Tonic sympathetic support of metabolic rate is attenuated with age, sedentary lifestyle, and female sex in healthy adults. J Clin Endocrinol Metab 86: 4440–4444, 2001.[Abstract/Free Full Text]
  8. Christou DD, Jones PP, and Seals DR. Baroreflex buffering in sedentary and endurance exercise-trained healthy men. Hypertension 41: 1219–1222, 2003.[Abstract/Free Full Text]
  9. Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K, Arnold K, Ruano G, and Liggett SB. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA 97: 10483–10488, 2000.[Abstract/Free Full Text]
  10. Eisenach JH, Barnes SA, Pike TL, Sokolnicki LA, Masuki S, Dietz NM, Rehfeldt KH, Turner ST, and Joyner MJ. Arg16/Gly {beta}2-adrenergic receptor polymorphism alters the cardiac output response to isometric exercise. J Appl Physiol 99: 1776–1781, 2005.[Abstract/Free Full Text]
  11. Eisenach JH, McGuire AM, Schwingler RM, Turner ST, and Joyner MJ. The Arg16/Gly beta2-adrenergic receptor polymorphism is associated with altered cardiovascular responses to isometric exercise. Physiol Genomics 16: 323–328, 2004.[Abstract/Free Full Text]
  12. Garovic VD, Joyner MJ, Dietz NM, Boerwinkle E, and Turner ST. Beta(2)-adrenergic receptor polymorphism and nitric oxide-dependent forearm blood flow responses to isoproterenol in humans. J Physiol 546: 583–589, 2003.[Abstract/Free Full Text]
  13. Gratze G, Fortin J, Labugger R, Binder A, Kotanko P, Timmermann B, Luft FC, Hoehe MR, and Skrabal F. Beta-2 adrenergic receptor variants affect resting blood pressure and agonist-induced vasodilation in young adult Caucasians. Hypertension 33: 1425–1430, 1999.[Abstract/Free Full Text]
  14. Hallman DM, Srinivasan SR, Chen W, Boerwinkle E, and Berenson GS. The beta(2)-adrenergic receptor Arg16-Gly polymorphism and interactions involving beta(2)- and beta(3)-adrenergic receptor polymorphisms are associated with variations in longitudinal serum lipid profiles: the Bogalusa Heart Study. Metabolism 53: 1184–1191, 2004.[CrossRef][ISI][Medline]
  15. Hoit BD, Suresh DP, Craft L, Walsh RA, and Liggett SB. Beta2-adrenergic receptor polymorphisms at amino acid 16 differentially influence agonist-stimulated blood pressure and peripheral blood flow in normal individuals. Am Heart J 139: 537–542, 2000.[ISI][Medline]
  16. Insel PA. Seminars in medicine of the Beth Israel Hospital, Boston. Adrenergic receptors—evolving concepts and clinical implications. N Engl J Med 334: 580–585., 1996.[Free Full Text]
  17. Jones PP, Van Pelt RE, Johnson DG, and Seals DR. Role of sympathetic neural activation in age- and habitual exercise-related differences in the thermic effect of food. J Clin Endocrinol Metab 89: 5138–5144, 2004.[Abstract/Free Full Text]
  18. Kerckhoffs DA, Blaak EE, Van Baak MA, and Saris WH. Effect of aging on beta-adrenergically mediated thermogenesis in men. Am J Physiol Endocrinol Metab 274: E1075–E1079, 1998.[Abstract/Free Full Text]
  19. Kurokawa N, Nakai K, Kameo S, Liu ZM, and Satoh H. Association of BMI with the beta3-adrenergic receptor gene polymorphism in Japanese: meta-analysis. Obesity Res 9: 741–745, 2001.[ISI][Medline]
  20. Lamont LS, Patel DG, and Kalhan SC. beta-Adrenergic blockade alters whole-body leucine metabolism in humans. J Appl Physiol 67: 221–225, 1989.[Abstract/Free Full Text]
  21. Lee DK, Bates CE, and Lipworth BJ. Acute systemic effects of inhaled salbutamol in asthmatic subjects expressing common homozygous beta2-adrenoceptor haplotypes at positions 16 and 27. Br J Clin Pharmacol 57: 100–104, 2004.[CrossRef][ISI][Medline]
  22. Liggett SB. Pharmacogenetics of beta-1- and beta-2-adrenergic receptors. Pharmacology 61: 167–173, 2000.[CrossRef][ISI][Medline]
  23. Lohse MJ, Engelhardt S, Danner S, and Bohm M. Mechanisms of beta-adrenergic receptor desensitization: from molecular biology to heart failure. Basic Res Cardiol 91: 29–34, 1996.
  24. Monroe MB, Seals DR, Shapiro LF, Bell C, Johnson D, and Jones PP. Direct evidence for tonic sympathetic support of resting metabolic rate in healthy adult humans. Am J Physiol Endocrinol Metab 280: E740–E744, 2001.[Abstract/Free Full Text]
  25. Oomen JM, van Rossum CT, Hoebee B, Saris WH, and van Baak MA. Beta2-adrenergic receptor polymorphisms and salbutamol-stimulated energy expenditure. J Clin Endocrinol Metab 90: 2301–2307, 2005.[Abstract/Free Full Text]
  26. Rosmond R, Ukkola O, Chagnon M, Bouchard C, and Bjorntorp P. Polymorphisms of the beta2-adrenergic receptor gene (ADRB2) in relation to cardiovascular risk factors in men. J Intern Med 248: 239–244, 2000.[CrossRef][ISI][Medline]
  27. Schiffelers SL, Saris WH, Boomsma F, and van Baak MA. Beta(1)- and beta(2)-adrenoceptor-mediated thermogenesis and lipid utilization in obese and lean men. J Clin Endocrinol Metab 86: 2191–2199, 2001.[Abstract/Free Full Text]
  28. Schwartz RS, Jaeger LF, and Veith RC. Effect of clonidine on the thermic effect of feeding in humans. Am J Physiol Regul Integr Comp Physiol 254: R90–R94, 1988.[Abstract/Free Full Text]
  29. Snyder EM, Joyner MJ, Turner ST, and Johnson BD. Blood pressure variation in healthy humans: a possible interaction with beta-2 adrenergic receptor genotype and renal epithelial sodium channels. Med Hypotheses 65: 296–299, 2005.[CrossRef][ISI][Medline]
  30. van Baak MA. The peripheral sympathetic nervous system in human obesity. Obesity Rev 2: 3–14, 2001.
  31. van Baak MA, Hul GB, Toubro S, Astrup A, Gottesdiener KM, DeSmet M, and Saris WH. Acute effect of L-796568, a novel beta 3-adrenergic receptor agonist, on energy expenditure in obese men. Clin Pharmacol Ther 71: 272–279, 2002.[CrossRef][ISI][Medline]
  32. Weir J. New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol 109: 1–9, 1949.[Free Full Text]
  33. Welle S, Schwartz RG, and Statt M. Reduced metabolic rate during beta-adrenergic blockade in humans. Metabolism 40: 619–622, 1991.[CrossRef][ISI][Medline]
  34. White M and Leenen FH. Aging and cardiovascular responsiveness to beta-agonist in humans: role of changes in beta-receptor responses versus baroreflex activity. Clin Pharmacol Ther 56: 543–553, 1994.[ISI][Medline]



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00411.2005v1
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