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Tonic Sympathetic Support of Metabolic Rate Is Attenuated with Age, Sedentary Lifestyle, and Female Sex in Healthy Adults

Department of Kinesiology and Applied Physiology University of Colorado (C.B., D.R.S., M.B.M., D.S.D., L.F.S., P.P.J.), Boulder, Colorado 80309; Department of Medicine, University of Colorado Health Sciences Center (D.R.S.), Denver, Colorado 80262; and Department of Medicine, University of Arizona (D.G.J.), Tucson, Arizona 85721

Address all correspondence and requests for reprints to: Christopher Bell, Ph.D., Department of Kinesiology and Applied Physiology, 354 UCB, University of Colorado, Boulder, Colorado 80309-0354. E-mail: christopher.bell{at}colorado.edu

Abstract

We recently demonstrated in young adult humans that the sympathetic nervous system contributes to the control of resting metabolic rate via tonic ß-adrenergic receptor stimulation. In the present follow-up study we determined the respective effects of age, habitual exercise status, and sex on this regulatory mechanism. Resting metabolic rate (ventilated hood, indirect calorimetry) was determined in 55 healthy sedentary or endurance exercise-trained adults, aged 18–35 or 60–75 yr (29 men and 26 women), before (baseline) and during the infusion of either a nonselective ß-adrenergic receptor antagonist (propranolol) or saline (control). Relative to baseline values, during ß-adrenergic receptor antagonism resting metabolic rate adjusted for fat-free mass was reduced to a lesser extent in older (mean ± SE, -130 ± 46 kJ/d) compared with young (-297 ± 46) adults, sedentary (-151 ± 50) compared with endurance exercise-trained (-268 ± 46) adults, and women (-105 ± 33) compared with men (-318 ± 50; all P < 0.01). Reductions in resting metabolic rate during ß-adrenergic receptor antagonism were positively related to higher baseline resting metabolic rate and plasma catecholamine concentrations and negatively related to adiposity (all P < 0.05). Resting metabolic rate was unchanged in response to saline control in all groups. These results provide experimental support for the hypothesis that aging, sedentary living, and female sex are associated with attenuated sympathetic nervous system support of resting metabolic rate in healthy adult humans.

RESTING METABOLIC rate (RMR) is the largest determinant of daily energy expenditure and, thus, plays an important role in energy balance and weight control. With such clinical implications, the physiological mechanisms involved in the regulation of RMR in various human populations are of obvious interest.

In this context, the contribution of tonic sympathetic nervous system (SNS) stimulation to RMR has been controversial (1, 2, 3, 4, 5, 6, 7, 8). Recently, we developed an experimental model to more definitively address this issue (9). Using this approach, we were able to confirm that tonic SNS stimulation contributes significantly to RMR in adults. However, the results of this initial study as well as those from the earlier investigations by others (7, 10, 11) have been limited primarily to normal young adults, in many cases exclusively males.

SNS support of RMR is mediated largely, if not exclusively, via ß-adrenergic pathways (7, 12, 13). In this regard, there is some evidence that tissue responsiveness to ß-adrenergic receptor stimulation may be attenuated with advancing age, physical inactivity, and female sex (14, 15, 16). If so, it could be postulated that tonic SNS support of RMR might be smaller in these populations.

Accordingly, we tested this hypothesis in the present study. To do so, our specific aim was to determine SNS ß-adrenergic support of RMR in groups of 1) young compared with older adults, 2) regularly exercising compared with sedentary adults, and 3) men compared with women.

Subjects and Methods

Subjects

Fifty-five nonobese adults, 26 women and 29 men, were studied. Of the 55, 29 were young (18–35 yr), and 26 were older (60–75 yr); 25 were sedentary, and 30 were regular exercisers (performed endurance exercise for a minimum of 40 min 4 d/wk). All subjects were healthy as assessed by medical history and fasting plasma glucose and insulin concentrations. In addition, middle-aged and older subjects underwent a physical examination with resting electrocardiogram (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. The nature, purpose, and risks of the study were explained to each subject before written informed consent was obtained. The experimental protocol was approved by the human research committee at the University of Colorado (Boulder, CO) and the Colorado multiple institutional review board.

Experimental procedures

All measurements were made in the morning after a 12-h fast and, in the habitually exercising subjects, after 24-h abstention from exercise. Subjects were studied under quiet resting conditions in the semirecumbent position. Premenopausal females were studied during the follicular phase of their menstrual cycle (d 1–10). Measurements were performed between 0600–0900 h in a dimly lit room at a comfortable temperature (23 C). SNS ß-adrenergic support of RMR was determined as recently described (9). RMR was measured before and during either ß-adrenergic receptor blockade (iv infusion of propranolol: 0.25 mg/kg bolus, followed by continuous infusion at 0.004 mg/kg·min) or saline infusion at the same rate (control) in a randomized order. Subjects were instrumented for measurement of heart rate (ECG) and blood pressure (finger photoplethysmography, Finapres blood pressure monitor, model 2300, Ohmeda, Englewood, CO). A catheter was placed in an antecubital vein and was kept patent with a slow saline drip. After a 30-min rest period following instrumentation, baseline RMR was measured. 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 Metabolic Monitor, SensorMedics Corp., Yorba Linda, CA). RMR was calculated from the average of the 30-min collection using the Weir formula (17). The hood then was removed while an iv bolus was given of either propranolol or saline (0.25 ml/kg). After a 5-min habituation period, RMR was measured again during continuous infusion of propranolol or saline (0.004 mg/kg·min). Blood was sampled at three time points for determination of plasma propranolol concentrations: immediately after the bolus and at 15 and 30 min during the second measurement of RMR. Before blood sampling the catheter and infusion line were flushed with saline and 2–3 ml "waste" blood to prevent contamination with propranolol. Propranolol concentrations were determined by HPLC (Associated Regional and University Pathologists, Salt Lake City, UT). In a subset of subjects (n = 15), the effectiveness of the ß-adrenergic receptor blockade was further documented using an isoproterenol challenge. Specifically, after measurement of baseline RMR, isoproterenol was infused via a second iv catheter in stepwise increments (sequentially for 6 min each at 0.05, 0.1, 0.2, and 0.3 ml/min) until an increase in heart rate of at least 25 beats/min above resting baseline was observed. The infusion was then stopped, followed by a 30-min washout period. The dose of isoproterenol that evoked an increase in heart rate of 25 beats/min or more was recorded as the challenge dose. Immediately after the second (ß-blocked) measurement of RMR, the isoproterenol challenge dose was infused again.

Body mass was measured on a physician’s scale. Fat mass and fat-free mass were measured using dual energy x-ray absorptiometry (DXA-IQ, Lunar Corp., Madison, WI; software version 4.1). Maximal oxygen consumption (VO₂max) was measured during graded treadmill exercise using open circuit spirometry as described previously (18).

Data analysis and statistics

RMR values were adjusted for fat-free mass using analysis of covariance. One-way ANOVA was used to examine differences in RMR between the groups at baseline. Changes in RMR in response to propranolol were examined using two-way repeated measures ANOVA. Multiple comparison of factor means were performed using the Newman-Keuls test. To determine whether effective ß-blockade was achieved 1) serum propranolol concentrations at each time point were assessed to ensure values of 100 ng/ml or more (19); and 2) differences between the heart rate responses to isoproterenol before and during ß-adrenergic receptor blockade were assessed using a two-way repeated measures ANOVA. 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 the mean ± SE.

Results

Effects of age

There was approximately a 40-yr difference in age between the young and older groups (Table 1). The older subjects had a higher percent body fat and a lower VO₂max than the young subjects (Table 1). There were no significant group differences in fasting baseline plasma concentrations of glucose, insulin, cortisol, leptin, or catecholamines (Table 2). Baseline RMR, absolute values and when adjusted for fat-free mass and total mass, was lower in the older (5552 ± 167, 5617 ± 100, and 5510 ± 105 kJ/d, respectively) than in the young (6653 ± 172, 6510 ± 109, and 6699 ± 116) subjects (P < 0.01). The older subjects demonstrated a smaller reduction in RMR than the young subjects in response to ß-adrenergic receptor blockade (Fig. 1A).

View larger version (16K): [in this window] [in a new window]   Figure 1. Reductions in RMR adjusted for fat-free mass during ß-adrenergic receptor blockade, where a greater magnitude of reduction represents a greater tonic sympathetic support of RMR. Tonic sympathetic support of RMR was greater (P < 0.01) in young compared with older healthy adults (A), habitually exercising compared with sedentary adults (B), and healthy adult males compared with females (C). Data are the mean ± SE.

The sedentary subjects had greater body mass and percent body fat, and lower VO₂max than the subjects who habitually exercised (Table 1). Fasting baseline plasma concentrations of insulin and leptin were higher, and cortisol was lower in the sedentary compared with the exercising subjects (Table 2). Both absolute baseline RMR and RMR adjusted for total mass were lower in the sedentary (6000 ± 205 and 5715 ± 191, respectively) compared with the exercising (6243 ± 195 and 6531 ± 124) subjects (P < 0.01), but baseline RMR adjusted for fat-free mass was not different in the two groups (6016 ± 185 vs. 6150 ± 117 kJ/d; P = 0.40). The sedentary subjects demonstrated a smaller reduction in RMR than the exercising subjects in response to ß-adrenergic receptor blockade (Fig. 1B).

Effects of sex

The female subjects had lesser height, body mass, and fat-free mass and greater percent body fat than the males (Table 1). Fasting baseline plasma concentrations of insulin were lower and those of cortisol and leptin were higher in the women (Table 2). Both absolute baseline RMR and RMR when adjusted for total mass were lower in the women (5430 ± 134 and 1323 ± 126, respectively) than in the men (6711 ± 155 and 6657 ± 144; P < 0.01), but baseline RMR adjusted for fat-free mass was not different in the two groups (6108 ± 125 vs. 6071 ± 142 kJ/d; P = 0.9). The female subjects demonstrated a smaller reduction in RMR than the male subjects in response to ß-adrenergic receptor blockade (Fig. 1C).

Responses to the control condition and verification of complete blockade

Baseline RMR was not different between saline control (6079 ± 100 kJ/d) and ß-antagonist (6088 ± 96 kJ/d) conditions and was unaffected by infusion of saline (change in RMR, -17 ± 34 kJ/d; ±1%). Complete ß-adrenergic blockade was verified by the observations that 1) concentrations of serum propranolol after bolus infusion (453 ± 71 ng/ml) and at 15 and 30 min during continuous infusion (244 ± 36 and 276 ± 52 ng/ml) were greater than 100 ng/ml; and 2) before propranolol infusion heart rate increased in response to isoproterenol (31 ± 2 beats/min), but was unchanged during propranolol infusion (2 ± 2 beats/min).

Physiological correlates of SNS ß-adrenergic support of RMR

In the pooled subject sample, the decrease in RMR in response to iv propranolol was positively related to baseline RMR (r = 0.34; P = 0.01), plasma epinephrine concentration (r = 0.54; P < 0.0001), and plasma norepinephrine concentration (r = 0.39; P < 0.005) and was inversely related to percent body fat (r = -0.45; P < 0.001) and plasma leptin concentration (r = -0.36; P < 0.01).

Discussion

The results of our recent study confirmed the presence of tonic SNS ß-adrenergic support of RMR in healthy young adults (9). However, whether other populations demonstrate this property and whether there are differences in the level of tonic SNS ß-adrenergic support of RMR among different populations could not be determined from this initial effort. Thus, the findings of the present investigation extend these earlier observations by showing that older age, sedentary lifestyle, and female sex all are associated with smaller tonic SNS ß-adrenergic support of RMR in healthy adults.

There are at least two possible explanations for the present results. First, it is possible that older, sedentary, and female adults have lower tonic SNS activity and/or norepinephrine release than their respective control groups. That is, the level of tonic SNS stimulation could be lower in these populations, and thus upon blockade of this influence with propranolol there is a smaller reduction in RMR. There is some evidence to support this possibility in premenopausal females who have lower resting muscle sympathetic nerve activity compared with age-matched males (20, 21). However, tonic muscle sympathetic nerve activity actually is higher in older compared with young adults (20, 22, 23) and is not consistently different in exercising and sedentary adults (24, 25, 26, 27). In the present study plasma catecholamine concentrations were not significantly different among the various groups. However, among the individual subjects the circulating levels of norepinephrine and epinephrine were significantly related to the corresponding changes in RMR after ß-adrenergic receptor blockade. These observations suggest that the baseline sympathoadrenal system activity may contribute to intersubject differences in ß-adrenergic support of RMR, but cannot explain the population differences noted here.

The second explanation is that SNS stimulus is equivalent or even greater with age, inactivity, and/or female sex, but the tissue responsiveness to tonic SNS stimulation is reduced in these populations. We have no direct experimental support for this possibility in the present study. However, the change in RMR per unit of baseline sympathoadrenal system activity (as estimated from basal plasma catecholamine concentrations) generally was significantly smaller in these three groups compared with that in their respective controls: change in RMR/baseline epinephrine: 0.27 ± 0.12 vs. 0.74 ± 0.11, older vs. young (P < 0.01); 0.38 ± 0.14 vs. 0.64 ± 0.11, sedentary vs. exercising (P < 0.05); 0.32 ± 0.12 vs. 0.69 ± 0.12, female vs. male (P < 0.01); and change in RMR/baseline norepinephrine: 71 ± 28 vs. 164 ± 21, older vs. young (P < 0.05); 99 ± 35 vs. 135 ± 21, sedentary vs. exercising (P = 0.19); 71 ± 28 vs. 163 ± 28, female vs. male (P = 0.01). Moreover, there are selective reports of reduced tissue responsiveness to ß-adrenergic stimulation in older age (16), with sustained physical inactivity (14, 15), and female sex (16). Thus, we speculate that this may be the key mechanism associated with reduced SNS ß-adrenergic support of RMR in one or more of these populations. Additional studies will be required to more precisely determine the relative contributions of differences in the baseline sympathoadrenal stimulus and tissue responsiveness to the specific group differences in tonic SNS ß-adrenergic support of RMR observed in the present investigation.

Other significant physiological correlates of tonic SNS ß-adrenergic support of RMR among the individual subjects included baseline RMR, percent body fat, and fasting plasma leptin concentrations. The reduction in RMR during ß-adrenergic receptor antagonism was positively related to baseline RMR adjusted for fat-free mass, indicating that greater SNS ß-adrenergic support of RMR contributes significantly to the higher chronic levels of RMR observed in some individuals. This finding is supported by previously published data on Caucasian men (28). The reduction in RMR during ß-adrenergic receptor antagonism was inversely related to the percent body fat and fasting plasma concentrations of leptin, which have been shown previously to be highly correlated (29). This indicates that SNS ß-adrenergic support of RMR tends to be smaller with increasing adiposity among healthy adult humans. Because tonic SNS activity is greater with increasing adiposity in adult Caucasians (21, 29, 30), it is likely that the tendency for reduced SNS ß-adrenergic support of RMR with elevations in body fatness is due to corresponding reductions in tissue metabolic responsiveness.

The present findings of reduced SNS ß-adrenergic support of RMR associated with aging sedentary living and female sex have important physiological, and perhaps even pathophysiological, implications. RMR represents 60–70% of the total daily energy expenditure and thus plays a critical role in the regulation of energy balance and weight control (31). RMR decreases progressively with age in sedentary adults (32, 33). This increases the challenge of weight maintenance for middle-aged and older adults and may contribute to the high prevalence of age-associated obesity and subsequent increased risks of cardiovascular and metabolic diseases. It also restricts the total daily allowable energy intake for energy balance and, therefore, poses a restriction to nutrient intake in older adults. In some cases this may potentially limit their ability to achieve recommended daily allowances of vitamins and nutrients. As such, older, sedentary, and female adults may be more greatly challenged and operate with less margin for error with regard to long-term weight control than their respective younger, habitually exercising, and/or male counterparts.

In conclusion, the present results provide the first experimental support for the concept that older age, a sedentary lifestyle, and female sex all are associated with attenuated SNS ß-adrenergic support of RMR among healthy adults. These observations may be of clinical relevance, as they pertain to the control of resting energy metabolism and the prevention of obesity in adults.

Acknowledgments

We thank Mary Jo Reiling and Jason Lashbrook for administrative and technical assistance.

Footnotes

This work was supported by NIH Awards HL-39966, AG-13038, AG-06537, AG-00828, and DK-07685 and American Heart Association Grants CWFW-0298 and 9920445Z.

Abbreviations: ECG, Electrocardiogram; RMR, resting metabolic rate; SNS, sympathetic nervous system; VO₂max, maximal oxygen consumption.

Received February 1, 2001.

Accepted May 17, 2001.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bell, C. Articles by Jones, P. P. Search for Related Content PubMed PubMed Citation Articles by Bell, C. Articles by Jones, P. P.