Nutrition Toxicology and Environment Research Institute Maastricht, Departments of 1 Human Biology and 2 Pulmonology, Maastricht University, NL-6200 MD Maastricht, The Netherlands
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ABSTRACT |
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The present study
investigated whether development or maintenance of a relatively
increased fat mass in normal-weight patients with chronic obstructive
pulmonary disease (COPD), despite periods of weight loss, may be
related to impaired -adrenoceptor-mediated responses in lipid
utilization and thermogenesis. Nine COPD patients and nine healthy
controls (body mass index: 23.0 ± 1.3 vs. 23.8 ± 0.6 kg/m2, not significant; fat mass: 19.0 ± 2.1 vs.
11.9 ± 1.5 kg, P < 0.01) received consecutive
30-min infusions of 6, 12, and 24 ng · kg fat free
mass
1 · min
1 isoproterenol. During
-adrenergic stimulation, nonesterified fatty acid levels
increased significantly less in COPD patients (P < 0.001). Respiratory exchange ratio decreased similarly in both groups,
indicating a similar change in the rate of lipid to carbohydrate
oxidation. Energy expenditure increased similarly in both groups during
-adrenergic stimulation. However, because plasma isoproterenol
concentrations were significantly higher in COPD patients,
thermogenesis related to isoproterenol concentration was significantly
reduced in this group (P < 0.05). In conclusion,
-adrenoceptor-mediated lipolysis and thermogenesis are impaired in
COPD patients. This may play a role in the development or maintenance of their relatively increased fat mass.
sympathetic nervous system; fat mass; energy expenditure
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INTRODUCTION |
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WEIGHT LOSS COMMONLY OCCURS in patients with chronic obstructive pulmonary disease (COPD), in particular in the emphysematous subtype (12). Different patterns of body compositional changes are observed in these patients. Although normal weight loss merely comprises loss of fat and fat-free mass, COPD patients may show a depletion of fat-free mass despite a relative preservation of fat mass (2, 10). In the latter group, functional capacity characterized by decreased muscle function, exercise capacity, and even health status is more impaired compared with underweight subjects with a normal fat-free mass (28). Furthermore, recent studies indicate that the relative or absolute increase in fat mass and decrease in fat-free mass in COPD patients might be related to intrinsic deviations in substrate metabolism, such as an impaired lipolytic response during exercise or insulin infusion (17, 19, 20) and an increased fasting protein turnover (11).
A blunted -adrenergic response might also play a role in the
development or maintenance of an increased fat mass (5). During the infusion of isoproterenol (a nonselective
-adrenoceptor agonist), obese men showed an impaired response in lipolysis and lipid
oxidation compared with lean men (3), which favors
the development or maintenance of their increased fat mass.
Furthermore, when very obese men were compared with very lean men, an
impaired thermogenic response was found as well (6). After
a weight loss period, these parameters remained impaired
(5), suggesting that a diminished capacity to utilize fat
may be a primary factor leading to the development of obesity rather
than a secondary factor as a result of the obese state.
The relatively increased fat mass in normal-weight patients with
COPD might also be explained by a primary impaired response to
-adrenergic stimulation but may also be secondary to their disease
or its treatment. COPD patients with emphysema have increased plasma
norepinephrine levels at rest (14), suggesting an
overstimulation of the sympathetic nervous system (SNS) in the basal
state, whereas their chronic
2-adrenoceptor agonist use
for bronchodilation causes downregulation of SNS responsiveness
(33, 43). Furthermore, several studies showed a decreased
oxidative capacity in peripheral skeletal muscle that could blunt lipid
utilization and thermogenesis (18, 25).
The aim of the present study was to investigate whether
development or maintenance of a relatively increased fat mass in
normal-weight patients with COPD, despite periods of weight loss, is
related to an impaired response in lipid utilization and thermogenesis induced by -adrenergic stimulation with isoproterenol.
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SUBJECTS AND METHODS |
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Subjects.
Nine male COPD patients with moderate to severe emphysema and nine
healthy male age-matched control subjects participated in this study.
COPD was diagnosed according to the criteria of the American Thoracic
Society (1), and macroscopic emphysema was diagnosed by
high-resolution computed tomography. All patients were in clinically
stable condition and were weight stable for 3 mo. However, on average
they had lost 3-4 kg body wt in the year preceding the experiment.
Patients used inhaled
2-sympathicomimetica and inhaled
corticosteroids. In the 24 h preceding the study, patients were
not allowed to use any sympathicomimetic drugs to prevent any acute
effect of these drugs on energy metabolism. Control subjects were in
good health as assessed by medical history and physical examination,
and none used
2-sympathicomimetic drugs. Data on whole
body thermogenesis of the control group have been published previously
(21). Both patients and controls spent no more than 2 h/wk
in organized sports activities; none of the subjects had a history of
hypertension, cardiovascular disease, or heart failure. Patients were
all ex-smokers, and controls were nonsmokers. The study protocol was
reviewed and approved by the Ethics Committee of Maastricht University,
and all subjects gave informed consent before participating in the study.
Experimental design.
Subjects were studied in the morning after an overnight fast. They came
to the laboratory by car or by bus to minimize the amount of physical
activity before the test. On arrival, a cannula was inserted into a
forearm vein of each arm. One cannula was used for the infusion of
drugs and the other cannula for the sampling of blood. All measurements
were done with the subject in supine position, and room temperature was
kept at 21-23°C. The study protocol consisted of four study
periods. After a 30-min baseline measurement, subjects received
consecutive infusions of 6, 12, and 24 ng · kg fat-free mass
(FFM)1 · min
1 isoproterenol
(Isoprenaline sulfate, Fresenius, 's Hertogenbosch, The Netherlands),
each dose for 30 min. At the end of each 30-min period, a blood sample
was taken.
Clinical methods. Body composition of COPD patients was measured by single frequency (50 kHz) bioelectrical impedance analysis (Xitron Technologies, San Diego, CA) with the subject in supine position. FFM was calculated according to the equation of Schols et al. (36), validated for this group of patients. Body density of the control group was determined by hydrostatic weighing with simultaneous lung volume measurement (Volugraph 2000, Mijnhardt, Bunnik, The Netherlands), and body composition was calculated according to the equation of Siri (38).
In patients with COPD, lung function was measured before the isoproterenol infusion test. Forced expiratory volume in 1 s (FEV1) and inspiratory vital capacity (IVC) were calculated from the flow-volume curve by use of a spirometer (Jaeger, Hoechberg, Germany). Lung function was expressed as percentage of reference value (29). Whole body energy expenditure and respiratory exchange ratio (RER) were measured by an open-circuit ventilated hood system (Oxycon beta, Mijnhardt, Bunnik, The Netherlands). The airflow rate and the O2 and CO2 concentrations of the in- and outflowing air were used to compute O2 consumption and CO2 production on-line through an automatic acquisition system connected to a personal computer. Energy expenditure was calculated according to the formula proposed by Weir (42). Energy expenditure and RER values were averaged over the last 10 min of each 30-min period during which steady state occurred. Heart rate was monitored continuously by conventional electrocardiography, and the mean value over the last 10 min of each 30-min period was used for further analysis.Analytical methods.
Blood samples for the determination of nonesterified fatty acids
(NEFA), glucose, and insulin were preserved in sodium-EDTA and those
for isoproterenol, norepinephrine, and epinephrine determination were
preserved in heparin plus glutathione (1.5% wt/vol). Blood samples
were immediately centrifuged for 10 min at 800 g at 4°C. Plasma was transferred into microtest tubes, rapidly frozen in liquid
nitrogen, and stored at 70°C until further analysis. Plasma NEFA
concentration was measured with the NEFA C kit (99475409, WAKO, Neuss,
Germany), and plasma glucose concentration was measured with a glucose
kit (Unimate 5, 0736724, Roche Diagnostica, Basel, Switzerland), both
on a Cobas-Fara centrifugal analyzer (Roche Diagnostica). Plasma
insulin concentration was determined with a double antibody
radioimmunoassay (Insulin RIA 100, Pharmacia, Uppsala, Sweden). Plasma
isoproterenol, norepinephrine, and epinephrine levels were determined
by high-performance liquid chromatography according to the method of
Smedes et al. (39). Standard samples with known
concentrations were included in each run for quality control.
Data analysis. All data are presented as means ± SE. Data for energy expenditure were adjusted for FFM for group comparison using linear regression analysis (30).
To summarize the response of each subject to isoproterenol infusion in a single value, ![]() |
RESULTS |
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Physical characteristics of the subjects are given in Table
1. Body weight and body mass index were
similar in the two groups. Although patients with COPD had lost
3-4 kg body wt in the year preceding the experiment, they had a
significantly higher fat mass (P < 0.01) and a
significantly lower FFM (P < 0.05) compared with
control subjects.
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Plasma isoproterenol concentrations significantly increased during
isoproterenol infusion in COPD patients and control subjects but were
significantly higher in the patient group (Fig.
1). At baseline, plasma norepinephrine
levels were significantly higher (P < 0.05) and plasma
epinephrine levels were slightly lower (P = 0.06) in
patients compared with controls. During -adrenergic stimulation with
isoproterenol, norepinephrine concentrations significantly increased
and epinephrine concentrations significantly decreased in both groups.
The changes in norepinephrine and epinephrine levels were comparable
between groups (Fig. 1).
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At baseline, plasma NEFA concentrations were similar in patients and
controls (Fig. 2). However, the increase
in plasma NEFA concentration was significantly reduced
(P < 0.001) in patients with COPD despite the greater
increase in plasma isoproterenol concentration, suggesting a blunted
-adrenergically mediated lipolytic response. Plasma glucose and
insulin levels were similar in both groups at baseline. Glucose and
insulin levels significantly increased during
-adrenergic
stimulation, but these increases were not significantly different
between groups (Table 2).
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Baseline energy expenditure was slightly lower in patients with COPD
compared with controls (4.71 ± 0.24 vs. 5.21 ± 0.22 kJ/min, P = 0.14), but after adjustment for FFM, baseline
energy expenditure was similar in both groups (Fig. 2). During
-adrenergic stimulation, energy expenditure significantly increased
in both groups. There was no significant difference in the increase in
energy expenditure between COPD patients and control subjects. In
addition, dose
EE=15% was not different between groups
(Table 3). However, when responses were
related to plasma isoproterenol concentrations,
conc
EE=15% was significantly higher (P < 0.05) in patients compared with controls, indicating a blunted
-adrenergically mediated thermogenic response in patients with COPD
(Fig. 3 and Table 3). RER was similar in
both groups at baseline and significantly decreased with isoproterenol,
indicating a similar change in the rate of lipid to carbohydrate
oxidation during
-adrenergic stimulation (Table 2).
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Heart rate was comparable in patients and controls at baseline and
similarly increased during -adrenergic stimulation (Fig. 2). Thus
CD25 was not significantly different between groups. When heart rate
responses were related to plasma isoproterenol concentrations, CC25 was
slightly higher in patients with COPD, but this difference did not
reach statistical significance (P = 0.11; Fig. 3 and
Table 3).
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DISCUSSION |
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The present study intended to investigate whether development or
maintenance of a relatively increased fat mass in normal-weight patients with COPD, despite periods of weight loss, is related to a
blunted increase in lipid utilization and thermogenesis during -adrenergic stimulation with isoproterenol. It was found that the
-adrenoceptor-mediated increase in NEFA concentration was impaired
in COPD patients, indicating a blunted lipolytic response. RER
decreased similarly in both groups, suggesting a similar change in the
rate of lipid to carbohydrate oxidation.
-Adrenoceptor-mediated thermogenesis was impaired when related to plasma isoproterenol concentrations. The impaired release of NEFA from adipose tissue and
the reduced thermogenic response may play a role in the development or
maintenance of relatively increased fat stores in patients with COPD,
even when they lost weight.
COPD patients and control subjects showed a similar response in energy
expenditure when related to the dose of isoproterenol infused. However,
patients with COPD had significantly higher plasma isoproterenol
concentrations and thus an impaired thermogenic response when related
to plasma isoproterenol concentration. The heart rate response was also
slightly lower in patients with COPD when related to plasma
isoproterenol concentration, but this did not reach statistical
significance. The differences in plasma isoproterenol concentrations
indicate that the pharmacokinetics of isoproterenol are different in
patients compared with healthy controls. The reason for this is not
clear. Differences in hepatic or renal clearance are not evident, since
none of the patients or control subjects were diagnosed with impaired
liver or renal function. Another explanation might be a reduction in
the number of -adrenoceptor binding sites. The literature shows that
a reduced
-adrenoceptor number on fat cells might be a primary
factor leading to the development or maintenance of a relatively
increased fat mass (32). On the other hand, chronic
2-adrenoceptor agonist administration is also found to
reduce the number of
-adrenoceptors on lymphocytes. Fourteen days of
oral terbutaline administration is known to reduce the lymphocyte
-adrenoceptor number by >50% in both normal subjects and asthmatic
patients (13, 40, 41). If the
-adrenoceptor number is
reduced in these and other tissues and a similar dose of isoproterenol
is given to patients and controls, less isoproterenol can bind to the
available receptors in patients, and as a consequence, the
concentration of free isoproterenol is increased in the patient group.
Furthermore, the significantly higher plasma isoproterenol
concentrations in the patient group make it clear that individual
plasma concentration-response curves instead of dose-response curves
should be used in the analysis of these kinds of experiments, because
plasma concentration-response curves increase the precision of these
infusion tests. This has already been emphasized by others (6,
21, 26).
To our knowledge, this is the first study to report a blunted isoproterenol-induced increase in plasma NEFA concentration in COPD patients. However, the impaired NEFA release might be explained by a decreased lipolytic response and/or increased reesterification within adipose tissue or other tissues. An impaired isoproterenol-induced lipolytic response has been reported before in obese subjects, both in vivo (3) and in vitro (31), indicating that this might be an important explanation for the blunted increase in NEFA concentration in COPD patients with a relatively increased fat mass.
This is also the first study to report an impaired thermogenic response
in COPD patients with moderate to severe emphysema. Only Creutzberg et
al. (9) did a comparable study in which they measured the
acute thermogenic effect after salbutamol nebulation. They found no
difference in thermogenesis between patients with COPD and age-matched
healthy control subjects. However, plasma salbutamol levels were not
measured in this experiment, so a possibly reduced thermogenic response
related to plasma salbutamol concentrations could not be demonstrated.
Furthermore, a reduced isoproterenol-induced increase in thermogenesis
has been reported in obese subjects (6). This blunted
response might be explained by the impaired lipolytic response, which
leads to a reduced NEFA availability in the blood. Therefore, less NEFA
can be taken up and oxidized by skeletal muscle, and as a consequence,
thermogenesis may be reduced. This hypothesis is supported by another
study from our group (34), in which lipolysis was
pharmacologically inhibited with acipimox. Concomitant
1-adrenergic stimulation resulted in a reduced increase
in lipolysis and thermogenesis compared with
1-adrenergic stimulation alone. Furthermore, reduced
oxidative capacities in peripheral skeletal muscle, reported both in
obesity (7, 37) and in COPD (18, 25), might
blunt lipid oxidation and thermogenesis.
The blunted -adrenoceptor-mediated lipolytic and thermogenic
response in patients with COPD might be a primary factor leading to the
development of their relatively increased fat stores. This might be
caused by an already developed impairment in
-adrenoceptor-mediated processes before the onset of the disease, as is the case in obesity. In vitro studies in fat cells from obese subjects suggest that the
impaired lipolytic response to isoproterenol is due to a significant reduction in cell surface density of the
2-adrenoceptor
(23, 32). In an in vivo study (35), we showed
that
2-adrenoceptor-mediated thermogenesis and lipid
utilization are blunted in obese compared with lean subjects, whereas
1-adrenoceptor-mediated responses are similar in the groups.
The blunted -adrenergic response might also be secondary to the
already developed increased fat stores. Because abdominal subcutaneous
adipose tissue blood flow is reduced in obesity (4), fat
cell lipolysis might not be fully stimulated, leading to a reduced
release of NEFA. Furthermore, due to a possibly reduced abdominal blood
flow, which is seen in obese subjects (4), only part of
the available NEFA in the interstitial fluid might be taken up into the
bloodstream, and the remaining part has to be stored again. These
factors might contribute to the maintenance of relatively increased
adipose tissue stores.
Regression analysis showed that there was a significant relationship
between percent body fat and the increase in plasma NEFA concentration
(r = 0.56, P < 0.02) and percent
body fat and the increase in plasma isoproterenol concentration
(r = 0.47, P < 0.05) for the whole
group. After reanalysis per subgroup (patients or controls), these
significant relationships disappeared, probably due to the small number
of subjects. Regression analysis between other combinations of
variables, like increase in plasma NEFA concentration, increase in
plasma isoproterenol concentration, baseline norepinephrine
concentration, and percent body fat revealed no further significant
relationships, either in the whole group or in one of the subgroups.
Whether the impaired
-adrenergic response in patients with COPD is a
cause or a consequence of their increased fat mass needs to be further explored.
Another explanation for the blunted -adrenergic response during
isoproterenol infusion in patients with COPD might be desensitization of the SNS due to the disease. COPD patients are found to have increased plasma norepinephrine levels and decreased plasma epinephrine levels at rest (14). This suggests that sympathetic nerve
activity is increased in the basal state. Because of this chronic
overstimulation of the SNS,
-adrenoceptors may become desensitized,
and consequently, the response to additional
-adrenergic stimulation
might be blunted.
Finally, the impaired SNS response might be related to chronic usage of
2-adrenoceptor agonists for bronchodilation. In normal subjects, 2 wk of regular salbutamol inhalation induced a blunted increase in plasma NEFA and glycerol concentrations during salbutamol infusion (15). Thirteen days of salbutamol inhalation
(43) or 2 wk of oral terbutaline administration
(33) induced impaired thermogenic responses after
salbutamol inhalation or isoproterenol infusion, respectively. In COPD
patients, the effect of chronic
2-adrenoceptor agonist
usage on thermogenesis and lipid utilization has never been studied.
However, in patients with moderate (22) to severe
(27) asthma, who also use
2-adrenergic
bronchodilators, a blunted increase in plasma NEFA concentration was
found during epinephrine infusion. Furthermore, in asthmatic patients
using large dosages of
-adrenergic bronchodilators, lymphocyte cAMP production during isoproterenol incubation was significantly reduced compared with that in control subjects (8, 40, 41) or in asthmatic patients on nonadrenergic drugs (8). Moreover,
when the asthmatic patients changed to nonadrenergic drugs
(8) or a placebo (41), their cAMP response to
isoproterenol returned to normal. Furthermore, Makino et al.
(24) showed that lymphocyte cAMP production was impaired
in asthmatic patients only during incubation with salbutamol and not
with norepinephrine (
1 >
2-adrenoceptor affinity) compared with healthy controls.
This suggests that chronic
2-adrenoceptor agonist
administration desensitizes only
2-adrenoceptors and not
1-adrenoceptors.
In our study, patients were asked to stop using their
2-adrenergic bronchodilators 24 h before the start
of the experiment to prevent any acute interference with our
isoprenaline infusion test. All patients used inhaled salbutamol
[plasma half-time (t1/2) = 4-6 h] or
inhaled salmeterol (plasma t1/2 unknown due to
very low plasma concentrations after inhalation) for bronchodilation. Considering 24-h withdrawal, plasma salbutamol concentrations would be <5% of that directly after inhalation and therefore will not
directly influence our study. However, the desensitizing effect of
chronic
2-adrenoceptor agonist usage on the measured
parameters is still present after 24-h withdrawal.
Our COPD patients also chronically inhaled corticosteroids, which are
known to potentiate the effect of -adrenergic stimulation. Hui et al. (16) showed that the reduction in lymphocyte
-adrenoceptor number induced by 3-5 wk of oral terbutaline
administration was completely reversed 16 h after a single
intravenous dose of methylprednisolone in both normal subjects and
asthmatic patients. Furthermore, Reynisdottir et al. (31)
showed that lipolytic sensitivity to isoproterenol in isolated
abdominal adipocytes from asthmatic patients (who only sporadically
needed inhaled
2-adrenoceptor agonists) increased 50-fold after 7 days of oral prednisolone treatment. Sensitivity to
terbutaline increased 25-fold, whereas sensitivity to dobutamine (
1-adrenoceptor agonist) remained unchanged after
treatment. Furthermore, the number of
2-adrenoceptor
binding sites increased by 60% after glucocorticosteroid treatment,
whereas
1-adrenoceptor binding sites were not affected.
This suggests that glucocorticosteroids selectively increase
2-adrenoceptor density and function and may possibly
reverse the desensitizing effect of chronic
2-adrenoceptor agonist usage.
In conclusion, -adrenoceptor-mediated lipolysis and thermogenesis
are reduced in normal-weight patients with COPD with a relatively
increased fat mass compared with healthy age-matched control subjects.
The impaired release of NEFA from adipose tissue and the reduced
thermogenic response may play a role in the development or maintenance
of the relatively increased fat stores in these patients, despite
periods of weight loss.
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ACKNOWLEDGEMENTS |
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This study was supported by a grant from The Netherlands Asthma Foundation, Grant 96.16, and the Dutch Diabetes Research Foundation.
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. L. H. Schiffelers, Dept. of Human Biology, Maastricht University, PO Box 616, NL-6200 MD Maastricht, The Netherlands (E-mail: s.schiffelers{at}hb.unimaas.nl).
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.
Received 6 July 2000; accepted in final form 20 October 2000.
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