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Original Studies |
Nutrition Toxicology and Environment Research Institute Maastricht, Department of Human Biology, Maastricht University (S.L.H.S., W.H.M.S., M.A.v.B.), NL-6200 MD Maastricht, The Netherlands; and Department of Internal Medicine I, University Hospital Dijkzigt, Erasmus University (F.B.), 3015 GD Rotterdam, The Netherlands
Address all correspondence and requests for reprints to: Dr. S. L. H. Schiffelers, Department of Human Biology, Maastricht University, P.O. Box 616, NL-6200 MD Maastricht, The Netherlands. E-mail: s.schiffelers{at}hb.unimaas.nl
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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- and ß-adrenoceptor agonists) are infused show
significant increases in energy expenditure, lipid oxidation, and
lipolysis. The roles of the individual adrenoceptor subtypes in
thermogenesis have also been studied. -Adrenergic stimulation does
not affect whole body thermogenesis (3, 6), whereas
nonselective ß-adrenergic stimulation with isoprenaline significantly
increases energy expenditure and lipid utilization (7).
During only ß1-adrenergic stimulation with
dobutamine (8, 9) or only
ß2-adrenergic stimulation with salbutamol
(6) or terbutaline (10), energy expenditure,
lipid oxidation, and lipolysis increase as well. In rats,
ß3-adrenergic stimulation leads to significant
increases in energy expenditure and lipid utilization (11, 12). However, the rat ß3-adrenoceptor
differs pharmacologically from the human
ß3-adrenoceptor (13, 14), and
consequently, the specific ß3-adrenoceptor
agonists used in rats are only weak agonists in humans. Until now, no
highly selective ß3-adrenoceptor agonist or
antagonist has been available for administration in humans. Obese subjects may show an impaired response of thermogenesis during norepinephrine infusion (15, 16), but responses similar to those in lean subjects are also frequently found during norepinephrine (17, 18), epinephrine (5, 19), and isoprenaline (7) infusion. Others only found an impaired thermogenic response when very obese men were compared with very lean men (20) or only during overfeeding (18). More evident are the differences in lipid utilization between obese and lean subjects. During epinephrine (5, 19) or isoprenaline (7) infusion, the increase in lipid oxidation is reduced in overweight men. Furthermore, their increases in plasma nonesterified fatty acids (NEFA) and glycerol concentrations are impaired during epinephrine (5, 21) or isoprenaline (7) infusion. Only Katzeff et al. (17) reported an opposite finding, e.g. that the increases in plasma glycerol and NEFA concentrations in response to norepinephrine infusion were proportional to the total fat mass of each individual and therefore were greater in the obese. Until now, it has been unclear which ß-adrenoceptor subtype is responsible for the impaired responses of thermogenesis and lipid utilization.
The aim of the present studies was to elucidate the roles of ß1- and ß2-adrenoceptors in thermogenesis, lipid oxidation, and lipolysis in obese and lean men.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Fourteen obese and 15 lean male volunteers participated in these
studies. Six obese and 6 lean men participated in both studies within a
time frame of 9 ± 2 months. The physical characteristics of the
subjects, grouped per study, are summarized in Table 1
. All subjects were in good health as
assessed by medical history and physical examination and were weight
stable for at least 6 months. Furthermore, both obese and lean subjects
spent no more than 2 h a week in organized sports activities. The
study protocols were reviewed and approved by the ethics committee of
Maastricht University, and all subjects gave informed consent before
participating in the tests.
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Subjects were studied in the morning after an overnight fast. They came to the laboratory by car or 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 one cannula was used for the sampling of blood. Next, ventilated hood measurements were started with the subject in supine position and continued for the remainder of the experiment. At the end of each study period, a blood sample was taken. Room temperature was kept at 21-23 C.
The ß1-adrenoceptor study consisted of four study periods. After a 30-min baseline measurement, subjects received consecutive infusions of 3, 6, and 9 µg/kg fat-free mass (FFM)·min dobutamine (Dobax, Byk, Zwanenburg, The Netherlands), each dose for 30 min.
The ß2-adrenoceptor study consisted of three study periods. At the start of the experiment, subjects received a priming dose of 50 µg/kg FFM atenolol (ß1-adrenoceptor antagonist, Tenormin, Zeneca Pharmaceuticals, Ridderkerk, The Netherlands) in 5 min, after which a continuous infusion of 1.2 µg/kg FFM·min atenolol was started for the remainder of the experiment. After a 45 min baseline measurement, subjects additionally received consecutive infusions of 50 and 100 ng/kg FFM·min salbutamol (Ventolin, GlaxoWellcome, Zeist, The Netherlands), each infusion for 45 min.
Clinical methods
Body density was determined by hydrostatic weighing with simultaneous lung volume measurement (Volugraph 2000, Mijnhardt, Bunnik, The Netherlands). Body composition was calculated according to the equation of Siri (22).
Whole body energy expenditure and respiratory exchange ratio (RER) were measured by indirect calorimetry, using an open-circuit ventilated hood system. In the ß1-adrenoceptor study, a homemade system was used (23). The volume of air drawn through the hood was measured by a dry gas meter (Schlumberger, Dordrecht, The Netherlands), and the composition of the in-flowing and out-flowing air was analyzed by a paramagnetic O2 analyzer (Servomex, Crowborough, UK) and an infrared CO2 analyzer (Hartmann and Braun, Frankfurt, Germany). In the ß2-adrenoceptor study, energy expenditure and RER were measured by an Oxycon (Mijnhardt, Bunnik, The Netherlands). The airflow rate and the O2 and CO2 concentrations of the in- and out-flowing air were used to compute O2 consumption and CO2 production on-line through an automatic acquisition system connected to a personal computer. The coefficient of variation for O2 consumption was 2.4% for the homemade system and 2.5% for the Oxycon; the coefficient of variation for CO2 production was 3.1% for the homemade system and 2.0% for the Oxycon. Energy expenditure was calculated according to the formula proposed by Weir (24). Energy expenditure and RER values were averaged over the last 10 min of each 30-min (ß1) or 45-min (ß2) period during which steady state occurred. During the ß2-adrenoceptor study, subjects collected their urine for nitrogen determination over a 12-h period before arriving at the laboratory. Nitrogen excretion was used to estimate protein oxidation at baseline and was assumed to be constant during the remainder of the test. For subjects who only participated in the ß1-adrenoceptor study, the mean nitrogen excretion rate for the corresponding group in the ß2-adrenoceptor study was used. After correction for protein oxidation, carbohydrate and lipid oxidation rates were calculated from O2 consumption and CO2 production as described by Ferrannini (25).
Heart rate was monitored continuously by conventional electrocardiography, and the mean value over the last 10 min of each measuring period was used for further analysis. Blood pressure was measured by an automated blood pressure device (Tonoprint, Speidel & Keller, Jungingen, Germany) during the last 10 min of each 30-min (ß1) or 45-min (ß2) interval. The means of four measurements per interval were used for further analysis.
Analytical methods
Blood samples for the determination of NEFA, glycerol, glucose, lactate, and insulin were preserved in sodium ethylenediamine tetraacetate; samples for potassium were preserved in heparin; and those for dobutamine, salbutamol, norepinephrine, and epinephrine were preserved in heparin plus glutathione (1.5%, wt/vol). Blood samples were immediately centrifuged for 10 min at 800 x g at 4 C. Plasma was transferred into microtest tubes, rapidly frozen in liquid nitrogen, and stored at -70 C until further analysis.
The plasma NEFA concentration was measured with a NEFA C kit (99475409, WAKO, Neuss, Germany), the plasma glycerol concentration was measured with a glycerol kit (148270, Roche, Mannheim, Germany), the plasma glucose concentration was measured with a glucose kit (Unimate 5, 0736724, Roche, Basel, Switzerland), and the plasma lactate concentration was measured by the method of Gutmann and Wahlefeld (26), all on a Cobas-Fara centrifugal analyzer (Roche, Basel, Switzerland). The plasma insulin concentration was determined with a double antibody RIA (Insulin RIA 100, Pharmacia, Uppsala, Sweden), and the plasma potassium concentration was determined by an ion-selective electrode (Salm & Kipp, Breukelen, The Netherlands). Plasma dobutamine, norepinephrine, and epinephrine levels were determined by high performance liquid chromatography according to the method described by Alberts et al. (27). Plasma salbutamol concentrations were measured by an in-house method (Analytico Medinet, Breda, The Netherlands) Salbutamol was first extracted from its matrix by means of a solid phase extraction procedure. After derivatization with BSTFA (trimethylsilyl-trifluoracetamide), its concentration was determined using a capillary gas chromatography-mass spectrometry method. Quantification was performed by monitoring the ion fragments at 456 m/z for salbutamol and 459 m/z for the internal standard D3-salbutamol and calculation of peak height ratio analyte/internal standard amounts. The limit of quantification in plasma was 1.0 nmol/L, based on a 1-mL sample volume. The calibration range was between 1 and 40 nmol/L. Standard samples with known concentrations were included in each run for quality control.
Data analysis
All data are presented as the mean ± SEM. Data for energy expenditure were adjusted for FFM for group comparison (28).
The effect of ß1- or ß2-adrenergic stimulation between groups was analyzed with two-way repeated measurements ANOVA. Post-hoc testing was performed with Student’s unpaired t test. P < 0.05 was regarded as statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Baseline energy expenditure was significantly higher in obese
compared with lean men (5.49 ± 0.21 vs. 4.61 ±
0.18 kJ/min; P < 0.01), but after adjustment for FFM,
it was comparable between groups (obese vs. lean, 5.19
± 0.25 vs. 5.15 ± 0.14 kJ/min adjusted for FFM;
P = NS). During ß1-adrenergic
stimulation, energy expenditure increased significantly (Fig. 1). RER was similar at baseline between
obese and lean men (0.799 ± 0.013 vs. 0.797 ±
0.011; P = NS). RER significantly decreased during
ß1-adrenergic stimulation. Lipid and
carbohydrate oxidations were comparable in obese and lean subjects at
baseline [lipid oxidation, 76 ± 7 vs. 66 ± 6
mg/min (P = NS); carbohydrate oxidation, 93 ± 19
vs. 77 ± 14 mg/min (P = NS)]. Lipid
oxidation significantly increased and carbohydrate oxidation
significantly decreased during ß1-adrenergic
stimulation. The changes in energy expenditure, RER, lipid oxidation,
and carbohydrate oxidation were similar in obese and lean men (Fig. 1).
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). Baseline glucose and
insulin levels were significantly higher in the obese compared with the
lean group (glucose, P < 0.05; insulin,
P < 0.01; Table 2).
Plasma glucose levels significantly decreased and plasma insulin levels
significantly increased during ß1adrenergic
stimulation with dobutamine. The changes in these parameters compared
with baseline were not significantly different between groups. At
baseline, plasma lactate and potassium concentrations were similar in
obese and lean men. During ß1-adrenergic
stimulation, plasma lactate levels remained similar, whereas plasma
potassium levels showed some variation, but no dose-dependent changes
in either group (Table 2).
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). Baseline norepinephrine and
epinephrine levels were comparable between overweight and normal weight
subjects (norepinephrine, 1.59 ± 0.35 vs. 1.47 ±
0.27 nmol/L; epinephrine, 0.19 ± 0.04 vs. 0.22 ±
0.03 nmol/L; both P = NS) and were significantly
decreased in both groups during ß1-adrenergic
stimulation (Fig. 3).
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), but diastolic blood pressure was
significantly higher in obese men (P < 0.01). Heart
rate and systolic blood pressure significantly increased, and diastolic
blood pressure significantly decreased in both groups during
ß1-adrenergic stimulation with dobutamine. The
changes in heart rate and in systolic and diastolic blood pressure were
comparable in both groups (Table 3).
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Baseline energy expenditure was similar in obese and lean men
(5.13 ± 0.16 vs. 4.97 ± 0.09 kJ/min adjusted for
FFM; P = NS). During
ß2-adrenergic stimulation, adjusted energy
expenditure significantly increased. However, the increase in energy
expenditure was significantly lower in the obese compared with the lean
group (ANOVA for energy expenditure x group, P <
0.05; Fig. 4). At baseline, RER was
similar in obese and lean men (0.838 ± 0.011 vs.
0.825 ± 0.008; P = NS). RER significantly
decreased during ß2-adrenergic stimulation, but
the decrease was significantly larger in the lean group (ANOVA for
RER x group, P < 0.05; Fig. 4). Baseline lipid
and carbohydrate oxidation were similar in obese and lean subjects
[lipid oxidation, 55 ± 6 vs. 42 ± 3 mg/min
(P = NS); carbohydrate oxidation, 143 ± 17
vs. 116 ± 9 mg/min (P = NS)]. Lipid
oxidation significantly increased during
ß2-adrenergic stimulation, but this increase
was significantly higher in the lean group (ANOVA for lipid
oxidation x group, P = 0.05). Carbohydrate
oxidation rates significantly decreased (ANOVA for treatment,
P < 0.05) during
ß2-adrenergic stimulation, but did not
differ significantly between groups (Fig. 4).
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). Baseline glycerol levels were
significantly higher in the overweight compared with the normal weight
group (76.5 ± 4.3 vs. 61.7 ± 4.8 µmol/L;
P < 0.05). During
ß2-adrenergic stimulation with salbutamol,
plasma NEFA and glycerol levels increased significantly more in the
lean compared with the obese group (ANOVA for group x treatment:
NEFA, P < 0.01; glycerol, P < 0.05;
Fig. 2). Plasma glucose and insulin levels were significantly higher in
the obese group at baseline (Table 4).
Plasma glucose levels remained similar in the overweight group, but
increased significantly in the normal weight group during
ß2-adrenergic stimulation. Plasma insulin
levels increased significantly more in the obese compared with the lean
group during salbutamol infusion. Baseline lactate and potassium
concentrations were similar in both groups. Lactate levels
significantly increased, and potassium levels significantly decreased
during ß2-adrenergic stimulation, but remained
comparable between groups (Table 5).
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). Baseline
norepinephrine levels were comparable between overweight and normal
weight subjects (2.57 ± 0.16 vs. 2.36 ± 0.16
nmol/L; P = NS), but baseline epinephrine levels were
significantly higher in the lean group (0.13 ± 0.02
vs. 0.22 ± 0.03 nmol/L; P < 0.01).
Norepinephrine levels increased similarly in both groups during
ß2-adrenergic stimulation. Epinephrine levels
decreased significantly in both groups during
ß2-adrenergic stimulation, but the decrease was
significantly higher in the lean group (Fig. 3).
Baseline values for heart rate and systolic and diastolic blood
pressure were not significantly different between obese and lean men
(Table 5). Heart rate significantly increased, systolic blood pressure
remained similar, and diastolic blood pressure significantly decreased
in both groups during ß2-adrenergic stimulation
with salbutamol. The changes in heart rate and systolic and diastolic
blood pressure were similar in obese and lean men (Table 5).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The interpretation of the data from our study highly depends on the selectivity of the ß-adrenoceptor agonists used. An earlier study from our group (9) showed that dobutamine induced ß1-adrenoceptor-specific changes in thermogenesis and lipid utilization in dosages of 10 µg/kg BW·min or less. The maximum dose we used was 9 µg/kg FFM·min, which is comparable with 7.5 µg/kg BW·min and thus lies within the range of ß1-adrenoceptor specificity. Our earlier study (9) also showed that the ß2-adrenoceptor agonist salbutamol in a concentration of 85 ng/kg BW·min (or 100 ng/kg FFM·min) also induced ß1-adrenoceptor-specific changes in lipid utilization. Addition of the ß1-adrenoceptor antagonist atenolol prevented simultaneous ß1-adrenergic stimulation, but did not affect ß2-adrenoceptor-specific changes. Therefore, in the current study salbutamol was given in combination with atenolol to investigate ß2-adrenoceptor specific changes in thermogenesis and lipid utilization.
Our study suggests that it is the ß2-adrenoceptor that is responsible for the impaired responses in thermogenesis, lipid oxidation, and lipolysis in the obese in vivo. In in vitro studies, similar results are found in relation to lipolysis. Glycerol release from sc abdominal fat cells from normal weight and overweight women was similar after incubation with dobutamine, but after incubation with isoprenaline or terbutaline, glycerol release was reduced in fat cells from the obese. This appeared to be due to a significant reduction in cell surface density of ß2-adrenoceptors, although messenger ribonucleic acid (mRNA) levels were similar in both groups (29). In another study, lean subjects with low isoprenaline sensitivity, as measured by in vitro sc abdominal fat cell lipolysis, appeared to have lower ß2-adrenoceptor number and mRNA level compared with lean subjects with high isoprenaline sensitivity, whereas ß1-adrenoceptor number and mRNA levels were similar in both groups (30). Both studies suggest that the ß2-adrenoceptor is responsible for the reduced ß-adrenoceptor-mediated increase in lipolysis, which is in line with our findings.
Further evidence for a role of the ß2-adrenoceptor in the etiology of obesity is provided by two recently found polymorphisms in the ß2-adrenoceptor that are associated with obesity. The Arg16Gly polymorphism in the ß2-adrenoceptor is associated with obesity in Japanese women (31). In a group of Swedish women, this mutation is not associated with obesity, but fat cells from women homozygous for Arg16 showed a 5-fold lower agonist sensitivity for ß2-adrenoceptors than women heterozygous or homozygous for Gly16 (32). The Gln27Glu polymorphism is associated with obesity in Japanese males and females (31, 33). Swedish women homozygous for Glu27 had an average fat mass excess of 20 kg and approximately 50% larger fat cells than women homozygous for Gln27. However, no significant association with changes in ß2-adrenoceptor function was observed, as assessed by in vitro fat cell lipolysis experiments (32). Obesity in Swedish males tends to be negatively associated with the Gln27Glu polymorphism (34). As we did not determine ß2-adrenoceptor polymorphisms, it is unknown whether the impaired responses in thermogenesis and lipid utilization found in our obese group are associated with one or both of the above-mentioned polymorphisms. Until now, no associations between polymorphisms in the ß1-adrenoceptor and obesity have been reported.
The reduced increases in thermogenesis and lipid oxidation during
ß2-adrenergic stimulation in the obese might
also be explained by the reduced increase in NEFA in blood. The amount
of NEFA presented to skeletal muscle was therefore reduced, which may
have resulted in a smaller increase in lipid oxidation and
thermogenesis. As shown in Fig. 5, there
was a clear relationship between the increases in plasma NEFA
concentration and the increases in energy expenditure and lipid
oxidation during ß1- and
ß2-adrenergic stimulation. Furthermore, we
recently reported that for a certain increase in plasma NEFA
concentration produced by lipid heparin infusion, similar increases in
thermogenesis and lipid oxidation are found in obese and lean men
(35). These data suggest that not only
ß2-adrenergic stimulation but also NEFA
availability might be related to the blunted responses in thermogenesis
and lipid oxidation. Other studies reported not only impaired responses
in adipose tissue metabolism, but also in skeletal muscle metabolism,
where thermogenesis and lipid oxidation are presumed to be
predominantly localized (36). Blaak et al.
(7) showed that although plasma NEFA levels increased
significantly during nonselective ß-adrenergic stimulation, no net
uptake of NEFA in skeletal muscle occurred in the obese. Moreover,
others found that obese women have a decreased capacity to oxidize
substrates and have increased glycolytic and anaerobic capacities, as
measured by the activities of several key enzymes in skeletal muscle
biopsies (37, 38). This suggests that lipid oxidation and
thermogenesis are impaired in the obese independently from NEFA
availability. Our ß1-adrenoceptor study and the
study using lipid heparin infusion (35) show that similar
increases in thermogenesis and lipid oxidation occur in obese and lean
men for a certain increase in plasma NEFA concentration, and therefore
do not support these findings.
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Aging is also known to reduce the sensitivity for catecholamines and thus for ß-adrenoceptor agonists (41, 42). In our ß2-adrenoceptor study, obese and lean subjects were of similar age, but in the ß1-adrenoceptor study, the obese group was slightly, but significantly, older than the lean one. However, as our groups differed by only 5 yr in age, whereas subjects in studies on the effect of aging commonly differ by more than 30 yr of age, we believe that the difference in catecholamine sensitivity between our subjects was only minor and therefore did not influence the interpretation of our data.
The impaired responses to ß2-adrenergic stimulation may be caused by differences in norepinephrine kinetics. Studies with tritiated norepinephrine have shown that norepinephrine appearance rates are similar (43, 44) or higher (45, 46) and norepinephrine clearance rates are similar (17, 45, 46) or lower (18) in subjects with a greater fat mass. This suggests that basal sympathetic nervous system activity may be chronically increased in the obese. As a consequence, ßadrenoceptors may become desensitized and/or down-regulated, resulting in reduced sympathetic nervous system responses during additional ß-adrenergic stimulation, as shown in this and other studies (5, 7, 15, 16, 19, 20, 21). With regard to our study, it is unclear why this desensitization and/or down-regulation would only affect the ß2-adrenoceptor and not the ß1-adrenoceptor.
The question remains of whether the impaired responses during ß2-adrenergic stimulation are a cause or a consequence of obesity. Blaak et al. (47) showed that ß-adrenoceptor-mediated thermogenesis tended to increase after weight loss. This suggests that the impaired sympathetic nervous system response is a consequence of the obese state. On the other hand, Astrup et al. (48) showed that glucose-induced increases in energy expenditure and norepinephrine levels improved in obese subjects after 30-kg weight loss, but were still lower than those in control subjects. Furthermore, Blaak et al. (47) showed that ß-adrenoceptor-mediated increases in arterial NEFA concentration and muscle NEFA uptake remained impaired after weight reduction. This suggests that a defective sympathetic nervous system may be a primary factor leading to the development of obesity rather than a secondary factor resulting from the obese state.
In conclusion, our studies suggest that ß1-adrenoceptor-mediated thermogenesis and lipid utilization are similar in obese and lean men, but ß2-adrenoceptor-mediated increases in energy expenditure, lipid oxidation, and lipolysis are impaired in the obese.
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Acknowledgments |
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Footnotes |
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Received June 7, 2000.
Revised September 11, 2000.
Accepted February 7, 2001.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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- and ß-adrenoceptors in sympathetically mediated
thermogenesis. Am J Physiol. 264:E11–E17.
- and ß-adrenoceptors in vitro. Naunyn
Schmiedebergs Arch Pharmacol. 326:317–326.[CrossRef][Medline]
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) and 10 lean (
) men. Values are the mean ±
SEM. ###, P < 0.001, by ANOVA for
treatment.
) in obese
(
) men.