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Original Article |
German Institute of Human Nutrition (M.B., S.K.), 14558 Potsdam, Germany; Franz-Volhard Clinical Research Center (C.S., J.T., G.K., A.M.S., F.C.L., J.J.), Medical Faculty of the Charité, Humboldt-University, Berlin 13125, Germany; Department of Internal Medicine and Endocrinology (N.J.C.), Herlev Hospital, University of Copenhagen, 2730 Copenhagen, Denmark; and Autonomic Dysfunction Service (I.B.), Vanderbilt University, Nashville, Tennessee 37232
Address all correspondence and requests for reprints to: Jens Jordan, M.D., Clinical Research Center, Haus 129, Franz-Volhard-Clinic, Humboldt University, Wiltbergstrasse 50, 13125 Berlin, Germany. E-mail: jordan{at}fvk-berlin.de.
Abstract
Genetic variability, numerous medications, and some illicit drugs influence norepinephrine transporter (NET) function; however, the metabolic consequences of NET inhibition are poorly understood. We performed a randomized, double-blind, cross-over trial in 15 healthy subjects who ingested 8 mg of the selective NET inhibitor reboxetine or placebo. Energy expenditure and substrate oxidation rates were determined by indirect calorimetry before and during iv infusion of 0.25, 0.5, 1, and 2 µg isoproterenol/min. Adipose tissue metabolism was studied by microdialysis before and during local isoproterenol perfusion. At rest, energy expenditure and substrate oxidation rates did not differ between reboxetine and placebo treatment. At 1 µg/min isoproterenol, energy expenditure was significantly increased in men (+15%) and women (+20%) with both reboxetine and placebo treatment. However, carbohydrate oxidation rate was significantly higher with reboxetine compared with placebo. Baseline and isoproterenol-stimulated adipose tissue blood flow was about 2-fold higher with reboxetine vs. placebo. Furthermore, glucose supply and metabolism was significantly increased and lipid mobilization much more stimulated in adipose tissue under reboxetine when compared with placebo at all isoproterenol concentrations used. We conclude that acute NET inhibition increases adipose tissue glucose uptake and metabolism. While lipid mobilization is increased, overall lipid oxidation is decreased during ß-adrenergic stimulation. This effect cannot be explained by increased systemic or adipose tissue norepinephrine concentrations. Instead, NET inhibition may sensitize adipose tissue to ß-adrenergic stimulation.
NOREPINEPHRINE RELEASED FROM postganglionic adrenergic neurons has a central role in the regulation of energy metabolism and blood pressure. Approximately 80–90% of the released norepinephrine is taken up again by postganglionic adrenergic neurons through the norepinephrine transporter (NET) (uptake-1) and repackaged or metabolized. Thus, changes in NET function may have important cardiovascular and metabolic effects. Intuitively, one would speculate that a decrease in NET function leads to an increase in adrenergic stimulation in peripheral tissues. Indeed, in one family, raised orthostatic heart rate and moderately increased plasma norepinephrine concentrations segregated with a functional mutation of the NET gene (1). A similar cardiovascular phenotype can be produced by selective NET blockade (2). In contrast, NET blockade strongly attenuates the pressor response to sympathetic stimuli (2). Moreover, NET blockade leads to a profound decrease in sympathetic nerve traffic and in systemic norepinephrine spillover (3). These paradoxical findings demonstrate that peripheral changes in NET function are strongly modulated by opposing central nervous system effects. The overall effect of NET inhibition results from the balance of peripheral and central effects. The metabolic consequences of the opposing effects on the sympathetic nervous system are poorly understood. Yet, NET inhibition is part of some pharmacological obesity treatments (4). We determined the effect of selective NET blockade on overall metabolic rate and on adipose tissue perfusion and metabolism at rest and during ß-adrenergic stimulation. Furthermore, we characterized the effect of NET blockade on plasma and interstitial norepinephrine concentrations.
Materials and Methods
Subjects
We studied 15 healthy subjects (8 men and 7 women). Written informed consent was obtained before study entry. All studies were approved by the institutional review board.
Protocol
None of the subjects ingested vasoactive medications that could interfere with testing. Twenty-four hours before study, volunteers received a diet free of substances that could interfere with catecholamine measurements. Subjects abstained from smoking during this period. Subjects did not eat 12.5 h before testing and did not drink 1.5 h before testing. We conducted three separate studies. In the first study (7 men and 7 women, age 31 ± 2 yr, body mass index 23 ± 0.8 kg/m2), we assessed the effect of selective NET blockade on supine and upright catecholamine levels. In the second study (4 men and 4 women, age 30 ± 2 yr, body mass index 22 ± 0.4 kg/m2), we characterized the effect of selective NET blockade on resting metabolic rate and on sensitivity to systemic isoproterenol infusion. In the third study (8 men, age 27 ± 2 yr, body mass index 25 ± 0.7 kg/m2), we used the microdialysis technique to determine the effect of NET blockade on basal and isoproterenol-stimulated metabolism, and on norepinephrine concentrations at the tissue level. In all studies, subjects ingested 8 mg reboxetine (Edronax, Pharmacia \|[amp ]\| Upjohn, Erlangen, Germany) or matching placebo 12 h and 1 h before the study. Studies with placebo and with reboxetine were conducted on separate days in a double-blind cross-over fashion.
Head-up tilt (HUT) testing
The subjects laid down on a motorized tilt table. A catheter was placed in an antecubital vein. After a recovery period of 30 min in the supine position, venous plasma catecholamines were determined. Then, the subjects were gradually tilted upright by 15 degrees every 3 min until 75-degree HUT was reached. The subjects remained at a 75-degree HUT for an additional 30 min or until presyncopal symptoms occurred. Upright plasma catecholamines were determined at the end of HUT testing.
Determination of resting and isoproterenol-stimulated circulatory condition and energy expenditure
Testing was conducted in the supine position. Two catheters were placed in large antecubital veins. Heart rate was determined by electrocardiogram. Beat-by-beat blood pressure (Finapres, Ohmeda, Luisville, CO) and brachial arterial blood pressure (Dinamap, Critikon, Newport, UK) were also determined. Oxygen uptake and carbon dioxide production were measured with use of a Deltatrac II metabolic cart (Datex Ohmeda, Duisburg, Germany) to assess resting and isoproterenol-induced changes in energy expenditure and respiratory quotient (RQ, [CO2] produced/[O2] consumed). After a run-in period of 15 min, resting energy expenditure was determined for 30 min. Then, incremental doses of the nonselective ß-adrenoreceptor agonist isoproterenol were infused. The infusion was started at a rate of 0.25 µg/min and increased in 5-min intervals until a heart rate increase of at least 25 beats per minute (bpm) was reached.
Microdialysis
Microdialysis studies were conducted as described previously (5). Briefly, one microdialysis catheter was inserted into sc adipose tissue at the level of the umbilicus. Before insertion of the catheter, the respective area was anesthetized with EMLA creme (Astra USA, Inc., Wedel, Germany). After insertion of the probe, perfusion of tissue was started at a flow rate of 2 µl/min with Ringer’s solution (Serumwerke Bernburg AG, Bernburg, Germany) supplemented with 50 mM ethanol (EtOH, for monitoring changes in blood flow) and 10 µM ascorbate. CMA/60 microdialysis catheters and CMA/102 microdialysis pumps (both from CMA Microdialysis AB, Solna, Sweden) were used. After a baseline period of 60 min, the microdialysis catheter was perfused with 0.01, 0.1, 1, and 10 µM isoproterenol (Abbot Laboratories, Ottignies, France).
Analytical methods
Ethanol concentration was determined in the perfusate (inflow) and dialysate (outflow) using a standard enzymatic assay (6). Dialysate concentrations of glycerol, glucose, and lactate were determined using the CMA/600 analyzer (CMA Microdialysis). Microdialysis samples for norepinephrine and epinephrine determination were processed as previously described (5, 7). Norepinephrine was analyzed by a radioenzymatic method. The 3H-labeled derivative normetanephrine was isolated by HPLC. The sensitivity of the assay was 0.5 pg. Plasma catecholamines were determined by a modification of a HPLC method (8).
Calculations and statistics
Changes in blood flow were determined by using the ethanol dilution technique based on Fick’s principle (9, 10, 11). Accordingly, a decrease in the ratio between ethanol in the dialysate and perfusate ([EtOH]d/[EtOH]p) corresponds to an increase in blood flow and vice versa. Dialysate glycerol concentration was measured to assess changes in lipolysis and/or lipid mobilization (12). Dialysate concentrations of glucose and lactate were determined to characterize glucose supply and glycolysis, respectively. In previous studies, in situ recovery for glycerol, glucose, and lactate in the dialysate was found to be approximately 30%, using near-equilibrium dialysis at 0.3 µl/min (13). All data are expressed as mean ± SEM. Intraindividual and interindividual differences were compared by paired and unpaired t tests, respectively. When necessary, i.e. rather small number of individuals (n = 4) or no normal distribution of the data, the respective nonparametric tests (Wilcoxon test and U test) were used. ANOVA testing for repeated measures was used for multiple comparisons. Relationship between parameters was assessed by linear regression analysis. A value for P less than 0.05 was considered significant.
Results
Supine and upright catecholamines
The results of the plasma catecholamine determination with placebo and with reboxetine are given in Table 1
. In the supine position, plasma norepinephrine concentration was significantly reduced with reboxetine when compared with placebo. In contrast, reboxetine markedly augmented upright plasma norepinephrine concentrations. Reboxetine significantly reduced plasma dihydroxyphenylglycol (DHPG) in the supine position and even more pronounced in the upright position. Reboxetine decreased the norepinephrine to DHPG ratio in the upright position. Plasma dihydroxyphenylalanine (DOPA) concentrations were not influenced by posture or reboxetine treatment.
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Reboxetine ingestion led to a moderate increase in supine resting heart rate and a slight increase in blood pressure. Heart rate was 64 ± 3 bpm with placebo and 69 ± 5 bpm with reboxetine (P < 0.05 by paired t test). Brachial blood pressure was 109 ± 4/63 ± 1 and 122 ± 5/71 ± 1 mm Hg with placebo and with reboxetine, respectively (P < 0.01 by paired t test for both, systolic and diastolic BP).
Resting energy expenditure was about 6800 and 5500 kJ/24 h for men and women, respectively, with no significant differences between placebo and reboxetine (Fig. 1). Resting RQ was about 0.75 and 0.80 for men and women, respectively. There were also no significant differences between both treatment groups (Fig. 1). In men, resting serum glucose was significantly higher with reboxetine vs. placebo (5.67 ± 0.21 vs. 5.19 ± 0.16 mmol/liter, P < 0.05, Wilcoxon-test, Fig. 2). In women, resting serum glucose did not differ significantly between the two treatment groups (4.90 ± 0.15 vs. 5.03 ± 0.22 mmol/liter). Resting serum glycerol did not differ significantly between reboxetine and placebo in men (57 ± 8 vs. 45 ± 5 µmol/liter), but it was significantly higher with reboxetine vs. placebo (125 ± 18 vs. 55 ± 2 µmol/liter, P < 0.05, Wilcoxon test) in women (Fig. 2). In both men and women, resting free fatty acids were significantly higher on reboxetine when compared with placebo (0.71 ± 0.11 vs. 0.48 ± 0.10 mmol/liter and 1.07 ± 0.24 vs. 0.55 ± 0.03 mmol/liter, P < 0.05, for men and women, respectively, Fig. 2).
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Isoproterenol sensitivity increased significantly with selective NET inhibition. The isoproterenol dose that increased heart rate 25 bpm was 1.3 ± 0.2 µg/min with placebo and 0.7 ± 0.1 µg/min with reboxetine (P < 0.01, Wilcoxon test). With placebo, incremental infusion of isoproterenol did not elicit a major change in blood pressure (Fig. 3). In contrast with reboxetine, isoproterenol elicited a dose-dependent depressor response. With the maximal dose of isoproterenol that was given during both interventions (0.9 ± 0.1 µg/min), systolic blood pressure changed -0.8 ± 3 (range -16 to +16) mm Hg during placebo and -18 ± 3 mm Hg (range -28 to -4) during reboxetine (P < 0.001, Wilcoxon test).
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). There were no significant differences between the treatment groups. Energy expenditure continued to increase with 2 µg/min isoproterenol on placebo treatment. On reboxetine, subjects did not tolerate isoproterenol doses above 1 µg/min due to side effects, such as palpitations. RQ increased dose dependently from about 0.75 and 0.80 to about 0.85 at 0.5 µg isoproterenol/min for both men and women, respectively (Fig. 1). Although RQ continued to increase at 1 µg isoproterenol/min on reboxetine, RQ persisted at about 0.85 with 1 and 2 µg isoproterenol/min on placebo.
The metabolic changes were accompanied by distinct changes in the concentrations of serum glucose, free fatty acids, and glycerol. In men, serum glucose concentrations increased slightly but not significantly during infusion of isoproterenol. However, at all isoproterenol concentrations used, serum glucose concentrations were significantly higher with reboxetine when compared with placebo (P < 0.01, Fig. 2). In women, serum glucose concentrations remained almost unchanged during isoproterenol perfusion in both treatment groups (Fig. 2). In contrast to that, serum concentrations of glycerol and free fatty acids showed some distinct changes during perfusion with isoproterenol (Fig. 2). In men, glycerol and free fatty acids were not significantly affected by isoproterenol at 0.25 and 0.5 µg/min, respectively. At 1.0 µg/min, however, isoproterenol elicited a significant increase in both metabolites (P < 0.05), and the values were also significantly higher with reboxetine when compared with placebo. In women, serum concentrations of glycerol and free fatty acids were already significantly increased at 0.5 µg isoproterenol/min (P < 0.05). In contrast to men, serum concentrations of glycerol and free fatty acids in women where significantly higher with reboxetine when compared with placebo at all isoproterenol concentrations used (Fig. 2). At 0.5 µg isoproterenol/min, for example, serum glycerol concentrations were 158 ± 40 and 94 ± 15 µmol/liter (P < 0.01), and concentrations of free fatty acid were 1.87 ± 0.16 and 1.00 ± 0.12 mmol/liter (P < 0.05) with reboxetine and placebo, respectively.
Resting adipose tissue perfusion and metabolism
Data on ethanol ratio and dialysate concentrations of glycerol, lactate, and glucose under resting conditions on placebo and reboxetine treatment are given in Fig. 4. Resting ethanol ratio was 0.42 ± 0.08 with placebo and 0.28 ± 0.05 with reboxetine (P < 0.05). Resting dialysate concentrations of glycerol, glucose, and lactate did not differ significantly between reboxetine and placebo (98 ± 15 µM vs. 68 ± 5 µM for glycerol, 1.53 ± 0.19 mM vs. 1.25 ± 0.25 mM for glucose, and 0.43 ± 0.09 mM vs. 0.41 ± 0.06 mM for lactate, for reboxetine and placebo, respectively, Fig. 4).
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Isoproterenol induced a dose-dependent decrease in ethanol ratio from 0.42 ± 0.08 and 0.28 ± 0.05 (baseline) to 0.29 ± 0.05 and 0.19 ± 0.04 (10 µM isoproterenol) on placebo and on reboxetine, respectively (P < 0.05, placebo vs. reboxetine at all isoproterenol concentrations used Fig. 4). Isoproterenol induced also a dose-dependent increase in dialysate glycerol concentration which was similar on placebo and on reboxetine (Fig. 4). During stimulation with 10 µM isoproterenol, dialysate glycerol concentration was 216 ± 15 µM on placebo and 242 ± 32 µM on reboxetine indicating a 3-fold increase in lipid mobilization. On placebo, dialysate lactate concentration was almost unchanged during isoproterenol perfusion (0.41 ± 0.06 mM at baseline and 0.50 ± 0.04 at 10 µM isoproterenol, not significant). On reboxetine, isoproterenol induced an dose-dependent increase in dialysate lactate concentration from 0.43 ± 0.09 (baseline) to 0.75 ± 0.19 (10 µM isoproterenol, P < 0.05). At all isoproterenol concentrations used dialysate lactate concentrations were significantly higher on reboxetine when compared with placebo (P < 0.05). Isoproterenol caused a small but consistent increase in dialysate glucose concentration from 1.25 ± 0.25 and 1.53 ± 0.19 mM (baseline) to 1.49 ± 0.123 and 1.74 ± 0.25 mM (1.0 µM isoproterenol, P < 0.01). However, at all isoproterenol concentrations used dialysate glucose concentrations were not different between placebo and reboxetine.
Adipose tissue norepinephrine
Baseline dialysate norepinephrine concentrations were about 0.5 nM on both reboxetine and placebo (Fig. 5). Perfusion with isoproterenol led to a dose-dependent increase in dialysate norepinephrine concentration that was significantly lower with reboxetine compared with placebo at 10 µM isoproterenol (Fig. 5).
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We assessed the effect of selective NET inhibition on systemic and on local (adipose tissue) catecholamine concentrations. In addition, we determined the effect of this manipulation of norepinephrine turnover on metabolism both systemically and at the tissue level. We used reboxetine as a pharmacological tool to block norepinephrine uptake. Reboxetine is a highly selective norepinephrine uptake inhibitor. Reboxetine does not inhibit dopamine or serotonin uptake. The drug does not bind to muscarinic cholinergic receptors or adrenoreceptors (14). Thus, the agent is ideally suited to study the effects of NET blockade in the absence of confounding nonspecific effects (2).
Norepinephrine uptake inhibition decreases the intraneuronal metabolism of norepinephrine to DHPG by monoamine oxidase (8). The marked decrease in DHPG and in upright DHPG to norepinephrine ratio with reboxetine is consistent with sufficient norepinephrine uptake inhibition in our study. A similar reduction in the DHPG to norepinephrine ratio is also observed in patients with familial NET dysfunction (1). When norepinephrine uptake inhibitors are applied to isolated organs or given in low intraarterial doses, norepinephrine washout is markedly increased (15). Contrary to what one might expect, systemic NET blockade with reboxetine led to a decrease in venous plasma norepinephrine concentration in the supine position. However, selective norepinephrine uptake inhibition markedly augmented upright plasma norepinephrine concentrations. Similarly, norepinephrine uptake inhibition with desipramine resulted in a decrease rather than an increase in whole body norepinephrine spillover in the supine position (3). The conversion of tyrosine to DOPA by tyrosine hydroxylase is the rate limiting step in norepinephrine synthesis. Venous DOPA concentrations were not affected by selective NET blockade. This observation might suggest that the changes in norepinephrine turnover cannot be explained by a major change in norepinephrine synthesis. Instead, the decrease in norepinephrine spillover might be related to a decrease in sympathetic outflow from the central nervous system. Systemic nonselective norepinephrine uptake inhibition leads to a profound decrease in sympathetic nerve traffic to skeletal muscle (3). A similar effect can be obtained when NET blockers are applied directly to the brain (16). Thus, peripheral responses to systemic NET inhibition are strongly modulated by a central sympatholytic effect.
Systemic norepinephrine concentrations or spillover may not reflect norepinephrine turnover at the organ or at the tissue level (17). For example, norepinephrine reuptake inhibition with desipramine decreased norepinephrine spillover in the forearm and in the kidney (3). In contrast, desipramine increased cardiac norepinephrine spillover (3). Moreover, the spillover technique does not correct for changes in overflow of norepinephrine from the interstitial space into the vascular space. We were particularly interested in the effect of selective NET blockade on adipose tissue norepinephrine. In the absence of isoproterenol, adipose tissue interstitial norepinephrine concentrations were similar with reboxetine and placebo. Isoproterenol elicited a substantial increase in interstitial norepinephrine concentration through stimulation of presynaptic ß-2 adrenoreceptors (5, 18). Remarkably, the isoproterenol induced increase in interstitial norepinephrine was lower with reboxetine when compared with placebo. This observation suggests that systemic NET blockade does not increase the norepinephrine concentration exposure of the adrenoreceptors.
The interstitial norepinephrine concentration is a function of norepinephrine release, neuronal uptake, and escape into circulation. The latter is strongly influenced by tissue blood flow. With and without isoproterenol stimulation, ethanol ratio was significantly lower with reboxetine when compared with placebo. Based on studies by Hickner et al. (19, 20), we estimate that NET blockade increased adipose tissue blood flow 2- to 3-fold. Therefore, removal of norepinephrine through the blood must have been increased with NET blockade. The fact that interstitial norepinephrine did not decrease with reboxetine despite a marked increase in blood flow is consistent with an increased flux of norepinephrine from the synaptic cleft into the interstitial space. This effect is presumably mediated through the decrease in neuronal norepinephrine uptake with reboxetine.
Although NET blockade did not increase systemic or interstitial norepinephrine concentrations, we observed substantial metabolic effects. In adipose tissue, NET blockade increased basal interstitial glycerol concentrations and tissue blood flow. With local isoproterenol stimulation, dialysate glycerol increased in a dose-dependent fashion. The response was similar with placebo and with reboxetine. Yet, tissue blood flow was consistently higher with reboxetine, which tends to increase glycerol clearance from the interstitial space. Therefore, blood flow-corrected primary release of glycerol should be at least twice as high with NET blockade both in the presence or in the absence of isoproterenol. Our findings suggest that NET blockade increased both basal and stimulated lipolytic rates. The slight increase in interstitial lactate with reboxetine during isoproterenol stimulation may suggest an enhanced glucose metabolism, which is also a typical ß-adrenergic response. NET blockade seems to increase the sensitivity of adipose tissue to the stimulation of postsynaptic ß-adrenoreceptors. A similar paradoxical observation is that NET blockade increases blood pressure even though norepinephrine spillover decreases. An alternative explanation is that interstitial concentrations of norepinephrine underestimate the norepinephrine concentrations acting upon adrenergic receptors.
Systemic administration of isoproterenol resulted in a clear dose-dependent increase in energy expenditure in both men and women with no significant differences between reboxetine and placebo treatment. As expected, the increase in energy expenditure was accompanied by an increase in RQ during this simulated stress situation indicating an increased carbohydrate oxidation rate. RQ values peaked at 0.50 µg isoproterenol/min with placebo. With NET blockade, however, RQ continued to increase at 1.00 µg/min. ß-adrenergic stimulation, therefore, results in an almost identical increase in energy expenditure in both treatment groups. But, when compared with placebo, the increase in energy metabolism on reboxetine, especially at higher isoproterenol doses, is fueled rather by oxidation of carbohydrates than by oxidation of lipids. Therefore, the increased lipid mobilization with NET blockade is associated with a decreased lipid utilization. Indeed, NET blockade was accompanied by increased concentrations of serum glycerol and free fatty acids at rest as well as during isoproterenol stimulation. This observation might suggest that NET function contributes to the variability in serum free fatty acid concentration. Chronic elevations in serum free fatty acid concentrations are associated with the development of the insulin resistance syndrome (21).
We conclude that the peripheral effects of NET blockade are strongly modulated and attenuated by a central sympatholytic effect. The balance between central and peripheral effects may be influenced by environmental, genetic and hormonal factors. However, in one study in nonhuman primates, ovarian steroid hormones did not have a major effect on NET expression in the brain (22). Norepinephrine transporter blockade does not increase systemic norepinephrine release or adipose tissue norepinephrine. The sympatholytic effect may be beneficial in that it attenuates the blood pressure raising effect of medications that inhibit NET function, such as some antidepressants and the antiobesity drug sibutramine. Yet, the sympatholytic effect may also diminish the effect of NET blockade on energy expenditure in the treatment of obesity. Moreover, NET blockade increases lipid mobilization but decreases lipid utilization, specifically with ß-adrenoreceptor stimulation. These observations are consistent with the idea that NET blockade increases the responsiveness of adipose tissue to the stimulation of postsynaptic adrenoreceptors. A similar effect may contribute to the pressor effect of NET inhibition.
Acknowledgments
The excellent, skillful technical assistance of Gabriele Franke, Mandy Stoffels, and Karin Schaller is gratefully acknowledged.
Footnotes
This study was supported in part by Deutsche Forschungsgemeinschaft Grant Jo 284/3-1. J.J. is recipient of a Helmholtz scholarship by the Max-Delbrueck-Center (MDC) of Molecular Medicine.
Abbreviations: bpm, Beats per minute; DHPG, dihydroxyphenylglycol; DOPA, dihydroxyphenylalanine; HUT, head-up tilt; NET, norepinephrine transporter; RQ, respiratory quotient.
Received April 4, 2002.
Accepted August 14, 2002.
References
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