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Am J Physiol Regul Integr Comp Physiol 279: R499-R504, 2000;
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Vol. 279, Issue 2, R499-R504, August 2000

Activation of alpha 2-adrenergic receptors impairs exercise-induced lipolysis in SCAT of obese subjects

Vladimir Stich1, Isabelle De Glisezinski2,3, Francois Crampes2,3, Jindra Hejnova1, Jean-Marie Cottet-Emard4, Jean Galitzky3,5, Max Lafontan3, Daniel Rivière2,3, and Michel Berlan3,5

1 Department of Sport Medicine, Third Faculty of Medicine, Charles University, 10000 Praha, Czech Republic; 2 Department of the Adaptation to Exercise, Purpan Hospital, Toulouse; 4 Department of Physiology, Claude Bernard University, 69373 Lyon; 5 Department of Medical and Clinical Pharmacology, Faculty of Medicine, 31073 Toulouse; and 3 Institut National de la Santé et de la Recherche Médicale Unité 317 Rangueil Hospital, Paul Sabatier University, 31403 Toulouse, France


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION
REFERENCES

With the use of the microdialysis method, exercise-induced lipolysis was investigated in subcutaneous adipose tissue (SCAT) in obese subjects and compared with lean ones, and the effect of blockade of alpha 2-adrenergic receptors (ARs) on lipolysis during exercise was explored. Changes in extracellular glycerol concentrations and blood flow were measured in SCAT in a control microdialysis probe at rest and during 60-min exercise bouts (50% of heart rate reserve) and in a probe supplemented with the alpha 2-AR antagonist phentolamine. At rest and during exercise, plasma norepinephrine and epinephrine concentrations were not different in obese compared with lean men. In the basal state, plasma and extracellular glycerol concentrations were higher, whereas blood flow was lower in SCAT of obese subjects. During exercise, the increase of plasma glycerol was higher in obese subjects (115 ± 35 vs. 65 ± 21 µmol/l). Oppositely, the exercise-induced increase in extracellular glycerol concentrations in SCAT was five- to sixfold lower in obese than in lean subjects (50 ± 14 vs. 318 ± 53 µmol/l). The exercise-induced increase in extracellular glycerol concentration was not significantly modified by phentolamine infusion in lean subjects but was strongly enhanced in the obese subjects and reached the concentrations found in lean sujects (297 ± 46 µmol/l). These findings demonstrate that the physiological stimulation of SCAT adipocyte alpha 2-ARs during exercice-induced sympathetic nervous system activation contributes to the blunted lipolysis noted in obese men.

microdialysis; catecholamines; blood flow; phentolamine; glycerol; lipid mobilization


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION
REFERENCES

HUMAN ADIPOCYTES EXPRESS SIGNIFICANT levels of beta 1-, beta 2-, and alpha 2-adrenergic receptors (ARs) that couple positively (beta 1- and beta 2-ARs) and negatively (alpha 2-AR) to adenylyl cyclase (24). The relative contributions of beta - and alpha 2-ARs to the fine tuning of the lipolytic response has been demonstrated by functional in vitro assays in isolated human fat cells. Moreover, binding studies with selective ligands have been used to determine the affinity patterns of the various fat cell AR subtypes for catecholamines (21, 22, 24, 30). In vitro studies in isolated human fat cells have shown that the activation of alpha 2-ARs by epinephrine and norepinephrine impairs the beta -adrenergic component of catecholamine-induced lipolysis. In human fat cells, where alpha 2-AR outnumber beta -AR, the preferential recruitment of the alpha 2-AR at the lowest catecholamine concentrations inhibits lipolysis (30). The strongest alpha 2-adrenergic effect has been observed in the adipocytes from subcutaneous adipose tissue (SCAT) from both men and women. The antilipolytic action of catecholamines, particularly that of epinephrine, which exhibits a higher affinity to alpha 2-AR (22), is particularly expressed in subcutaneous adipocytes from obese subjects (29). Whatever the number of converging in vitro results suggesting an important role for fat cell alpha 2-ARs in the control of lipolysis in obese subjects, convincing demonstrations of their involvement in physiological situations are still lacking. In the search for relevant physiological protocols, exercise was selected as a prerequisite to activate the sympathetic nervous system (SNS). Exercise-increased SNS activity is responsible for exercise-promoted lipid mobilization in normal subjects. Catecholamines are of major importance for the regulation of lipid mobilization in human adipose tissue during exercise (8, 9, 19) and for the increase of nonesterified fatty acid (NEFA) supply to the working muscle (8, 16). Microdialysis is a method particularly suitable to study the in vivo lipolytic responses of adipose tissue to pharmacological or endogenous stimulation (2-4, 12, 20, 28, 33). In a recent study using microdialysis, it was demonstrated that alpha 2-ARs are involved in the regulation of lipolysis during an acute bout of exercise (33). Taking into account that the adipocytes of SCAT express the highest known alpha 2-AR-mediated antilipolytic component in vitro in obese men (29), it is of interest to study the extent of the catecholamine-induced alpha 2-AR activation in adipose tissue in obese subjects during exercise compared with nonobese counterparts.

The aim of the present study was to reveal the incidence of physiological activation of fat cell alpha 2-ARs in SCAT and to delineate the importance of alpha 2-AR-mediated pathways in the adipose tissue of obese subjects. With the use of in situ microdialysis, the changes in lipolysis and local blood flow were studied in SCAT of obese subjects during exercise (60 min, 50% of their heart rate reserve) and the effect of the blockade of alpha 2-ARs on these changes was explored. The results were compared with those of lean subjects.

The present study demonstrates that exercise-induced lipolysis in SCAT is impaired in obese subjects and that the physiological stimulation of adipocyte alpha 2-ARs during exercise contributes to this impairment. The blunting of lipid mobilization was suppressed by local administration of an alpha 2-AR antagonist.


    SUBJECTS AND METHODS
TOP
ABSTRACT
INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects. Seven lean untrained men (mean age 22.9 ± 0.8 yr) and seven obese men (24.9 ± 2.8 yr) participated in the study. The mean body weight and body mass index (BMI) of the lean subjects were 73.6 ± 3.5 kg (range 70-81.5 kg) and 23.2 ± 1.2 kg/m2 (range 21.2-25.2 kg/m2), respectively. The mean body weight and BMI of the obese subjects were 96.9 ± 3.4 kg (range 89-110 kg) and 31.4 ± 1.4 kg/m2 (range 29-38 kg/m2), respectively. All were drug free, and their weights had remained stable for at least 3 mo before the beginning of the study. All subjects had given their written informed consent before the experiments began. The studies were performed according to the Declaration of Helsinki and approved by the Ethical Committee of Third Faculty of Medicine (Prague, Czech Republic).

Experimental protocol. The subjects were investigated at 0800 after an overnight fast and were placed in a semirecumbent position. Microdialysis probes (Carnegie Medecin, Stockholm, Sweden) of 20 × 0.5 mm and 20,000-molecular wt cut-off were inserted percutaneously after epidermal anesthesia (200 µl of 1% lidocaine, Roger-Bellon, Neuilly-s-Seine, France) into the abdominal SCAT at a distance of 10 cm immediately to the right of the umbilicus. Two probes, separated by at least 10 cm, were connected to a microinjection pump (Harvard apparatus, Les Ulis, France). One probe was perfused with Ringer solution (in mmol/l: 139 sodium, 2.7 potassium, 0.9 calcium, and 140.5 chloride) and the second with Ringer plus 0.1 mmol/l phentolamine (alpha -AR antagonist). This nonselective alpha 1-/alpha 2-antagonist, having an efficient alpha 2-AR antagonist action in human fat cells in vitro, was the only agent allowed by the ethical committee for use in microdialysis assays in humans. The two perfusate solutions were supplemented with ethanol (1.7 g/l). Ethanol was added to the perfusate to estimate changes occurring in the local blood flow of SCAT, as previously described (11-13). After a 30-min equilibration period, a 30-min fraction of dialysate was then collected at a flow rate of 0.5 µl/min. Then, the perfusion was set at 2.5 µl/min for the remaining experimental period. A calibration procedure using various perfusion rates for determination of interstitial glycerol concentration in SCAT has already been reported by our group (3, 4). A simplified, but relevant and less time-consuming method was selected in this study. The estimated extracellular glycerol concentrations were calculated by plotting (after log transformation) the concentration of glycerol in the dialysate measured at 0.5 and 2.5 µl/min against the perfusion rates. The values of extracellular glycerol concentrations found in the present study fit with previous determinations performed in lean and obese subjects (17, 18).

After the calibration of the probes, two 15-min fractions of the outgoing dialysate were collected and the subjects then performed exercise for 60 min at an imposed power level corresponding to 50% of their heart rate reserve on a cycle ergometer. The heart rate was continuously monitored with a Baumann BHL 6000 cardiometer during the exercise. Then, the subjects rested in the semirecumbent position for 60 min. During the exercise and the recovery periods, 15-min fractions of the dialysate were collected. Water intake was allowed ad libitum during the experimental period.

Before exercise and every 30 min, 10 ml of blood were collected for plasma determinations from an indwelling polyethylene catheter inserted into an antecubital vein. The catheter was kept patent by slow infusion of saline. Blood was collected on 50 µl of an anticoagulant and antioxidant cocktail (Immunotech SA, Marseille, France), to prevent catecholamine oxidation, and processed immediately in a refrigerated centrifuge. The plasma was stored at -80°C until analysis.

Drugs and analytical methods. Phentolamine methanesulfonate (Regitine) was obtained from Ciba-Geigy (Reuil-Malmaison, France). Glycerol in dialysate (10 µl) and in plasma (20 µl) was analyzed with an ultrasensitive radiometric method (7); the intra-assay and interassay variabilities were 5.0% and 9.2%, respectively. Ethanol in dialysate and perfusate (5 µl) was determined with an enzymatic method (6); the intra-assay and interassay variabilities were 3.0% and 4.5%, respectively. Plasma glucose was determined with a glucose-oxidase technique (Biotrol kit, Merck-Clevenot, Nogent-s-Marne, France) and NEFA by an enzymatic procedure (Wako kit, Unipath, Dardilly, France). Plasma insulin concentrations were measured using RIA kits from Sanofi Diagnostics Pasteur (Marnes la Coquette, France). Plasma epinephrine and norepinephrine were assayed in 1-ml aliquots of plasma by high-pressure liquid chromatography using electrochemical (amperometric) detection (10). The detection limit was 20 pg/sample. Day-to-day variability was 4% and within-run variability 3%.

Statististical analysis. All the values are means ± SE. The responses to exercise were analyzed using a paired t-test and ANOVA when appropriate. During exercise, plasma and extracellular response curves were calculated as the total integrated changes over baseline values [area under the curves (AUC)] using the trapezoidal method; P < 0.05 was considered statistically significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION
REFERENCES

General observations. The power developed by the subjects was regularly adjusted to maintain the heart rate constant over the exercise bout. Similar power was developed by obese and lean subjects during exercise (Table 1).

                              
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  		Table 1.   Heart rate and power developed during exercise (0-60 min) in lean and obese men

Extracellular glycerol concentration in SCAT at rest and during exercise. At rest, the baseline extracellular glycerol concentrations in SCAT were higher in obese (275 ± 38 µmol/l) than in lean subjects (194 ± 39 µmol/l) in the control probes. Adipose tissue glycerol levels at rest were two to three times higher than those in venous plasma in both groups of subjects. No modifications in basal extracellular glycerol concentration were observed in the probes containing phentolamine (280 ± 35 and 238 ± 30 µmol/l in SCAT of obese and lean, respectively) compared with the control probes.

During exercise, the extracellular glycerol concentration increased in the control probe in both groups of subjects, the increase being significant from the 15th min of exercise (Fig. 1). The exercise-induced increase of glycerol was 19% of the baseline value in obese subjects and was markedly lower compared with lean men (172% of baseline). Absolute values of exercise-induced increment were 52 ± 14 vs. 318 ± 53 µmol/l after 60 min of exercise in obese and lean subjects, respectively. The calculated average AUC for glycerol increase over 60 min of exercise was significantly lower in obese than in lean subjects (2,345 ± 342 vs. 9,430 ± 1,301 µmol · l-1 · 60 min-1, P < 0.006).


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  		Fig. 1.   Time course of extracellular glycerol concentration in subcutaneous adipose tissue (SCAT) calculated from dialysate glycerol levels during the 60-min cycle-ergometer exercise in lean and obese subjects. The alpha 2-adrenergic receptor antagonist phentolamine was () or was not (open circle ) added to the perfusion medium. Data are expressed as means ± SE. * P < 0.05 compared with baseline value.

In obese subjects, in the probe perfused with phentolamine, the extracellular glycerol concentration increased significantly, starting from 15 min of exercise, and reached 297 ± 47 µmol/l at the 60th min. The extracellular glycerol concentration was higher throughout exercise in the phentolamine probe compared with the control one. The exercise-induced increase of glycerol, when assessed with AUCs, was significantly (4.3-fold) higher in the phentolamine than in the control probe (9,870 ± 1,887 vs. 2,345 ± 342 µmol · l-1 · 60 min-1; P < 0.01). It is noteworthy that the exercise-induced increase in the phentolamine probe in the obese group reached that observed in the control probe in lean subjects. In individual cases, the rise of glycerol during exercise in the phentolamine probe was about four- to sixfold higher when compared with the control one. In lean subjects, the exercise-induced rise in extracellular glycerol was enhanced in the probe perfused with phentolamine, but the corresponding AUC for glycerol response (14,632 ± 5,885 vs. 9,430 ± 1,301 µmol · l-1 · 60 min-1) was far from being statistically different compared with the control probe (P < 0.2).

SCAT blood flow. Adipose tissue blood flow was assessed by ethanol outflow-to-inflow ratios [ethanol concentration measured in the dialysate divided by the ethanol concentration measured in the perfusate × 100 (%)] from the two probes, and the results are reported in Fig. 2. In rest conditions and during exercise, the ethanol outflow-to-inflow ratio was higher in obese than in lean subjects (P < 0.05). In both groups, no significant variations of the ethanol outflow-to-inflow ratio were observed during the exercise bout either in the control probe or in the probe with phentolamine (Fig. 2).


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  		Fig. 2.   Ethanol ratio in SCAT in lean and obese subjects. The ethanol ratios (dialysate ethanol/perfusate ethanol × 100) are the mean of 2 15-min fractions determined before each exercise (rest) and of 4 15-min fractions collected during exercise and those during recovery. Filled bars represent the results from the probe perfused with phentolamine.

Plasma NEFA and glycerol levels. During the baseline period, plasma NEFA and glycerol concentrations were higher in obese subjects (Table 2). In both groups, plasma NEFA concentrations did not significantly change throughout the exercise period. The plasma glycerol level increased 30 min after the beginning of exercise in both groups and peaked at the 60th min of exercise. During recovery, it decreased to values not different from those found in basal conditions. The average exercise-induced increment was 115 ± 35 and 65 ± 21 µmol/l in obese and lean subjects, respectively (Table 2). The calculated AUC for the plasma glycerol response was higher in obese than in lean subjects (4,792 ± 875 vs. 2,084 ± 697 µmol · l-1 · 60 min-1, P < 0.01).

                              
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  		Table 2.   Effect of 60 min exercise (0-60 min) on plasma catecholamines, NEFA, glycerol, glucose, and insulin concentrations in lean and obese men

Plasma catecholamine concentrations. At rest, plasma norepinephrine and epinephrine concentrations were similar in the two groups. Plasma norepinephrine concentration increased significantly at the 30th min of exercise; the increase during subsequent 30 min of exercise was not significant. The plasma epinephrine concentration rose at the 30th min of exercise and continued to increase (P < 0.01) until the end of exercise. During recovery, 60 min after the end of exercise, both catecholamines decreased to values not different from the baseline (Table 2). The AUC calculated for the exercise-induced increases in norepinephrine (35,005 ± 4,464 vs. 33,005 ± 4,283 pg · ml-1 · 60 min-1 in lean and obese, respectively) and epinephrine plasma levels (2,335 ± 493 vs. 3,639 ± 1,868 pg · ml-1 · 60 min-1 in lean and obese, respectively) showed no significant differences between the two groups of subjects.

Plasma glucose and insulin concentrations. During the baseline period, the plasma concentration of glucose was similar in both groups, whereas the plasma insulin level was higher in obese subjects (Table 2). No significant variations of plasma glucose level were observed in either group during the exercise bout. A significant decrease in plasma insulin concentration was observed at the end of the exercise period in obese and lean subjects. The AUC calculated for glucose and insulin variations in the plasma during the exercise bouts did not show significant differences between the two groups.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The present study demonstrates that the exercise-induced lipolysis is impaired in SCAT in obese subjects and that the physiological activation of alpha 2-ARs during exercise (60 min, 50% of the heart rate reserve of the subjects) contributes to the blunted lipolysis. The involvement of alpha 2-ARs in the suppression of lipolysis was demonstrated by the enhancement of exercise-induced lipolysis produced by local perfusion of the alpha 2-AR-antagonist phentolamine. The action of catecholamines on lipolysis is determined by the differential stimulation of lipolysis-promoting beta -ARs and antilipolytic alpha 2-ARs (1, 23, 29, 30). In in vivo physiological conditions, epinephrine secretion is typically elevated during exercise. It was demonstrated in our previous study (33) that the increased activation of alpha 2-ARs by epinephrine during a bout of moderate exercise produces an antilipolytic effect, i.e., the antilipolytic alpha 2-ARs are involved in the control of exercise-induced lipolysis. The aim of this study was to investigate in situ, using microdialysis, the lipolytic response to exercise in SCAT in obese subjects and its hormonal regulation. Namely, we hypothesized that the previously demonstrated involvement of the antilipolytic alpha 2-ARs could be enhanced in exercising obese men.

In agreement with previous human studies, the basal extracellular glycerol concentrations in SCAT as well as basal plasma glycerol and NEFA were higher in obese than in lean fasting subjects, suggesting that basal spontaneous SCAT glycerol production is increased in obesity (4, 17, 31). The local blood flow, evaluated with the ethanol escape method, was found to be lower in obese subjects (Fig. 2). Our data agree with a previous report that revealed a lower blood flow in SCAT of obese than lean subjects, as assessed by the 133Xe-clearance method (35).

During exercise, a higher increase in plasma glycerol was observed in obese than in lean subjects. The epinephrine and norepinephrine responses to exercise were not different in both groups. The average plasma insulin level was higher in obese subjects, whereas the well-known exercise-induced reduction in plasma insulin concentration was similar in both groups. Consequently, the higher plasma glycerol levels observed during the time course of exercise in obese subjects could be related to the increased adipose tissue mass. Moreover, it is not excluded that the increased plasma glycerol levels could be related to the higher efficacy of catecholamines to induce lipid mobilization in omental and visceral adipocytes, which are known for their strong beta -adrenergic responsiveness and reduced alpha 2-AR-mediated responses (27, 30).

Unlike plasma responses, the exercise-induced increase in extracellular glycerol concentration was markedly lower (+19%) in obese than in lean subjects (+172%). This observation could reflect not solely the exercise-induced local lipolytic response of the adipocytes, but could be influenced by changes occurring in local blood flow in SCAT (11, 13). In this study, the adipose tissue blood flow did not show a significant variation during the exercise neither in lean nor in obese subjects as previously shown (14, 32, 33). Similarly, no exercise-induced variations were found in the probe with phentolamine. Consequently, the differences in exercise-induced changes in extracellular glycerol concentration between the two groups cannot be attributed to changes in the local adipose tissue blood flow.

The fact that the exercise-induced increase of extracellular glycerol was potentiated by the local phentolamine perfusion in obese subjects demonstrates that the reduced lipid mobilization in SCAT is, at least partly, due to the stimulation of fat cell antilipolytic alpha 2-ARs by exercise-released catecholamines. Phentolamine is also known for its alpha 1-antagonist properties. However, alpha 1-AR stimulation or blockade has never been shown to alter lipolytic processes. In conditions of alpha 2-AR blockade, the inhibitory action mediated by alpha 2-AR stimulation was completely suppressed and the lipid-mobilizing activity induced by exercise reached that observed in lean subjects. In lean subjects, phentolamine also produced an enhancement of the lipolytic response to exercise, but the effect was not significant, and in absolute terms, it was much lower than in obese subjects.

Whatever the importance of the alpha 2-AR in SCAT of obese patients, we must keep in mind that beta -AR-mediated responses also represent a major element in the control of lipolytic processes. Exercise-induced lipid mobilization is suppressed by beta -adrenergic blockade in lean subjects (2). However, no major disturbances have been reported in vitro in fat cells from SCAT of lean and obese subjects except in patients with a specific beta 2-AR gene polymorphism associated with altered adipocyte beta 2-AR function (26) or in obesity associated with other diseases such as diabetes or hyperlipidemia (25). Any reduction of the beta -AR-mediated pathway would tend to strengthen the counterregulatory action of the alpha 2-AR-dependent pathway and worsen the lipid-mobilizing defect.

In summary, these in vivo results provide evidence, for the first time, of the important contribution played by alpha 2-ARs in the physiological impairement of lipolysis in the adipose tissue of the obese men. Such an observation reconciles a number of results obtained in previously reported in vitro studies with physiological approaches in men.

Perspectives

The present results stress on the great potential of exploring fat deposits from different anatomical locations using in situ microdialysis. The role of alpha 2-ARs must be explored in other fat deposits, both in men and women, in which the adipocytes express a high level of alpha 2-ARs largely outnumbering those of beta -ARs (30). Moreover, the lipolytic response to exercise has been shown to be sex- and anatomical site-dependent (2). These findings may have important physiopathological implication in men developing large subcutaneous fat deposits and women with excessive hip and femoral fat deposits. It is tempting to speculate that adipocyte alpha 2-ARs may have a major contribution in the resistance of SCAT to fat loss during very low-calorie diets (15) and during slimming programs including physical activity in obese subjects (34). Administration of an alpha 2-AR antagonist could represent a possible strategy to facilitate mobilization of SCAT when obese subjects are submitted to periods of exercise in dietary conditions facilitating NEFA use (5). It has been reported that oral yohimbine (alpha 2-AR antagonist) administration potentiated lipolysis and exercise-induced energy expenditure (36). The balance between fatty acid and carbohydrate use, with and without alpha 2-AR antagonist administration, merit further studies in the exercising conditions.


    ACKNOWLEDGEMENTS

The authors express gratitude to M.-T. Canal and Z. Parizkova for contributions to the study.


    FOOTNOTES

This study was financially supported by the Charles University, Czech Republic Grant GAUK 199, the Commission of the European Communities specific RTD programme CT98-4141 (FATLINK: Dietary fat, body weight control, and links between obesity and cardiovascular disease), and the Fondation pour la Recherche Médicale.

Address for reprint requests and other correspondence: M. Berlan, Institut National de la Santé et de la Recherche Médicale U 317, Laboratoire de Pharmacologie Médicale et Clinique, Faculté de Médecine, 37 Allées Jules Guesde, 31073 Toulouse Cedex, France (E-mail: berlan{at}cict.fr).

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. §1734 solely to indicate this fact.

Received 29 December 1999; accepted in final form 29 February 2000.


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ABSTRACT
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RESULTS
DISCUSSION
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Am J Physiol Regul Integr Comp Physiol 279(2):R499-R504
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