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Franco-Czech Laboratory for Clinical Research on Obesity, French Institute of Health and Medical Research (Institut National de la Santé et de la Recherche Médicale, Unité 586), and Third Faculty of Medicine, Charles University (B.R., V.S., C.M., J.P., E.K., M.M., I.H., N.V., F.C., D.L., M.L., M.B.), Prague, Czech Republic; Unité de Recherches sur les Obésités (Institut National de la Santé et de la Recherche Médicale, Unité 586), Institut Louis Bugnard, Centre Hospitalier Universitaire de Toulouse (C.M., I.H., N.V., F.C., D.L., M.L., M.B.), Université Paul Sabatier, 31403 Toulouse, France; Department of Sport Medicine and Obesity Unit, Third Faculty of Medicine, Charles University (B.R., V.S., J.P., E.K., M.M.), 10000 Prague, Czech Republic; and Laboratory of Medical and Clinical Pharmacology, Faculty of Medicine, Purpan Hospital (M.B.), 31073 Toulouse, France
Address all correspondence and requests for reprints to: Dr. Michel Berlan, Institut National de la Santé et de la Recherche Médicale, Unité 586, Laboratoire de Pharmacologie Médicale et Clinique, Faculté de Médecine, 37 allées Jules Guesde, 31073 Toulouse Cedex, France. E-mail: berlan{at}cict.fr.
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Abstract |
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2- and ß-adrenergic receptor (ARs) in the control of lipolysis in SCAAT was studied using local perfusion of epinephrine alone or supplemented with phentolamine, an 2-AR antagonist. In addition, the variation in dialysate glycerol concentrations during exercise (50% peak oxygen consumption at 40 min) in a probe perfused with Ringer’s solution was compared with that obtained in a probe perfused with Ringer’s solution plus phentolamine. Training did not promote changes in the expression of key genes of the lipolytic pathway. The epinephrine-induced rise in the dialysate glycerol concentration was identical before and after training and was similarly potentiated by phentolamine. During exercise, the potentiating effect of phentolamine on the glycerol response was apparent before, but not after, training. The exercise-induced increase in plasma norepinephrine was lower after training (P = 0.04). In conclusion, training did not modify either the expression of genes involved in the control of lipolysis or 2- and ß-ARs in situ sensitivity to epinephrine in SCAAT. Training reduced the antilipolytic action of catecholamines mediated by 2-ARs during exercise, probably due to a reduction of exercise-induced catecholamine increase. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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2-adrenergic receptors (2-ARs). The relative contributions of ß- and 2-ARs to the fine tuning of the lipolytic response has been demonstrated by functional in vitro studies in isolated human fat cells (5). Studies of lipolysis have shown that the activation of 2-ARs by epinephrine and norepinephrine impairs the ß-adrenergic component of catecholamine-induced lipolysis. In human sc fat cells, where 2-ARs outnumber ß-ARs, the preferential recruitment of the 2-AR at the lowest catecholamine concentrations inhibits lipolysis (5, 6). The antilipolytic action of catecholamines, particularly that of epinephrine, which exhibits a high affinity for the 2-AR (7), has been shown to be elevated in isolated sc adipocytes from obese subjects (8). Using microdialysis, it has been shown that 2-ARs are involved in the regulation of lipolysis during an acute bout of exercise (9). Taking into account that the adipocytes of SCAAT from obese subjects have a high 2-AR-mediated antilipolytic component in vitro (6), it has been demonstrated that the exercise-induced lipolysis in SCAAT is impaired in obese subjects of both genders and that it is the enhanced physiological stimulation of adipocyte 2-ARs during exercise that contributes to this impairment (4, 10). Furthermore, it has been shown that the 2-mediated antilipolytic action of catecholamines during exercise can be reduced during a hypocaloric diet (10). The aim of the present study was to investigate whether an alternative intervention, a program of aerobic physical activity, produces changes in the 2- and ß-adrenergic pathways of adrenergic regulation of lipolysis in SCAAT at rest and during exercise. We investigated the adrenergic regulation of lipolysis in SCAAT in situ using microdialysis and the expression of key genes involved in lipolysis regulation in biopsy samples of SCAAT using the quantification of mRNA levels by quantitative RT-PCR. |
Subjects and Methods |
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Eleven obese women (39.2 ± 1.9 yr of age) participated in the study. Mean body weight and body mass index (BMI) were 86.4 ± 2.1 kg and 31.3 ± 0.6 kg/m2, respectively. All subjects were drug-free, and their weight had remained stable for at least 3 months before the beginning of the study. They all gave written informed consent before the experiments began. The studies were performed according to the Declaration of Helsinki and approved by the ethical committee of the Third Faculty of Medicine (Prague, Czech Republic).
Experimental protocol
The subjects were investigated at 0800 h after an overnight fast while they were in a semirecumbent position, before and after the last day of a 12-wk training program.
Peak oxygen consumption (VO2max) determination
Five days before each investigation, a maximum exercise test was performed on a bicycle ergometer (Ergoline 800) for each subject to determine the VO2max (Vmax, Sensor Medics, Yorba Linda, CA). An initial workload of 60 watts was followed by a sequential increase in workload of 30 watts every 3 min until exhaustion. Verbal encouragement was given to attain maximal performance. Heart rate was continuously monitored. The highest VO2 achieved was taken as the VO2max, and the workload corresponding to 50% for each subject was calculated.
Microdialysis protocol
At each investigation two microdialysis probes (Carnegie Medicine, Stockholm, Sweden) of 20 x 0.5 mm with a 20,000 mol wt cut-off were inserted percutaneously after epidermal anesthesia (200 µl of 1% lidocaine, Roger-Bellon, Neuilly-sur-Seine, France) into the abdominal SCAAT at a distance of 10 cm to the right of the umbilicus. The 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’s solution (139 mmol/liter sodium, 2.7 mmol/liter potassium, 0.9 mmol/liter calcium, and 140.5 mmol/liter chloride), and the second was perfused with Ringer’s solution plus 0.1 mmol/liter phentolamine (-AR antagonist). This nonselective 1-/2-AR antagonist with an efficient 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. Ethanol (40 mmol/liter) was added to the perfusate to estimate changes in the blood flow, as previously described (11, 12). The ethanol ratio was calculated as: ethanol ratio (%) = (ethanol concentration in outgoing dialysate/ethanol concentration in ingoing perfusate) x 100. The variations in the ethanol ratio were taken as an index of variations of adipose tissue blood flow.
The perfusion rate was set at 2.5 µl/min for the experimental period. Two 10-min fractions of the outgoing dialysate were collected, and then increasing successive concentrations of epinephrine alone (0.01, 0.1, and 1 µmol/liter) were infused in one probe, and epinephrine associated with 100 µmol/liter phentolamine were infused in the second one. Epinephrine at each concentration was infused during 30 min and then was withdrawn from the perfusate. After a recovery period of 90 min, the subjects performed exercise at a load corresponding to 50% of their individual VO2max for 40 min on a bicycle ergometer. The oxygen consumption and heart rate were monitored (Vmax, Sensor Medics) during the exercise. After the exercise, subjects rested in the semirecumbent position for 30 min. During all protocols, i.e. epinephrine perfusions and exercise and recovery periods, 10-min fractions of the dialysate were collected. Water intake was allowed ad libitum during the experimental period.
Blood sampling
Before exercise and every 10 min during exercise and recovery, blood samples were collected from an indwelling polyethylene catheter inserted into an antecubital vein for plasma determinations. The catheter was kept patent by a slow infusion of saline. Every 20 min, a supplementary blood sample was collected on 50 µl of an anticoagulant and antioxidant cocktail (Immunotech SA, Marseilles, France) for catecholamine measurement. The plasma was stored at -80 C until analysis.
Adipose tissue biopsies
Four days after the microdialysis experimental protocol described above, a needle biopsy of SCAAT was performed. The biopsy samples were frozen at -80 C and stored for further analysis of mRNA content.
Training program
The training program started after completion of the 2 investigation d. The program consisted of sessions of aerobic exercise 5 d/wk: twice a week an aerobic exercise in the gymnasium supervised by an exercise instructor, and three times a week an individual exercise on a bicycle ergometer (at home). Subjects were instructed to exercise for 45 min at the intensity corresponding to the individually recommended heart rates; the individual heart rate was determined as that corresponding to 50% of their VO2max as determined during a maximum exercise test. Each participant was provided with a cardiometer (Polar Accurex Plus Cardiometer, Monitor, France) to follow the heart rate during exercise sessions.
Dietary regimen
Throughout the training program the patients were instructed to maintain their habitual diet, which was estimated by a 7-d weighed food record before the beginning of the study. The maintenance of the dietary regimen was controlled twice every 4 wk of the study using a 3-d food record.
Drugs and analytical methods
Phentolamine methanesulfonate (Regitine) was obtained from Ciba-Geigy (Reuil-Malmaison, France). Glycerol in dialysate (10 µl) and that in plasma (20 µl) were analyzed with an ultrasensitive radiometric method (13). Ethanol in dialysate and perfusate (5 µl) was determined with an enzymatic method (14). Plasma glucose was determined with a glucose oxidase technique (Biotrol kit, Merck-Clevenot, Nogent-s-Marne, France), and nonesterified fatty acid (NEFA) was determined 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 HPLC using electrochemical (amperometric) detection.
RNA analysis
After chloroform lipid extraction of adipose tissue biopsies, total RNA was extracted using the RNeasy kit (Qiagen, Chatsworth, CA) and stored at -80 C until analysis. Total RNA concentrations were determined using a fluorometric assay (Ribogreen, Fluoroskan Ascent). RT was performed using 1 µg total RNA, Thermoscript reverse transcriptase (Invitrogen, Carlsbad, CA), and random hexamers as recommended by the manufacturer. Real-time quantitative RT-PCR was performed on GeneAmp 5700 Sequence Detection System using SYBR Green chemistry (PE Applied Biosystems, Courtaboeuf, France). A set of primers was designed for each gene using the software Primer Express 1.5 (PE Applied Biosystems). Amplicons of 65–90 bp with Tm between 79 and 82 C were selected. Ten nanograms of cDNA were used as template for real-time PCR in duplicate. A dissociation curve was generated at the end of the PCR cycles to verify that a single gene product was amplified. For each primer pair a standard curve was obtained using serial dilutions of human adipose tissue cDNA. mRNA levels were assessed using the following primers: for 2-AR, 5'-gcgagatcaacgaccagaagt-3' and 5'-cttggcgatctggtagat-3'; for ß2-AR, 5'-ccgaaagttcccgtacgtca-3' and 5'-cagcccgtgctctgaagaa-3'; for phosphodiesterase 3B, 5'-gacttgcatttgaaatggacagaa-3' and 5'-atgggcagaccaagatttgc-3'; and for hormone-sensitive lipase, 5'-gtgcaaagacggaggaccactcca-3' and 5'-gacgtctcggagtttcccctcag-3'. We used 18S ribosomal RNA as control to normalize gene expression using the Ribosomal RNA Control TaqMan Assay Kit (PR Applied Biosystems).
Statistical analysis
All values are the mean ± SEM. The responses to exercise were analyzed using a paired t test and ANOVA when appropriate. During epinephrine infusion and exercise, the changes in dialysate concentrations were analyzed using a paired t test on the mean changes over the baseline values. P < 0.05 was considered statistically significant.
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Results |
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). The VO2max was higher after training (Table 1). Resting heart rate and systolic and diastolic blood pressures remained unchanged (not shown). The maximal power output and the mean load at 50% VO2max during the exercise test were higher after 12 wk of training (Table 1). At the end of the training period, resting plasma insulin concentrations were unchanged compared with pretraining values (2.6 ± 0.6 vs. 3.7 ± 0.6 µU/ml). Training did not modify the resting plasma concentrations of NEFA (460 ± 37 vs. 498 ± 58 µmol/liter) and induced an increase in plasma glycerol concentrations (126 ± 12 vs. 99 ± 11 µmol/liter; P < 0.05). Consequently, the NEFA/glycerol concentrations ratio decreased (3.78 ± 0.36 vs. 5.21 ± 0.49; P < 0.05). Training induced a reduction in resting plasma glucose concentrations (4.18 ± 0.10 vs. 4.57 ± 0.10 mmol/liter; P < 0.02), an elevation in plasma norepinephrine levels, and a reduction in epinephrine concentration (Table 2).
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mRNA levels for key genes involved in lipolysis regulation in adipose tissue i.e. 2-AR, ß2-AR, hormone-sensitive lipase, and phosphodiesterase 3B, were quantified in SCAAT by real-time RT-PCR in nine subjects before and at the end of the training period (Table 1
). The training did not induce changes in gene expression.
Lipolytic response in SCAAT to epinephrine perfusion at rest and to exercise: effect of training
Epinephrine perfusion at rest.
Training did not modify the concentration of glycerol in the dialysate at rest. Before training, the resting concentration in dialysate glycerol was significantly increased by the addition of phentolamine to the perfusate (51 ± 6 vs. 40 ± 4 µmol/liter; P < 0.01). After the training, the resting concentration in dialysate glycerol remained higher in presence of phentolamine (49 ± 8 vs. 41 ± 8 µmol/liter; P < 0.02). The perfusion of epinephrine through microdialysis probe induced a concentration-dependent increase in the glycerol concentration in dialysate (Fig. 1). At each concentration of epinephrine, the addition of phentolamine potentiated the increase in glycerol concentrations in the dialysate. Neither the response of the dialysate glycerol concentration to epinephrine perfusion nor the potentiating effect of phentolamine on the epinephrine-induced increase in glycerol was modified after the training. Training did not modify the ethanol ratio at rest in both probes (with epinephrine and epinephrine plus phentolamine). Whatever the concentration of epinephrine added to the perfusate, no change in the ethanol ratio was observed during epinephrine perfusion before as well as after the training. The addition of phentolamine did not induce any significant change in the ethanol ratio before or during epinephrine perfusion (not shown).
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). The exercise-induced glycerol increase in the probe with phentolamine was higher than that in the control probe; glycerol increase reached 82 ± 12 µmol/liter at the 40th min. The calculated average area under the curve for glycerol increase over the 40-min exercise period was significantly higher in the probe containing phentolamine than in the control probe (P < 0.02).
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). The calculated average area under the curve for glycerol increase over 40 min of exercise tended to be higher than the pretraining value (P = 0.07). The dialysate glycerol increase in the probe with phentolamine was not different from that in the control probe; glycerol increase reached 104 ± 18 µmol/liter at the 40th min.
During exercise, the ethanol outflow/inflow ratio decreased (P < 0.05) in both probes before as well as after the training. The exercise-induced decrease in the ethanol ratio was not different after compared with before training. There were no differences, before or after the training, in the exercise-induced decrease in the ethanol ratio between the control probe and the probe with phentolamine (Fig. 3).
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Plasma NEFA concentrations decreased during the first 15 min of exercise, then progressively increased until the end of the exercise bout, and remained elevated during the recovery period (Fig. 4). No difference was found in the time course of the plasma NEFA concentration changes before and after training. The plasma glycerol level increased 15 min after the beginning of exercise and peaked at the 40th min of exercise. During recovery it decreased to values similar to those found under basal conditions. The calculated average AUC for NEFA and glycerol changes over 40 min of exercise were not different before and after training.
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At rest, plasma norepinephrine values were higher after training than before, but the absolute values during exercise were not different (Table 2). At rest and during exercise, the plasma epinephrine values were lower after than before training. Consequently, the exercise-induced increase in plasma norepinephrine was lower after training (P = 0.04), and that of epinephrine tended to be reduced (P = 0.07). The time courses of changes in plasma glucose and insulin concentrations were not different before and after training (Fig. 5).
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Discussion |
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2-AR-mediated antilipolytic effect of catechol- amines in SCAAT in situ or the expression of the 2-AR gene (mRNA levels) in sc adipose tissue. Furthermore, training did not modify either epinephrine-stimulated lipolysis in situ in SCAAT or the expression of genes involved in the regulation of lipolysis at receptor (ß2-AR) and postreceptor (hormone-sensitive lipase and phosphodiesterase 3B) levels. The regulation of lipolysis during exercise was modified by the training; the involvement of the 2-mediated antilipolytic action of catecholamines during exercise was reduced after training.
The contribution of 2-ARs in the control of lipolysis at rest was evaluated by a local pharmacological challenge (i.e. infusion of epinephrine alone and associated with phentolamine directly in the microdialysis probe). An enhancement of the epinephrine-induced increase in lipolysis by addition of the 2-AR antagonist to the perfusate was observed. It is a functional test to reveal the intrinsic 2-AR effect related to epinephrine alone. The response is probably related to the number/coupling efficiency of the 2-ARs existing in fat cells of the sc deposit. Before training, spontaneous glycerol release at rest as well as glycerol release induced by increasing epinephrine concentrations perfused through the probe were potentiated after blockade of 2-ARs in obese women. This result demonstrates the in situ interplay between ß- and 2-ARs in the adipose tissue of obese subjects. The data represent the in vivo validation of all previous data collected in vitro in human isolated fat cells that have demonstrated the antagonistic action of ß- and 2-ARs (5, 6). Results show that training did not change the 2-AR response in resting conditions, because the blockade of antilipolytic 2-ARs similarly enhanced epinephrine-induced glycerol increment in the dialysate before and after training. These results are supported by the lack of change in 2-ARs mRNA levels consecutive to training.
The findings of the unchanged epinephrine lipolytic action in this study fit with the findings of transversal (15) and longitudinal studies (16) showing that training did not modify catecholamine-induced lipolysis in situ at rest.
Despite the lack of the training-induced change in the 2-mediated antilipolytic activity at rest, we observed a reduction of the involvement of 2-ARs in the exercise-induced lipid mobilization. Therefore, neuroendocrine regulatory factors might be implied in this training-induced modification. In previous reports (17, 18) it was shown that epinephrine is involved in the control of lipolysis during exercise through activation of antilipolytic 2-ARs and that the magnitude of 2-AR-mediated antilipolytic action during exercise is dependent on the magnitude of the exercise-induced increase in epinephrine. In the present study the exercise-induced increase in catecholamines, epinephrine and norepinephrine, in plasma were lower after the training. As the circulating catecholamines are determinant for the exercise-induced lipolytic response (19), this implies a lower 2-AR-mediated antilipolytic effect. Therefore, the results suggest that the reduction of 2-mediated antilipolytic effect after training is due to the lower plasma catecholamine response, whereas the training does not modify the adipocyte response to 2-AR-mediated action. Plasma levels of insulin might be suggested to interfere with the described training-induced changes in lipolysis in SCAAT during exercise. The interference of insulin with the results of this study might be mediated by either training-induced changes in sensitivity to insulin action or changes in plasma insulin levels. In sc adipose tissue, the short-term training does not modify the sensitivity to antilipolytic effect of insulin (20). The lack of a modification of the sensitivity to insulin antilipolytic action in SCAAT has been also found during very low calorie diet (21). The training did not induce a significant decrease in plasma insulin levels in the present study. However, as hyperinsulinemia was shown to increase the relative contribution of 2-AR-mediated antilipolytic effect of epinephrine, it might be speculated that even the small, nonsignificant, decrease in plasma insulin levels during training could contribute to the changes in 2-AR-mediated responsiveness found in this study (22).
Adipose tissue blood flow (ATBF) is known to influence glycerol dialysate concentration originating from adipose tissue (23). In the present study the ethanol method was used for evaluation of ATBF. It does not enable the corrections in individual results for adipose tissue blood flow values, but it provides the possibility to assess whether and in which sense the changes occur. At the concentration used, epinephrine alone or associated with phentolamine (1/2-AR antagonist) did not induce a change in ATBF before or after training. The exercise-induced vasodilatation (reduction of the ethanol ratio) was not modified after training. In the presence of phentolamine, the exercise-induced vasodilatation was not different from that with the control probe, and training did not change the ethanol ratios during exercise. Thus, in the present study the effects of training on glycerol concentration variations were not influenced by ATBF.
In a previous study in obese women submitted to a 12-wk hypocaloric diet, we found a reduction of 2-AR mRNA in adipose tissue and a reduction of 2-AR-mediated antilipolytic action in vivo after the diet (10). The apparent difference in the results of the present study and those of the latter may be related to a lower weight decrease during training (compared with dietary intervention) and/or the different characters of the intervention (diet vs. exercise).
In a previous study carried out in men, we found that exercise-induced lipid mobilization (60 min at a similar relative power, as assessed by the increase in plasma norepinephrine) was largely impaired in SCAAT in obese subjects (4). Another study performed in obese women showed that this impairment was comparatively weaker (10). A gender-related difference was reported in young nonobese subjects (18). The gender difference in fat mobilization and utilization has been previously discussed (24, 25, 26, 27). The sex-related difference in exercise-induced lipid mobilization could be related to the lower involvement of the antilipolytic 2-adrenergic effect on fat cells during exercise in women, which may be a consequence of a lower exercise-induced increase in epinephrine during exercise of the same relative intensity in women compared with men (18).
This study also raises questions about the relationship existing between the degree of obesity and the ß- and 2-ARs interplay operating in adipose tissue during exercise. In a previous study performed in obese women with a BMI of 34, i.e. higher than in the present study (BMI of 31), it was observed that during a similar standardized exercise, the potentiating effect of phentolamine on dialysate glycerol was 46% (10). In the present study the women exhibited a lower BMI, and the potentiating effect of phentolamine was only 26%. Moreover, in nonobese women, the results reported by Hellström et al. (18) demonstrated that phentolamine did not produce any additive effect on the increment in the dialysate glycerol concentration during exercise. Together, these observations suggest that the exercise-induced 2-adrenergic responsiveness is related to fat mass extent; the higher the fat mass, the stronger the inhibitory effect of 2-ARs during exercise.
In conclusion, the present study demonstrates that medium-term aerobic training does not produce any changes in ß2- and 2-AR gene expression in adipose tissue of obese women and does not modify the 2-AR antilipolytic effect in situ at rest. During exercise, the lower 2-AR effect induced by training is not related to changes in 2-AR gene expression, but may be associated with reduced exercise-induced epinephrine secretion.
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Acknowledgments |
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Footnotes |
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Abbreviations: AR, Adrenergic receptor; ATBF, adipose tissue blood flow; BMI, body mass index; NEFA, nonesterified fatty acid; SCAAT, sc abdominal adipose tissue; VO2max, peak oxygen consumption.
Received June 9, 2003.
Accepted November 21, 2003.
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References |
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2-adrenergic receptors impairs exercise-induced lipolysis in subcutaneous adipose tissue of obese subjects. Am J Physiol 279:R499–R504
2-adrenoceptor binding sites in human fat cells from various fat deposits: functional consequences. Eur J Clin Invest 17:156–165[Medline]
2-adrenoceptors properties. Eur J Clin Invest 15:341–346[Medline]
2-adrenergic receptors by epinephrine during exercise in human adipose tissue. Am J Physiol 277:R1076–R1083
2-adrenergic antilipolytic effect and 2-adrenergic receptor mRNA levels in adipose tissue of obese women. J Clin Endocrinol Metab 87:1274–12812-adrenergic receptors by epinephrine during exercise in human adipose tissue. Am J Physiol 277:R1076–R1083
2-adrenergic receptors blunts epinephrine- induced lipolysis in subcutaneous adipose tissue during a hyperinsulinemic euglycemic clamp in men. Am J Physiol 285:E599–E607
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