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Original Studies |
Lipid Research Center (P.M., D.P., J.P.D.), Diabetes Research Unit (A.N.), CHUQ Medical Research Center, Physical Activity Sciences Laboratory, Department of Social and Preventive Medicine, Laval University (P.M., P.I., D.P., A.T.), and Québec Heart Institute, Laval Hospital (J.P.D.), Québec, Canada
Address all correspondence and requests for reprints to: Pascale Mauriège, Ph.D., Lipid Research Center, Laval University Medical Research Center, CHUL, 2705 boulevard Laurier, Room TR-93, Ste-Foy, Québec, Canada G1V 4G2. E-mail: diabolo{at}internetclub.fr
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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2-adrenergic agonist) assessed in sc
adipocytes were similar in pre- and postmenopausal women. In addition,
neither the ß- nor the 2-adrenoceptor sensitivity of
sc adipose cells differed according to subjects’ age. Finally, maximal
lipolysis promoted by postadrenoceptor agents and
AT-lipoprotein lipase activity did not vary among adipose regions or
between groups. Taken together, these results suggest that menopause
per se does not influence sc AT metabolism once the
variation related to adipose cell size and total body fatness is taken
into account. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Although our understanding about the clustering of alterations in metabolic risk factors that accompanies menopause made progress over the last decade (19, 20, 21, 22, 23), there has been little investigation of the role of adipose tissue metabolism, an important factor to be considered when studying obesity-related metabolic complications. Indeed, discordant results have been reported concerning either the lack (13, 24) or the presence (25) of site differences in AT-LPL activity in postmenopausal women. A lack of regional variation in lipolysis with age has also been observed by some investigators (13, 26), whereas others have reported that sc abdominal fat cells were more responsive to catecholamine stimulation than gluteal adipocytes (24, 27). One reason for these conflicting data could be that the pre- and postmenopausal women compared in these previous studies (13, 25) were not matched for total adiposity and regional fat distribution. Nicklas et al. (27) recently reported that an increased visceral adipose tissue accumulation was associated with higher rates of lipolysis in both sc abdominal and gluteal adipocytes, thus suggesting an important role for regional fat distribution in the age-related variation in adipose cell lipolytic activity.
Therefore, the aims of the present study were 1) to examine whether regional variation persists in sc adipose tissue metabolism at menopause, and 2) to verify whether differences in adipocyte metabolic activities between pre- and postmenopausal women would remain once the concomitant variation in both adipose cell size and body fat distribution is taken into account.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Sixteen healthy Caucasian, moderately overweight women were recruited through the media and gave their written informed consent to participate in this study, which was approved by the Laval University medical ethics committee. Eight pairs of subjects matched for both levels of sc abdominal adipose tissue (within 15 cm2) measured by computed tomography and for sc abdominal fat cell weight (within 0.02 µg lipid/cell), but displaying marked differences in age (premenopausal vs. postmenopausal), were compared for potential differences in sc adipose cell metabolism. All participants underwent a physical examination by a physician, which included medical history. Subjects with cardiovascular disease, diabetes, or other endocrine disorders or those taking medication that could have affected blood pressure or glucose or lipid metabolism were excluded. All women were sedentary (i.e. they performed <30 min of exercise/week), nonsmokers, and moderate alcohol and caffeine consumers and had stable body weights at the time of the study (i.e. no subject had been involved in a weight loss program for the last 6 months). Women who had undergone surgical menopause were excluded from the study. Subjects were considered postmenopausal if they had not menstruated for at least 2 yr and if their plasma estradiol concentrations were lower than 120 pg/mL. None of them was taking or had ever taken hormonal replacement therapy. Premenopausal women had regular menstrual cycles, and none was using oral contraceptives or was lactating at the time of the study. All measurements were performed while the subjects were in the early follicular phase of the menstrual cycle.
Body fatness and regional fat distribution
Body weight was determined with a standard beam scale. Body density was determined by the underwater weighing technique, and percent body fat was derived from body density (28). Pulmonary residual volume was measured using the helium dilution method (29). Fat mass was calculated from the derived percentage of body fat and total body weight. Fat-free mass was then simply calculated as the subtraction of fat mass from total body weight. Body density, fat mass, and fat-free mass are highly reproducible variables that show reliability coefficients greater than 0.97 (30). Waist girth was measured according to the procedures recommended at the Airlie Conference (31). Lemieux et al. (32) reported that the coefficient of variation between two consecutive measurements of waist girth is very low (0.32%). Computed tomography (CT) was performed on a Siemens Somatom DRH scanner (Erlangen, Germany), according to the methodology previously described (33). Briefly, subjects were examined in the supine position with both arms stretched above the head. CT scans were performed at the abdominal (between L4 and L5 vertebrae) level, using an abdominal scout radiograph to establish the position of the scan to the nearest millimeter. Total adipose tissue (AT) areas were calculated by delineating these areas with a graph pen and then computing the AT surfaces with an attenuation range of -190 to -30 Houndsfield units (34). Abdominal visceral AT area was determined by drawing a line within the muscle wall surrounding the abdominal cavity. The abdominal sc AT area was calculated by subtracting the visceral AT area from the total abdominal AT area. A high coefficient of reliability (r = 0.99) has been reported by our group for the determination of sc and visceral fat accumulation by CT (35).
Adipose tissue biopsy procedure and LPL activity
After an overnight fast, women were subjected to biopsies of sc fat, one performed in the periumbilical region (abdominal site) and the other at the anterior midthigh level (femoral site). A small cutaneous incision (1 cm) was performed in both sites under local anesthesia (1% lidocaine, without epinephrine), and about 350 mg sc adipose tissue were surgically removed from the two fat depots. Samples of approximately 100 mg adipose tissue from each region were immediately frozen in liquid nitrogen and stored at -80 C for later measurement of heparin-releasable LPL activity according to the method of Savard et al. (36). AT-LPL activity was expressed as micromoles of free fatty acids released per h/106 cells. As AT-LPL activity is associated with fat cell size (36), AT-LPL was also expressed per cell surface area (i.e. nanomoles of free fatty acids per h/µm2 times 108).
Adipocyte lipolysis
Samples of approximately 250 mg AT from each site were used for the measurement of fat cell lipolysis. Adipocytes were isolated according to the method of Rodbell (37) in a Krebs-Ringer bicarbonate buffer (pH 7.4) containing 4% BSA (KRBA) and 5 mmol/L glucose plus 1 mg/mL collagenase, as previously described (36). Digestion took place in a shaking water bath under an air-gas phase of 95% O2 and 5% CO2, for 40 min at 37 C. The suspension was then filtered, and the cellular filtrate obtained was rinsed three times with 5 mL KRBA. Isolated adipocytes were finally resuspended in KRBA to obtain a final concentration of approximately 1000 cells/100 µL.
Extracellular glycerol release was used as the indicator of adipocyte lipolysis. One hundred-microliter aliquots of the continuously stirred cell suspension were placed in 1.5-mL conical tubes. Two of these tubes were used for cell counting and sizing; two others containing 20 µL KRB were immediately placed on ice and provided an evaluation of the initial concentration of glycerol in the medium. Agents for lipolysis stimulation or inhibition were added just before the beginning of the assay in 20-µL portions to obtain the desired final concentration. After a 2-h incubation at 37 C in a shaking water bath under an air-gas phase of 95% O2 and 5% CO2, 100 µL HCl (1 N) were added to all tubes to stop the reaction, then 100 µL NaOH (1 N) were added to neutralize the medium. All tubes were stoppered and stored at -20 C until glycerol determination according to the method of Mauriège et al. (38). The NADH concentration was measured by bioluminescence with a luciferase solution, using a 2250 Dynatech Corp. luminometer (Chantilly, VA) (17, 18). For each concentration of stimulator or inhibitor agent, the amount of glycerol was taken as the average of the quantities obtained from the two incubated tubes. Glycerol measurement by bioluminescence is very sensitive and is especially well adapted when only small amounts of adipose tissue are available (17, 18, 38). The mean adipose cell diameter was assessed from the measurement of at least 500 cells/site and per subject, using a Leitz microscope equipped with a graduated ocular (Rockleigh, NJ). Because of the spherical shape and high lipid content of the adipocytes (95%), both the adipose cell volume and the surface area can be calculated from the mean adipocyte diameter, and the density of triolein (0.915 g/mL) was used to transform adipose cell volume into fat cell weight, as previously described (39).
The lipolytic activity of the isolated fat cells was tested with
isoproterenol (nonselective ß-agonist), UK-14304 (selective
2-agonist), and epinephrine, which is a mixed
agonist (2/ß) with a higher affinity for
2-adrenoceptor sites (16). Ascorbic acid (0.1
mmol/L) was included in the incubation medium to prevent
catecholamine degradation. Some experiments were conducted with
forskolin (direct activator of adenylate cyclase), dibutyryl cAMP
(stimulator of the protein kinase hormone-sensitive lipase complex and
phosphodiesterase-resistant cAMP analog), and theophyline (mainly
inhibitor of cGMP-inhibited phosphodiesterase) (17). When antilipolytic
effects were investigated, the incubation buffer was supplemented with
5 µg/mL adenosine deaminase (ADA) to remove adenosine released into
the incubation medium by the isolated fat cells; this procedure allowed
better investigations of
2-adrenoceptor-mediated antilipolytic effects
(16, 18, 38). Lipolysis was expressed either per cell number
(i.e. in micromoles of glycerol per
106 cells/2 h) or per unit of cell surface area
(i.e. in nanomoles of glycerol per
µm2/108·2 h) to
compensate for variations in fat cell size (18, 38). In cases where
complete concentration-response curves were obtained, they were
compared for both responsiveness and sensitivity. The responsiveness
was expressed as the difference between basal glycerol release and the
lipolytic rate at maximum effective concentration of the agents tested
(10-5 mol/L isoproterenol
or forskolin, 10-3 mol/L
dibutyryl cAMP or theophyline). The ß-adrenergic sensitivity was
considered as the concentration of isoproterenol giving half-maximal
stimulation of lipolysis (EC50), whereas the
2-adrenergic sensitivity was calculated as the
concentration of UK-14304 that produced half-maximal inhibition of
lipolysis (IC50). Both were evaluated by
logarithmic conversion of each concentration-response curve. The higher
the EC50 (isoproterenol) or
IC50 (UK-14304) value, the lower the ß- or the
2-adrenergic sensitivity, respectively.
Oral glucose tolerance test (OGTT)
A 75-g OGTT was performed in the morning after an overnight fast. Blood samples were collected in tubes containing ethylenediamine tetraacetate and Trasylol (Miles Pharmaceutics, Rexdale, Canada) through a venous catheter from an antecubital vein at -15, 0, 15, 30, 45, 60, 90, 120, 150, and 180 min. Plasma glucose was measured enzymatically (40), whereas the plasma insulin concentration was determined by RIA with polyethylene glycol separation (41). The total glucose and insulin areas under the curve during OGTT were calculated with the trapezoid method.
Plasma lipids and lipoproteins
Blood samples were obtained in the morning after a 12-h fast from an antecubital vein. Cholesterol (CHOL) and triglyceride levels in plasma and lipoprotein fractions were measured enzymatically on a RA-1000 automated analyzer (Technicon Instruments Corp., Tarrytown, NY) referenced to Centers for Disease Control (Atlanta, GA). Plasma very low density lipoproteins (density, <1.006 g/mL) were isolated by ultracentrifugation (42), and the high density lipoprotein fraction was obtained after precipitation of low density lipoprotein (LDL) in the infranatant (density, >1.006 g/mL) with heparin and MnCl2 (43).
Drugs and chemicals
Collagenase, BSA, adenosine deaminase, and enzymes for glycerol assays were obtained from Roche Molecular Biochemicals (Laval, Canada). Ascorbic acid, theophyline, forskolin, dibutyryl cAMP, (-)isoproterenol bitartrate, (-)epinephrine bitartrate, and cold triolein were purchased from Sigma (St. Louis, MO). [14C]Triolein was obtained from NEN Life Science Products-DuPont (Missisauga, Canada). UK-14304 [5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline] was provided by Dr. D.A. Faulkner (Pfizer, Inc., Sandwich, England). All other chemicals and organic solvents were of the highest purity grade commercially available. The same batches of hormones, pharmacological agents, collagenase, and albumin were used in all experiments.
Statistical methods
Two subgroups of eight women displaying both similar sc abdominal AT area measured by CT and fat cell size, but differing in age, were compared. Student’s t test was used for comparison of anthropometric and metabolic variables between pre- and postmenopausal women. The effects of age (young vs. middle-aged) and of adipose site (abdominal vs. femoral) on adipose tissue lipolytic curves were tested by two-way ANOVA for repeated measures. All statistical analyses were performed using Jump software 3.2.2. from SAS Institute, Inc. (Cary, NC), adapted for Macintosh computers.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The physical characteristics of our sample of moderately
overweight women are presented in Table 1
. As expected from the design, a
significant difference was observed in the subjects’ age
(P < 0.0001). However, neither body mass index nor fat
mass differed among pre- and postmenopausal women. Both groups also
displayed similar visceral and sc abdominal AT areas, measured by CT,
as well as comparable sc fat cell weights. No regional variation was
found in adipose cell size within both groups. The metabolic
characteristics of subjects are shown in Table 2. With the exception of plasma
cholesterol and LDL-CHOL concentrations being significantly lower in
pre- than postmenopausal women (P < 0.05), the
lipid-lipoprotein profile did not differ between groups. In addition,
no difference in fasting plasma glucose and insulin levels or in the
corresponding responses to an oral glucose load was found between pre-
and postmenopausal women (Fig. 1).
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As illustrated in Fig. 2, neither
regional variation nor difference between groups was observed in AT-LPL
activity, although it tended to be higher in pre- than in
postmenopausal women (P = 0.06–0.09). Similar results
were obtained when this enzyme activity was expressed per cell number
(not shown).
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Basal lipolytic rate and ADA-stimulated lipolysis. As shown in
Fig. 3, basal lipolysis was not
significantly different between groups or among adipose regions.
Addition of ADA at 5 µg/mL increased the basal lipolytic rate by
about 1.5–2 times in adipocytes of premenopausal women. However, the
level of glycerol release achieved with this enzyme did not vary with
the adipose region in postmenopausal subjects. Indeed, although
ADA-stimulated adipose cell lipolysis tended to be higher in pre- than
postmenopausal women, this difference did not reach statistical
significance (P = 0.06–0.09).
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2/ß) adrenergic properties on lipolysis,
initiated a similar biphasic responsiveness in all cell types (main
effects for age: F1, 21 = 1.09; P
= 0.31; main effects for site: F1, 21 = 0.98;
P = 0.33; Fig. 4).
Inhibition of lipolysis was observed at the lowest concentrations (from
10-9–10-7
mol/L); this effect was completely reversed at higher doses (from
10-6–10-5
mol/L), where the hormone exerted a lipolytic action, thus suggesting
differential recruitment of 2- and
ß-adrenoceptors.
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2- and ß-adrenergic effects. As
epinephrine responsiveness results from both 2- and
ß-adrenoceptor stimulation, selective adrenergic agonists were used
to discriminate between these two antagonistic effects.
To study the influence of the 2-adrenoceptor
component, the effect of the selective
2-agonist, UK-14304, was tested on
ADA-stimulated lipolysis (Fig. 5).
UK-14304 exerted a similar antilipolytic response in both groups
(F1,13 = 1.09; P = 0.31) and
adipose sites (F1,13 = 0.47; P =
0.50). Moreover, the 2-adrenergic sensitivity,
estimated as the half-maximal antilipolysis induced by UK-14304 (which
clustered at 1–3 nmol/L), was not significantly different among
adipose depots or between the two matched groups.
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). Stimulation of lipolysis induced by
isoproterenol did not differ among adipose regions
(F1,21 = 2.91; P = 0.10) or
between the two matched groups (F1,21 = 0.47;
P = 0.78). In addition, ß-adrenergic sensitivity,
defined as the concentration of isoproterenol required for half-maximal
lipolysis (values ranging from 20–60 nmol/L), was not significantly
different regardless of the anatomical location of fat and the
subject’s age. Similar results were observed for epinephrine-,
isoproterenol-, and UK 14304-induced lipolysis expressed per cell
number (data not shown).
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). For this
purpose, adipose cells were incubated without ADA in the presence of
dibutyryl cAMP (10-3
mol/L), forskolin (10-5
mol/L), or theophyline
(10-3 mol/L). As expected,
there was no regional variation and no difference between pre- and
postmenopausal women when lipolysis was stimulated with maximal
concentrations of these postadrenoceptor agents.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Postmenopausal women in the present study were characterized by lower sc abdominal and visceral adipose tissue areas measured by CT compared to those in other studies (27, 44). Such a discrepancy could be easily explained by the age and menopausal status of the participants, as women from the two latter studies were older than our subjects. On the other hand, the finding that aging in women does not seem to be associated with changes in the adipose tissue lipid storage capacity has recently been reported in middle-aged men (45). The similar adipose tissue LPL activity found in sc abdominal and femoral depots of postmenopausal women is largely the consequence of the absence of regional variation in fat cell size that we observed in our group. This finding is consistent with most (13, 24, 26, 44), but not all (25), previous findings.
The similar biphasic epinephrine response profile in all cell types
probably reflects the interaction of the hormone with both types of
adrenoceptors and supports the idea of the differential recruitment of
2- and ß-sites (16, 17, 18, 38). These data
suggest that hypertrophy of adipose cells, which is commonly associated
with an expanded adipose tissue mass rather than age per se,
is a critical correlate of the increased
2-adrenoceptor component in obesity (10, 46).
The absence of difference in basal lipolytic rate regardless of either the adipose region or the group considered is consistent with the unaltered ADA-stimulated lipolysis and agrees with previous studies conducted on middle-aged men (45) and women (13, 27). The tendency for a lower ADA-simulated lipolysis in adipose cells of post- vs. premenopausal women may reflect a greater inhibition of lipolysis by adenosine with aging, as previously suggested in old rats (47, 48). Further studies are therefore needed to address this issue. Once again, the finding that basal lipolysis did not vary among adipose regions and groups could be explained by the similar adipose cell size, as this variable was highly correlated with basal glycerol release (9). On the other hand, comparison of epinephrine- or isoproterenol-induced maximal lipolysis (at 10-5 mol/L) revealed no regional variation or any group difference. This observation was further strengthened by the similar lipolytic effects of agents acting selectively at the adenylate cyclase, the lipase-protein kinase A complex, or the phosphodiesterase level, findings concordant with an unaltered postadrenoceptor lipolytic pathway. The observation that adipose cell lipolytic capacity was not impaired in postmenopausal women seems to be in contrast with previous observations (45, 49). In these studies, however, the decreased lipid mobilization, which may be linked to a defect at the hormone-sensitive lipase level observed with aging, was probably due to the fact that middle-aged men had higher amounts of visceral adipose tissue than young individuals. In the present study, pre- vs. postmenopausal women had similar levels of total and abdominal fat. These differences among studies emphasize the importance of visceral fat accumulation as a critical correlate of sc adipose cell lipolysis (27).
The fact that postmenopausal women displayed higher plasma cholesterol levels has been observed by others, and the higher levels of LDL-CHOL accounted for most of the increased total cholesterol concentration commonly observed at menopause (19, 20, 21, 22, 23). The lack of alterations in plasma insulin and glucose levels with aging may be partly explained by the design of our study, as both groups of women had similar levels of visceral adipose tissue. Indeed, postmenopausal women with a large visceral AT deposition had higher plasma insulin levels than middle-aged women displaying a low intraabdominal fat accumulation (27). Thus, the increased visceral adiposity that is generally observed at menopause appears to be an important factor for the metabolic deteriorations that occur in women during this period. However, the increase in LDL-CHOL levels that we observed with age appears to be largely independent of the concomitant variation in adiposity, a finding that we have previously reported in both genders (50). Although visceral AT accumulation and its related metabolic dysfunctions are associated with changes in circulating sex steroid hormones, it is clear that high androgen levels are characteristic features of intraabdominal obesity in pre- and postmenopausal women, whereas the reverse situation is generally found in men (7, 8, 51). In this regard, whether 1) the similar visceral AT deposition observed in pre- and postmenopausal women may account for the lack of difference in the lipolytic capacity of sc abdominal adipocytes, or 2) a third factor related to visceral adipose tissue, such as an altered sex steroid hormone profile, which could lead to alterations in sc adipose cell metabolism, is controlled by our matching procedure is presently unknown. Based upon the fact that abdominal obese women are hyperandrogenic regardless of their menopausal status and that testosterone exerts a lipolytic action on sc adipose tissue (52), it seems reasonable to assume that our matching of pre- and postmenopausal women for regional fat distribution may have also allowed us to "control" the effect of sex steroids on adipose tissue lipolysis. Further studies are needed, however, to test this hypothesis.
Taken together, our data show that regional variation in sc adipose tissue metabolism is not observed in the early phase of menopause. In addition, once the concomitant variation in body fatness, body fat distribution, and adipose cell size is taken into account, our sample of pre- and postmenopausal women displays similar sc adipose tissue lipolysis and LPL activity. These results suggest that regional fat distribution is an important determinant that should be considered when investigating age-related effects on adipose tissue metabolism in women.
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Acknowledgments |
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Footnotes |
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Received October 13, 1999.
Revised March 25, 2000.
Accepted March 29, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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2-adrenoceptors: the regulation of fat cell
function and lipolysis. Endocr Rev. 16:716–738.This article has been cited by other articles:
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