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Ovarian Hormone Status and Abdominal Visceral Adipose Tissue Metabolism

Molecular Endocrinology and Oncology Research Center (A.T., A.D., C.Ri.), Department of Nutrition (A.T., A.D.), and Gynecology Unit (P.L., M.D., J.M., C.Rh., P.D.), Laval University Medical Research Center and Laval University, Québec, Canada G1V 4G2

Address all correspondence and requests for reprints to: André Tchernof, Ph.D., Molecular Endocrinology and Oncology Research Center, Laval University Medical Research Center, 2705 Laurier Boulevard (T3–67), Québec, PQ, Canada G1V 4G2. E-mail: andre.tchernof{at}crchul.ulaval.ca.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We examined abdominal sc and visceral adipose tissue metabolism in a sample of 19 regularly cycling premenopausal women (age 46.3 ± 3.7 yr) and 10 women with natural menopause or pharmacological ovarian suppression (age 51.1 ± 9.2 yr). Subcutaneous and visceral (omental, epiploic) adipose tissue biopsies were obtained during abdominal hysterectomies. Body composition and adipose tissue distribution were measured before the surgery by dual x-ray absorptiometry and computed tomography, respectively. Ovarian hormone-deficient women tended to be older (P = 0.08) and were characterized by increased visceral adipose tissue area (P < 0.05). Subcutaneous adipocyte size, lipoprotein lipase (LPL) activity, and basal lipolysis were not significantly different between groups. On the other hand, omental fat cell size was significantly higher in ovarian hormone-deficient women, compared with premenopausal women (P < 0.05). The omental/sc LPL activity ratio and omental adipocyte basal lipolysis were also significantly higher in ovarian hormone-deficient women (P < 0.05 for both comparisons). Significant positive correlations were found between visceral adipose tissue area and omental LPL activity (r = 0.54, P < 0.003), omental adipocyte basal lipolysis (r = 0.66, P < 0.0001), and omental fat cell size (r = 0.81, P < 0.0001). In multivariate analyses, ovarian status was no longer a significant predictor of adipose cell metabolism variables after visceral adipose tissue area was entered into the model, with the exception of the omental/sc LPL activity ratio, which remained independently associated with ovarian status. In conclusion, although the size of the visceral adipose tissue compartment was an important determinant of adipocyte metabolism in this depot, the increased omental/sc LPL activity ratio in ovarian hormone-deficient women supports the notion of a predominant visceral fat storage in these women.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
ALTHOUGH NOT ALL studies on cardiovascular disease in women support a significant effect of the menopause transition on disease incidence, the fact that several risk factors are directly affected by estrogens led to the general idea that postmenopausal women have an increased risk, compared with their premenopausal counterpart (1). To this end, excess visceral adipose tissue accumulation is the central component of a constellation of high-risk features such as dyslipidemia, insulin resistance, and a prothrombotic-proinflammatory state now defined as the metabolic syndrome (2, 3, 4). A large survey recently demonstrated an increased prevalence of this condition in postmenopausal women (5), which suggests that changes in body fat distribution related to the loss of ovarian function may contribute to the apparent increase in cardiovascular disease after menopause (6, 7)

Studies using radiologic imaging techniques such as dual energy x-ray absorptiometry or computed tomography found that postmenopausal women are characterized by higher abdominal/visceral adipose tissue accumulations, compared with premenopausal women (7, 8, 9, 10), which suggests that the menopause, or the ovarian hormone-deficient state, is associated with a redistribution of fat toward the abdominal compartment. At the cellular level, recent studies published by Mauriège et al. (11) and Ferrara et al. (12) have examined the impact of menopause on sc adipose tissue metabolism. The first study (11) was performed in lean women and demonstrated that sc adipose tissue was not influenced by menopause when total and computed tomography-measured visceral adiposity were controlled for. The second study (12), which was performed in obese peri- and postmenopausal women matched for whole-body composition, showed higher abdominal lipoprotein lipase (LPL) activity and lower lipolysis in menopausal compared with perimenopausal women. Although these data were obtained with sc adipocytes, they suggest that control for group differences in total and regional fat accumulation may be critical when examining the effects of ovarian hormone status on adipose tissue metabolism.

Only one study examined both sc and omental fat metabolism in pre- and postmenopausal women. However, the sample examined presented large age and body fat distribution differences that were not controlled for (13). We hereby report on adipocyte metabolism in sc and omental biopsies obtained in a sample of 19 regularly cycling premenopausal women and 10 women with natural menopause or pharmacological ovarian suppression. A detailed assessment of body composition and body fat distribution was performed. We tested the hypothesis that the ovarian hormone-deficient state is associated with alterations in omental and sc adipocyte metabolism, reflecting a predominant visceral fat storage, independent of differences in age, body fat mass, and visceral adipose tissue accumulation.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Women of this study were recruited through the elective surgery schedule of the Gynecology Unit of the Laval University Medical Center. The study included 29 healthy women aged 40.1–68.3 yr undergoing abdominal gynecological surgery. Women of the study elected for total (n = 28) or subtotal (n = 1) abdominal hysterectomies, some with salpingo-oophorectomy of one (n = 1) or two (n = 19) ovaries. Reasons for surgery included one or more of the following: menorrhagia (n = 9), myoma/fibroids (n = 17), pelvic pain (n = 4), benign cyst (n = 1), endometriosis (n = 4), cystitis (n = 1), and mittelschmerz (n = 1). Ovarian hormone status was established by examining medical files and questionnaires on menstrual history and medication use as well as plasma hormone levels. A total of 10 women were classified as being postmenopausal on the basis of the absence of menses for more than 12 months and no concomitant hormone replacement use (n = 4) or the use of a GnRH agonist and no concomitant hormone replacement use (n = 6). Nineteen women reported a regular menstrual cycle (average cycle length 27.4 ± 1.9 d) and were classified as regularly cycling premenopausal women. Phase of the cycle was obtained for 18 premenopausal women. Plasma levels of estradiol and FSH were measured to confirm ovarian hormone status. This study was approved by the medical ethics committees of Laval University and Laval University Medical Center. All subjects provided written informed consent before their inclusion in the study.

Body fatness and body fat distribution measurements

These tests were performed on the morning of or a few days before the surgery. Measures of total body fat mass, fat percentage, and fat-free mass were determined by dual energy x-ray absorptiometry, using a Hologic QDR-2000 densitometer and the enhanced array whole-body software V5.73A (Hologic Inc., Bedford, MA). Measurement of abdominal sc and visceral adipose tissue cross-sectional areas was performed by computed tomography as previously described (14), using a GE Light Speed 1.1 CT scanner (General Electric Medical Systems, Milwaukee, WI) and the Light Speed QX/I 1.0 production software. Subjects were examined in the supine position, with arms stretched above the head. The scan was performed at the L4-L5 vertebrae level using a scout image of the body to establish the precise scanning position. The quantification of visceral adipose tissue area was done by delineating the intraabdominal cavity at the internal most aspect of the abdominal and oblique muscle walls surrounding the cavity and the posterior aspect of the vertebral body with the computer interface of the scanner. Adipose tissue was highlighted and computed using an attenuation range of –190 to –30 Hounsfield units. The coefficient of variation between two analyses (n = 10, same observer) were 0, 0.50, and 2.14%, for total, sc, and visceral adipose tissue areas, respectively.

Plasma hormone measurements

Blood samples were obtained after a 12-h fast on the morning of surgery. Plasma FSH concentrations were determined with a RIA from Diagnostic System Laboratories (Webster, TX). Estradiol levels were measured by competitive immunological assay using the Immuno-1 apparatus (Bayer, Tarrytown, NJ). The coefficient of variation for this measurement was 3.5%.

Adipose tissue sampling

Paired omental (epiploic) and sc adipose tissue samples were collected during the surgical procedure and immediately carried to the laboratory in 0.9% saline preheated at 37 C. A portion of the biopsy was used for adipocyte isolation and the remaining tissue was immediately frozen at –80 C for subsequent analyses.

Adipocyte isolation, lipolysis, and LPL activity

Tissue samples were digested with collagenase type I in Krebs-Ringer-Henseleit buffer for 45 min at 37 C according to a modified version of the Rodbell method (15). Adipocyte suspensions were filtered through nylon mesh and washed three times with Krebs-Ringer-Henseleit buffer. For cell size measurements, mature adipocyte suspensions were visualized using a contrast microscope attached to a camera and computer interface. Pictures of cell suspensions were taken and the Scion Image software was used to measure the size (diameter) of 250 adipocytes for each tissue sample.

Lipolysis experiments were performed by incubating isolated cell suspensions for 2 h at 37 C with or without ß-adrenergic receptor agonist isoproterenol (10^–6 M) or postreceptor adenylate cyclase-stimulating agent forskolin (10^–5 M). Glycerol release in the medium was measured by bioluminescence using the nicotinamide adenine dinucleotide hydroxide-linked bacterial luciferase assay (16, 17), a Berthold Microlumat plus bioluminometer (LB 96 V) and the WinGlow software (EG&G, Bad Wildbad, Germany). The average coefficient of variation for duplicate glycerol release measurements was 14.1%. Lipid weight of the cell suspension was measured by performing Dole’s extraction, and lipolysis results were expressed as a function of adipocyte surface area (micromoles glycerol per square micrometer x 10⁸/2 h).

LPL activity was determined in 30- to 50-mg frozen adipose tissue samples by the method of Taskinen et al. (18). Tissue eluates were obtained by incubating the sample in Krebs Ringer phosphate buffer and heparin at 37 C for 45 min. The eluates were then incubated with excess concentrations of unlabeled and ¹⁴C-labeled triolein in a Tris-albumin buffer emulsified with ultrasound. The reaction was carried out at 37 C for 45 min with agitation. The resulting free fatty acids liberated from triolein by the LPL reaction were isolated by the Belfrage extraction procedure. Porcine plasma was used as a source of Apo-CII to stimulate LPL activity, and unpasteurized cow’s milk as an internal LPL activity standard for interassay variations. Activity results were expressed in micromoles oleate per 10⁶ cells per minute.

Statistical analyses

Group differences were compared using unpaired t tests. Comparisons were performed on log₁₀-transformed values when variables were nonnormally distributed (age, visceral adipose tissue area, sc and omental LPL activity, basal and stimulated lipolysis in omental and sc adipocytes as well as lipolysis fold inductions over basal level in both depots). Log₁₀-transfromed LPL activity and basal lipolysis were used in the figure. Age- and visceral fat-adjusted comparisons were performed using analysis of covariance and least-square means contrasts. Spearman rank correlation coefficients were computed with untransformed variables to quantify the associations between visceral adipose tissue accumulation and adipose tissue metabolism measures. Multivariate regression analyses were used to examine independent correlates of adipose tissue metabolism variables. All statistical analyses were performed using the JMP statistical software (SAS Institute, Cary, NC).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Sample characteristics

Physical and metabolic characteristics of the women are shown in Table 1. Ovarian hormone-deficient women tended to be older than regularly cycling women (P = 0.08). No significant difference was noted in body weight, body mass index (BMI), body fat mass, body fat percentage, or lean body mass. However, computed tomography-measured visceral adipose tissue area was significantly higher in ovarian hormone-deficient women, compared with their premenopausal counterparts (P = 0.04). Areas of the sc abdominal fat compartment were not significantly different between groups. Plasma estradiol levels were significantly lower in ovarian hormone-deficient women, compared with regularly cycling women (35 ± 30 vs. 104 ± 75 pg/ml, respectively, P < 0.02). No significant difference was found between premenopausal women in the follicular (n = 8) vs. the luteal/menstrual phase (n = 10) for any of the variables examined. Moreover, women with natural menopause were not different from women with pharmacological ovarian suppression for any variable with the exception of age, which was significantly higher in postmenopausal women (not shown).

Group differences in abdominal omental and sc adipose tissue metabolism are shown in Table 2. Subcutaneous adipose tissue-isolated fat cell size was not significantly different (P = 0.95). However, a significantly increased omental fat cell size was observed in ovarian hormone-deficient women vs. premenopausal women (P = 0.04). Omental LPL activity tended to be higher (P = 0.16) in hormone-deficient vs. premenopausal women, whereas sc LPL activity was not significantly different between groups (P = 0.99). Omental adipocyte basal lipolysis was significantly higher in ovarian hormone-deficient vs. premenopausal women (P = 0.01). Statistical control for age did not abolish significant differences (P 0.06 for all comparisons).

The omental/sc LPL activity ratio was calculated as an indirect measure of relative fatty acid uptake in the omental vs. sc fat compartment. This variable was significantly higher in ovarian hormone-deficient compared with regularly cycling women (1.27 ± 0.20 vs. 0.66 ± 0.15, P = 0.02). Statistical control for both age and visceral fat area did not affect this difference (1.28 ± 0.23 vs. 0.65 ± 0.16, P = 0.04). On the other hand, statistical control for visceral adipose tissue area abolished all other significant group differences in adipose tissue metabolism variables (not shown).

Correlation and multiple regression analyses

We found significant associations between omental adipose tissue metabolism variables and computed tomography-measured visceral adipose tissue area (Fig. 1). Specifically, omental adipocyte size, LPL activity, and basal lipolysis were all significantly and positively associated with visceral adipose tissue area.

View larger version (19K): [in this window] [in a new window]   FIG. 1. Correlations among omental adipocyte size, basal lipolysis, LPL activity, and computed tomography-measured visceral adipose tissue area. Spearman rank correlation coefficients computed with untransformed data are presented. gly, Glycerol.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In the present study, we tested the hypothesis that the ovarian hormone-deficient state is associated with alterations in omental and sc adipocyte metabolism, reflecting a predominant visceral fat storage, independent of differences in age, body fat mass, and visceral adipose tissue accumulation. Omental adipocyte size and basal lipolysis as well as the omental/sc LPL activity ratio were significantly higher in ovarian hormone-deficient women, compared with regularly cycling women. Group differences in visceral adipose tissue accumulation accounted for an important part of these differences, with the exception of the omental/sc LPL activity ratio, which remained significantly associated with ovarian status independent of age and visceral fat accumulation. These results are consistent with the notion of a redistribution of fat toward the visceral fat compartment in ovarian hormone-deficient women. To our knowledge, this is the first study to examine the effect of ovarian status on both sc and omental fat metabolism in a sample of women that has been well characterized with regard to body composition and body fat distribution.

The majority of previous studies on menopausal status and regional adipose tissue metabolism have examined sc adipocytes (11, 12, 19, 20). These studies are, therefore, uninformative with regard to the visceral fat compartment, which is increasingly recognized as being critical in the association between abdominal obesity and concomitant health hazards (2, 3). The invasive nature of omental fat sampling may account for the relatively small number of studies focusing on this fat depot. Only one study examined both sc and omental fat metabolism in pre- and postmenopausal women (13). However, results from that study are difficult to interpret because the two study groups were characterized by large differences in abdominal fat distribution and age (22 yr average difference between pre- and postmenopausal women), and no statistical controls were performed. In the present sample, the age difference was small and did not reach significance. Moreover, statistical control for this variable did not affect ovarian hormone status-related differences in adipose tissue metabolism.

Group differences in either body composition or body fat distribution may also have been important confounders of previous studies on menopause and regional fat metabolism. Studies by Rebuffé-Scrive et al. (19) and Raison et al. (20) were performed in pre- and postmenopausal women that presented either similar BMI values (19) or similar BMI and waist-hip ratio values (20). Accordingly, no significant differences in abdominal sc adipose tissue fat cell size or LPL activity were found in these studies (19, 20). The second study by Rebuffé-Scrive et al. (13) found significantly higher values of fat cell size, LPL activity, and lipolysis in abdominal sc fat from pre- vs. postmenopausal women. However, these two subgroups were also characterized by different waist-hip ratio values, which were not controlled for (13). More recently, Mauriège et al. (11) found no significant difference in abdominal sc adipose tissue LPL activity and lipolysis in a sample of pre- and postmenopausal women that were matched for computed tomography-measured visceral adipose tissue area (11). Finally, Ferrara et al. (12) examined a sample of peri- and postmenopausal women who were matched for body fat mass and body fat percentage. Although abdominal sc fat cell weight and lipolysis were not significantly different in that study, a significant difference in abdominal sc adipose tissue LPL activity was found. Interestingly, postmenopausal women of that study were characterized by higher visceral and sc adipose tissue accumulations, although these differences did not reach statistical significance (12). Thus, the finding of statistically significant differences in parameters of abdominal adipocyte metabolism in previous studies may have been related to adiposity characteristics of the study samples.

Much like in previous samples, ovarian hormone-deficient women of the present study were characterized by an increased visceral adipose tissue area, compared with their premenopausal counterparts. In addition, we found significant positive correlations between computed tomography-measured visceral adipose tissue area and fat cell weight, LPL activity, and basal lipolysis in the omentum. Visceral adipose tissue area was an important contributor to omental adipose tissue metabolism variation, and statistical control for this variable abolished the differences in fat cell size and omental adipocyte basal lipolysis. On the other hand, sc fat metabolism measures were not significantly affected by ovarian hormone status in the present sample, irrespective of the control for age and body fat distribution differences. We suggest that this may be related to the fact that abdominal sc areas and total body fat mass were not significantly different in the groups examined.

The cross-sectional design of the present study prevents from reaching conclusions on cause-and-effect relationships. Thus, it is not possible to determine whether the increased omental/sc LPL activity ratio of the present study was a cause of the increased visceral adipose tissue area found in ovarian hormone-deficient women or simply a consequence of other physiological conditions leading to higher visceral fat accumulation in this group. However, studies have shown that estrogens may exert important regulatory effects on adipocyte metabolism. The presence of both estrogen receptor isoforms- and -ß in human adipose tissue is well established (21, 22, 23). Moreover, animal studies have reported evidence for regional differences in estrogen receptor levels and regulation (24, 25). A study by Price et al. (26) showed that transdermal estradiol treatment significantly decreased gluteal adipose tissue LPL activity, and that this phenomenon was attributable to posttranscriptional modification of protein levels. Recent in vitro studies also support an important regulatory role of estradiol on adipocyte metabolism and function. Palin et al. (27) found that high doses (10^–7 M) of estradiol decreased LPL and increased hormone-sensitive lipase protein levels in abdominal sc isolated adipocytes. Interestingly, lower estradiol doses had the opposite effect, which suggests a biphasic action of the hormone at the cellular level (27).

Previous studies have suggested a direct effect of estrogens on lipolysis (27, 28). The finding of a significant ovarian status difference in basal lipolysis in the present study is consistent with these publications. However, the lack of differences in agonist-stimulated glycerol release over basal suggests an unaltered adrenoreceptor and postadrenoreceptor lipolytic pathway. Accordingly, the study by Jensen et al. (28) demonstrated that, although estrogen deficiency was associated with a 10–20% increase in adipose tissue free fatty acid release, these differences did not appear to be attributable to changes in the adrenergic regulation of lipolysis (28). Other mechanisms may also possibly explain results of the present study. For example, progesterone may also be involved in the regulation of regional fat distribution through a possible antiglucocorticoid action in adipose tissue (29, 30). Taken together, current in vivo and in vitro evidence suggest that ovarian hormones may play an important role in the regulation of regional fat metabolism in women, a concept also supported by the present study. Further investigations in animals and in vitro models are needed to confirm our cross-sectional observations.

In summary, we found that omental adipocyte size and basal lipolysis as well as the omental/sc LPL activity ratio were significantly higher in ovarian hormone-deficient women, compared with regularly cycling women. However, group differences in visceral adipose tissue accumulation appeared to account for an important part of these differences. Ovarian hormone-deficient women were characterized by a higher omental/sc LPL activity ratio, independent of age and visceral adipose tissue accumulation, which supports the notion of a predominant fat storage in the omental depot in these women.

	Acknowledgments

 
The invaluable help of study coordinator Guylaine Chainé; nurses Denise Parsons, Johanne Baillargeon, Carole Boisvert, Danielle Bélanger, Carole Bérubé, and Diane Chamberland; and radiology technicians Suzanne Brulotte, Lyne Bargone, Linda Marcotte, Louise Mailloux, Diane Bastien, and Monique Caron is gratefully acknowledged. The authors also thank all women who participated in the study for their excellent collaboration.

	Footnotes

 
This work was supported by the Canadian Diabetes Association and the Canadian Institutes of Health Research. Preliminary results for this study were also obtained with the support of a pilot study grant from the North American Association for the Study of Obesity. A.T. is the recipient of scholarships from the Fonds de la Recherche en Santé du Québec (2000–2003) and the Canadian Institutes of Health Research.

Abbreviations: BMI, Body mass index; LPL, lipoprotein lipase.

Received September 5, 2003.

Accepted April 5, 2004.

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