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The Metabolic Syndrome in Obese Postmenopausal Women: Relationship to Body Composition, Visceral Fat, and Inflammation

Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine (T.Y., B.J.N.), Winston-Salem, North Carolina 27157; and Division of Gerontology, University of Maryland School of Medicine and the Geriatric Research, Education and Clinical Center of the Baltimore Veterans Affairs Medical Center (A.S.R.), Baltimore, Maryland 21201

Address all correspondence and requests for reprints to: Dr. Tongjian You, Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157. E-mail: tyou{at}wfubmc.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The purpose of this study was to investigate whether aerobic fitness, body composition, body fat distribution, and inflammation are different in obese postmenopausal women with and without the metabolic syndrome (MS), and whether the severity of MS is associated with these characteristics. Fifty-eight women (age, 59 ± 1 yr; body mass index, 33.0 ± 0.6 kg/m²) completed testing of maximal aerobic capacity, body composition (fat mass, lean mass, and percent body fat), body fat distribution (sc and visceral fat areas, and regional adipocyte sizes), and inflammation (C-reactive protein, IL-6, and TNF-, and their soluble receptors). Lean mass (44.4 ± 0.9 vs. 41.2 ± 0.9 kg; P < 0.05), visceral fat area (180 ± 10 vs. 135 ± 7 cm²; P < 0.001), and plasma soluble TNF receptor 1 (sTNFR1; 860 ± 25 vs. 765 ± 42 pg/ml; P < 0.05) were higher in women with the MS (n = 27) than in those without the MS (n = 31). The number of MS components was directly related to weight, body mass index, fat mass, lean mass, visceral fat area, and plasma sTNFR1. We conclude that obese older women with the MS are characterized by high lean mass, high visceral fat, and elevated sTNFR1, and the severity of the MS is associated with body composition, visceral adiposity, and inflammation.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
AN INCREASE IN total and central obesity usually occurs in older women, especially after the menopause transition (1, 2, 3). This has been linked with a number of metabolic complications, such as dyslipidemia, insulin resistance, hypertension, and an increased risk of coronary heart disease (4, 5, 6, 7). In 2001, the National Cholesterol Education Program (NCEP)’s Adult Treatment Panel III defined the components of the metabolic syndrome (MS) (8). According to the NCEP criteria, the MS is diagnosed when three or more of the following risk components are present: 1) waist circumference greater than 102 cm for men and greater than 88 cm for women; 2) triglyceride (TG) levels of 150 mg/dl or more; 3) high density lipoprotein cholesterol (HDL-C) levels less than 40 mg/dl for men and less than 50 mg/dl for women; 4) blood pressure (BP) of 130/85 mm Hg or higher; and 5) fasting glucose levels of 110 mg/dl or more. In the United States, the overall prevalence of the MS in adults over the age of 20 yr is 23.7% (9). It is higher among Mexican Americans (31.9%) than among Caucasians (24.0%) and African-Americans (23.4%) (9). The prevalence increases with age and body mass index (BMI). The rate is 6.7% in the third decade and reaches 43.5% in the seventh decade (9). In addition, only 6% of normal weight adults have MS, but the prevalence increases to 60% in moderately obese adults (10).

Although the MS is associated with obesity, not all obese individuals have this clustering of risk factors, and some only show one or two of the MS components or none at all (10). Therefore, comparisons of aerobic fitness, body composition, body fat distribution, and inflammation in obese subjects with and without the MS can help clarify the underlying pathophysiological mechanism of the syndrome. In addition, most previous studies investigated the relationship of individual components of the MS to fitness level (11), body composition (12, 13), body fat distribution (12), and inflammation (14, 15, 16), rather than exploring the strength of the association between these factors and the clustering of multiple components.

Currently, the presence of three risk components is used as a cut-off point for the diagnosis of the MS according to NCEP criteria. However, the number of MS components (n = 0–5) may be a more accurate indicator of the overall severity of the disease. To date, a few studies reported that the clustering of MS components was negatively related to aerobic fitness (17, 18) and positively related to circulating levels of C-reactive protein (CRP) (19, 20). It is not known whether aerobic fitness, body composition, body fat distribution, or markers of inflammation are associated with the number of MS components in obese postmenopausal women.

Thus, the purpose of this study was to investigate 1) whether aerobic fitness, body composition (fat mass, lean mass, and percent body fat), body fat distribution (sc fat, visceral fat, and regional adipocyte sizes), and inflammation (plasma CRP, IL-6, and TNF as well as their soluble receptors) are different in obese postmenopausal women with and without the MS; and 2) whether the number of MS components is associated with aerobic fitness, body composition, body fat distribution, and inflammation in these women.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

All subjects were nonsmoking, overweight and obese (BMI, 25–40 kg/m²), postmenopausal (no menstruation for at least 1 yr) women, aged 50–70 yr. The women were sedentary (<20 min of exercise, twice weekly) and weight-stable (<2.0 kg weight change) for at least 1 yr before enrollment. All women provided informed consent to participate in the study according to the guidelines of the University of Maryland institutional review board for human research. Initial evaluations included a medical history review, physical examination, fasting blood profile, and 12-lead resting electrocardiogram. Subjects with evidence of untreated hypertension (blood pressure, >160/90 mm Hg); hypertriglyceridemia (TG, >400 mg/dl); cancer, liver, renal, or hematological disease; or other medical disorders were excluded. Women were given a 2-h oral glucose tolerance test to exclude those with diabetes (fasting blood glucose, >126 mg/dl; 2-h glucose, >200 mg/dl). A total of 60 women met all the criteria and were enrolled into the study.

Study design

After fulfillment of recruitment inclusion/exclusion criteria, all women underwent research testing over the course of 2 wk. All participants were told to maintain their current dietary habits and sedentary lifestyle before and during initial research testing. The first day of testing consisted of the anthropometric, dual energy absorptiometry, and computed tomography measurements, followed by measurement of maximal aerobic capacity (VO₂max). On the second testing day, a fasting blood sample was drawn for the determination of lipids, glucose, insulin, and markers of inflammation. The fat biopsy in abdominal and gluteal sites took place on the third testing day along with a second fasting blood draw for the determination of lipoprotein lipids in duplicate.

Maximal aerobic capacity

VO₂max was measured on a motor-driven treadmill (Quinton Instruments, Seattle, WA) during a progressive exercise test to voluntary exhaustion, as previously described (21). A valid VO₂max was obtained when at least two of these three criteria were met: 1) maximal heart rate greater than 90% of age-predicted maximal heart rate (220 beats/min – age), 2) respiratory exchange ratio of at least 1.10, and 3) plateau in VO₂ (<200 ml/min change) with increasing work rate.

Body composition

Height and weight were measured to calculate the BMI (kilograms per meter squared). Waist (minimal circumference) was measured in duplicate. Fat mass, lean mass, and percent body fat were measured by dual energy absorptiometry (model DPX-L; Lunar Radiation Corp., Madison, WI). Visceral and sc adipose tissue areas were measured by a single-slice computed tomography scan taken midway between L4 and L5 using a High Speed Advantage 9800 scanner (General Electric, Fairfield, CT).

Adipocyte sizes

Subcutaneous adipose tissue from both the abdominal and gluteal regions was taken by aspiration with a 16-gauge needle under local anesthesia (2% xylocaine) after an overnight fast. Adipocytes were isolated in a Krebs-Ringer-HEPES buffer (pH 7.4) containing 4% BSA, 5 mM glucose, 200 nM adenosine, and 1 mg/ml collagenase. Isolation took place in a shaking water bath at 100 rpm at 37 C for 45 min. Isolated cells were filtered through 250-µm pore size nylon mesh and washed three times with enzyme-free Krebs-Ringer-HEPES buffer and resuspended to a final concentration of 20,000–30,000 cells/ml. The diameters of 100 cells/site were counted in an aliquot of the cell suspension to calculate the average size (22).

Analysis of blood samples

Blood samples were collected via venipuncture in the early morning (0700–0900 h) after a 12-h fast. Plasma samples for assays of lipids, glucose, insulin, and inflammatory markers were collected in EDTA-treated collection tubes and separated after centrifugation for 20 min at 4 C. The blood samples were centrifuged at 4 C, and plasma was stored at –70C until analysis. Plasma HDL-C and TG were measured by standardized hospital laboratory procedures. Plasma glucose was measured with the glucose oxidase method (Beckman Coulter, Fullerton, CA). Plasma insulin was determined by RIA with an insulin-specific antibody (Linco Research, Inc., St. Charles, MO). The estimate of insulin sensitivity by homeostasis model assessment (HOMA) score was calculated with the formula: fasting plasma insulin (µU/ml) x fasting plasma glucose (mmol/liter)/22.5 (23). All cytokines and cytokine soluble receptors were measured using Quantikine ELISA kits (R&D Systems, Minneapolis, MN). In our laboratory, the inter- and intraassay coefficients of variation for IL-6 were 5.4% and 3.5%, respectively; those for TNF were 11.8% and 6.2%, respectively; and those for the soluble receptor assays were less than 5%. CRP was measured using an automated immunoanalyzer (IMMULITE; Diagnostics Products Corp., Los Angeles, CA). The inter- and intraassay coefficients of variation for the CRP assay were 7.5% and 4.4%, respectively.

Statistical analysis

Statistical analyses were performed using JMP version 4.0 for Windows (SAS Institute, Cary, NC). The CRP, IL-6, and TNF data were not normally distributed, so the logarithm of each was used for parametric statistical analyses. Group differences were determined using both a t test and multivariate analysis with age as a covariant. Pearson’s correlation coefficients were calculated for relationships between variables. Multivariate analysis was used to determine partial correlations of the number of MS components with body composition, body fat distribution, and inflammatory markers. All data are presented as the mean ± SE, and the level of significance was set at P < 0.05 for all analyses.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Descriptive characteristics and MS profile

All 60 women completed the study; however, two women were not included in the data analysis due to missing data for waist circumference and blood pressure. The number of MS components was counted following the NCEP criteria (8) in the remaining 58 women. Women taking antihypertensive medications were counted as having hypertension. The number of MS components in the entire cohort ranged from 0–5, and there were 27 women with MS (three or more components) and 31 without MS (less than three components; Table 1).

Aerobic fitness, body composition, body fat distribution, and plasma inflammatory markers were compared between women with and without the MS (Table 3). There were no between-group differences in VO₂max, body weight, BMI, fat mass, percent body fat, sc fat area, abdominal adipocyte size, or gluteal adipocyte size. However, lean mass (P < 0.05) and visceral fat area were significantly higher (P < 0.001) in the MS group, and the group differences were still significant after adjustment for age (lean mass, P < 0.01; visceral fat, P < 0.01).

Relationships between number of MS components and aerobic fitness, body composition, body fat distribution, and inflammation

Correlations between MS component number and age, aerobic fitness, body composition, body fat distribution, and inflammatory markers were calculated in the entire cohort. The number of MS components was not related to age (r = 0.18), VO₂max (r = 0.18), percent body fat (r = –0.02), sc fat (r = 0.17), abdominal adipocyte size (r = 0.18), or gluteal adipocyte size (r = 0.15). However, the MS component number correlated significantly with body weight (r = 0.42; P < 0.01), BMI (r = 0.45; P < 0.001), fat mass (r = 0.26; P < 0.05), lean mass (r = 0.49; P < 0.001; Fig. 1), and visceral fat area (r = 0.45; P < 0.001; Fig. 2). The correlations were not significantly altered when the woman with all five risk components was removed (data not shown). When MS component number was used as the independent variable, and lean mass and visceral fat were used as the dependent variables in a multivariate model, the MS component number still significantly correlated with lean mass (r = 0.42; P < 0.01) and visceral fat (r = 39; P < 0.01). After adjustment for lean mass and visceral fat, the MS component number did not correlate with body weight (r = 0.12), BMI (r = 0.27), or fat mass (r = 0.05). In addition, lean mass tended to correlate with visceral fat (r = 0.26; P = 0.05).

View larger version (13K): [in this window] [in a new window]   FIG. 1. Relationship of MS component number to lean mass (r = 0.49; P < 0.001) in obese postmenopausal women.

View larger version (13K): [in this window] [in a new window]   FIG. 2. Relationship of MS component number to visceral fat area (r = 0.45; P < 0.001) in obese postmenopausal women.

View larger version (13K): [in this window] [in a new window]   FIG. 3. Relationship of MS component number to plasma sTNFR1 (r = 0.40; P < 0.01) in obese postmenopausal women.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Our findings support those of a previous study by Brochu et al. (12), in which the physical characteristics associated with a metabolically normal profile were examined in 43 obese postmenopausal women. A cut-point for insulin sensitivity (glucose disposal rate, 8.0 mg/min·kg lean mass), instead of MS risk components, was used for the classification of the MS. They found that there was a subgroup of obese, but metabolically normal, women who displayed high levels of insulin sensitivity despite having a high amount of body fat. Our finding that obese postmenopausal women without the MS have a lower HOMA score (high insulin sensitivity) is in line with these findings. Moreover, Brochu et al. (12) reported that both lean mass and visceral fat were higher in metabolically abnormal compared with metabolically normal obese women. Our findings strongly confirm the importance of visceral adiposity in determining the presence of the MS in obese postmenopausal women and specifically indicate that women with the MS tend to have an androgenic body type compared with healthier obese women.

In healthy women there is a negative correlation between amount of visceral fat and in vivo measures of protein catabolism, suggesting that there may be an underlying mechanism linking the amount of visceral fat and lean mass (24). The possible mechanisms include increased concentrations of free androgens due to diminished levels of SHBG (25, 26, 27), a protein-sparing effect due to increased lipid metabolism (28, 29), and changes in muscle capillarization and fiber composition due to visceral adiposity (30). Therefore, in the current study the difference in lean mass between women with and without the MS may be partly due to the difference in amount of visceral fat. However, the number of MS components still correlated with lean mass even when the effect of visceral fat was considered. Obviously, there is another underlying factor(s) that influences lean mass and the MS in these obese women.

Prior studies show that the MS is related to low aerobic fitness in healthy individuals (11, 17, 18). In addition, poor aerobic fitness is important in the development of hemorheological abnormalities associated with the MS (31). Conversely, we did not see a significant relationship between the MS and aerobic fitness in these women. It should be noted that all of these women were very sedentary, with a below average fitness level, because we excluded any physically active woman. Thus, the range of fitness levels may have not been large enough to see an association with MS. However, this could be seen as an advantage of this study, because we eliminated a potential confounder of the relationship between MS and body composition.

In the current study women with the MS did not show significantly different body weight, BMI, fat mass, or even waist circumference, which is a MS risk component. Although body weight, BMI, and fat mass were related to the severity of the MS in the current study, these relationships were actually due to the effects of lean mass and visceral fat, which independently correlated with the number of MS components. Considering the effect of visceral fat on metabolism and the relatively small variance in lean mass, visceral fat is probably the most important physical characteristic associated with the MS.

It has been reported that sc abdominal adipocyte hypertrophy is related to plasma TG, total cholesterol, and total cholesterol/HDL-C ratio in middle-aged individuals with a wide range of fatness (BMI, 18–57 kg/m²) (32). In addition, sc abdominal adipocyte size is an independent predictor of type 2 diabetes (33). In the present study neither between-group comparisons nor correlation analyses supported any relationship between the MS and sc adipocyte sizes. The possible reason is the relatively small variances of these variables due to the small range of fatness (BMI, 25–40 kg/m²) of women in the current study. In a study conducted in obese individuals who had undergone abdominal surgery, both visceral fat and sc fat were obtained, and the results showed that an adverse lipid profile had a higher correlation with visceral adipocyte size than with sc adipocyte size (16). Because visceral adipocyte size, but not sc adipocyte size, is directly related to visceral fat area (16), it may be that the MS is more closely linked with visceral adipocyte size. However, there are only limited data regarding the relationship of the MS to regional adipocyte hypertrophy; therefore, more studies are needed.

Gene expression and production of IL-6 and TNF in adipose tissue are elevated with overall and abdominal obesity (34, 35, 36). These adipokines may act in either an autocrine or a paracrine fashion to mediate the effect of adiposity on a number of physiological functions and disease processes (37, 38). It has been reported that circulating levels of CRP and IL-6 are higher in metabolically abnormal type 2 diabetics when TG, HDL-C, blood pressure, cardiovascular evidence, and BMI are used for the diagnosis of the MS (39). Moreover, both individual (14, 15, 20) and clustering (19, 20) of MS components are linked with CRP levels. However, we did not find significantly different levels of CRP and cytokines between the two groups, and the severity of the MS was not significantly related to CRP and cytokines. The possible reason for the nonsignificant results may be due to the relatively small sample size in the study.

Current evidence indicates that cytokine soluble receptors have a longer half-life, which may allow them to prolong the biological effects of the cytokines (40, 41). Therefore, the functions of these soluble receptors are not limited to signal transduction, but include extracellular regulation of cytokine bioavailability (42, 43). Emerging data support the idea that circulating levels of sTNFRs are directly linked with lipoprotein disturbance (44, 45), insulin resistance (46), and obesity (47). In this study we found a significant between-group difference in sTNFR1 levels and a significant correlation between the number of MS components and sTNFR1 in the obese women. These results support the idea that the overall MS is linked with this inflammatory cytokine receptor. It has been suggested that sTNF preferentially binds to sTNFR1, rather than to sTNFR2 (48); therefore, sTNFR1 is probably more important in the extracellular regulation of TNF action on MS. Because gene expression of sTNFRs in adipose tissue is increased with obesity (49), it is possible that both visceral fat mass and sTNFR1 production from visceral fat per se are responsible for the link between the MS and plasma sTNFR1. Moreover, sTNFR1 is produced by a number of cell types, including leukocyte subpopulations (monocytes, neutrophils, T cells, and B cells), endothelial cells, and adipocytes (42, 49). Mechanisms other than total and visceral adiposity need to be clarified by future studies.

In summary, this study demonstrates that lean mass, visceral fat area, and plasma sTNFR1 concentration were significantly higher in obese postmenopausal women with the MS than in those without the MS. In addition, lean mass, visceral fat area, and sTNFR1 concentrations were independently related to the number of MS components in these women. Thus, obese older women with the MS are characterized by high lean mass, high visceral fat, and increased sTNFR1, and the severity of the syndrome is associated with body composition, visceral fatness, and inflammation.

	Acknowledgments

 
We are grateful to the study coordinators, nurses, laboratory technicians, and exercise physiologists of the Division of Gerontology, University of Maryland School of Medicine, and the Baltimore Veterans Affairs Geriatric Research, Education, and Clinical Center for their assistance with this project. We also thank the laboratory technicians at Wake Forest University School of Medicine for their work on the cytokine assays. Finally, we especially thank all of the women who volunteered to participate in this study.

	Footnotes

 
This work was supported by NIH Grants R01-AG/DK-20583, R01-AG-19310, R29-AG-14066, K01-AG-00747, K01-AG-00685, P60-AG-12583, and P30-AG-21332; the Baltimore Veterans Affairs Geriatric Research, Education, and Clinical Center; and the Baltimore Veterans Affairs Medical Research Service.

First Published Online October 14, 2004

Abbreviations: BMI, Body mass index; BP, blood pressure; CRP, C-reactive protein; HDL-C, high density lipoprotein cholesterol; HOMA, homeostasis model assessment; MS, metabolic syndrome; sTNFR, soluble TNF receptor; TG, triglyceride; VO₂max, maximal aerobic capacity.

Received March 30, 2004.

Accepted July 23, 2004.

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