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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 63:414-419 (2008)
© 2008 The Gerontological Society of America

The Metabolic Syndrome Is Associated With Circulating Adipokines in Older Adults Across a Wide Range of Adiposity

Tongjian You, Barbara J. Nicklas, Jingzhong Ding, Brenda W. J. H. Penninx, Bret H. Goodpaster, Douglas C. Bauer, Frances A. Tylavsky, Tamara B. Harris, Stephen B. Kritchevsky and for the Health, Aging and Body Composition Study

1 Department of Exercise and Nutrition Sciences, University at Buffalo, The State University of New York, Buffalo.
2 Sticht Center on Aging, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
3 EMGO Institute and Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands.
4 Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pennsylvania.
5 Department of Epidemiology and Biostatistics and the Division of General Internal Medicine, University of California, San Francisco.
6 Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis.
7 Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, Maryland.

Address correspondence to Tongjian You, PhD, Department of Exercise and Nutrition Sciences, 214A Kimball Tower, University at Buffalo, Buffalo, NY 14214. E-mail: tyou{at}buffalo.edu


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background. Circulating levels of adipokines are elevated with adiposity and are closely linked with the clustering of traditional metabolic risk factors for cardiovascular disease. The purpose of this study was to examine the relationship of metabolic syndrome to several adipokines and the role of total and visceral adiposity in influencing this relationship in older adults.

Methods. A cross-sectional analysis was conducted including 1914 individuals aged 70–79 years without cardiovascular disease or type 2 diabetes. The metabolic syndrome was defined by the updated Adult Treatment Panel III criteria. Circulating levels of leptin, adiponectin, plasminogen activator inhibitor type 1 (PAI-1), interleukin-6 (IL-6), tumor necrosis factor-{alpha} (TNF-{alpha}), and C-reactive protein (CRP) were measured. Body composition and abdominal visceral fat area were determined.

Results. Both the presence of metabolic syndrome and the number of metabolic syndrome components were associated with higher levels of leptin, PAI-1, IL-6, TNF-{alpha}, and CRP and with lower levels of adiponectin (all p <.0001). The odds ratios for the prevalence of metabolic syndrome associated with adipokines were attenuated after adjustment for total fat mass and/or visceral fat area, but remained significant. Levels of leptin, PAI-1, IL-6, and TNF-{alpha} were higher (all p <.05 to p <.0001), and adiponectin was lower (all p <.0001), in persons with, compared to those without, metabolic syndrome within each tertile of percent body fat.

Conclusion. The metabolic syndrome is associated with adipokines in older adults across a wide range of adiposity, including in those with low or normal overall fatness.

Key Words: Metabolic syndrome • Adipokines • Adiposity • Aging

THE metabolic syndrome describes the clustering of abdominal obesity, lipid abnormalities, hypertension, and hyperglycemia, and is a strong, independent contributor to the onset of coronary heart disease and type 2 diabetes (1). Although the mechanisms underlying the metabolic syndrome are not well understood, current evidence supports that obesity plays a central role (2,3). In addition, a proinflammatory state, as indicated by elevated circulating interleukin-6 (IL-6), tumor necrosis factor-{alpha} (TNF-{alpha}), and the acute phase reactant, C-reactive protein (CRP), as well as a prothrombotic state, evidenced by increased plasminogen activator inhibitor type 1 (PAI-1), are usually present with the metabolic syndrome (4,5).

As an endocrine organ, adipose tissue produces a number of cytokines that contribute to the proinflammatory and prothrombotic states (6). Certain cytokines, such as leptin, are mainly associated with total obesity (7), whereas others such as IL-6, TNF-{alpha}, PAI-1, and adiponectin (an anti-inflammatory cytokine) may be more closely linked with abdominal adiposity (8–13). It has been hypothesized that "adipokines" are a possible link between obesity and the other components of the metabolic syndrome (14). For example, in obese older women, gene expression levels of adipokines in abdominal adipose tissue are associated with hyperinsulinemia, glucose intolerance, and the metabolic syndrome (15).

Although prevalence of metabolic syndrome is greater in obese people, not all obese persons have metabolic syndrome, and it is also present in nonobese individuals (16,17). However, whether levels of adipokines are altered in lean persons with metabolic syndrome, and how total and abdominal adiposity may influence the relationship between metabolic syndrome and levels of adipokines, is not known. Thus, the purpose of this study was to determine: (i) whether the presence and severity of the metabolic syndrome (number of syndrome components) are associated with circulating adipokine levels; (ii) whether this association is influenced by total or visceral adiposity; and (iii) whether this association exists in a wide range of adiposity, as indicated by percent body fat tertiles.


   METHODS
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Participants
Participants were older individuals participating in the Health, Aging, and Body Composition (Health ABC) Study. The Health ABC cohort included 3075 well-functioning, community-dwelling men and women who were recruited primarily from a random sample of white and all black Medicare beneficiaries residing in designated ZIP code areas surrounding Pittsburgh, Pennsylvania, and Memphis, Tennessee. The study protocol was approved by the institutional review boards of both study sites, and all participants provided written informed consent.

Data included in this investigation were collected at the baseline visit. Participants with missing data on metabolic syndrome components, body composition, or abdominal visceral fat (total N = 208) were excluded. For the rest of the participants, individuals with diabetic fasting glucose (≥126 mg/dL) or currently taking glucose-lowering drugs and/or those with coronary heart disease or currently on anti-anginal treatment (total N = 953) were also excluded. Thus, a total of 1914 participants were studied.

Criteria for Metabolic Syndrome
The metabolic syndrome was defined following the updated National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) definition in 2005 (5), as the presence of three or more of the following five risk components: (i) waist circumference ≥102 cm for men and ≥88 cm for women; (ii) triglycerides (TG) ≥150 mg/dL, or currently on drug treatment for high TG; (iii) high-density lipoprotein (HDL) cholesterol <40 mg/dL for men and <50 mg/dL for women, or currently on drug treatment for low HDL cholesterol; (iv) blood pressure (BP) ≥130/85 mmHg, or currently on antihypertensive drug treatment; (v) fasting glucose ≥100 mg/dL. Waist girth was measured as the smallest circumference at the level of the navel. Systolic and diastolic BPs were determined using a conventional mercury sphygmomanometer with the participant in a seated position. Blood samples were drawn after an overnight fast and analyzed for TG and HDL cholesterol using a chemical analyzer (Vitros 950; Johnson & Johnson, Raritan, NJ). Plasma glucose was determined using the automated glucose oxidase reaction (YSI 2300 Glucose Analyzer; Yellow Springs Instruments, Yellow Springs, OH). In the Health ABC study, we identified gemfibrozil and nicotinic acid as drugs for the treatment of high TG and low HDL cholesterol.

Body Composition
Body weight and height were measured with participants in a standing position, wearing light clothing and without shoes, and body mass index (BMI) was calculated as weight divided by the square of height (kg/m2). Body fat mass, lean mass, and percent body fat were determined by dual-energy x-ray absorptiometry (QDR 4500; Hologic Inc, Waltham, MA). Abdominal subcutaneous and visceral fat areas were determined on a single axial image at the L4-5 vertebral disk space obtained by computed tomography in Pittsburgh (9800 Advantage; General Electric Co, Milwaukee, WI) and Memphis (Somatom Plus; Siemens, Iselin, NJ or PQ2000S; Picker, Cleveland, OH).

Adipokines
Circulating levels of leptin, adiponectin, PAI-1, IL-6, TNF-{alpha}, and CRP were all measured in duplicate. Serum leptin and adiponectin concentrations were measured by radioimmunoassay (Linco Research Inc., St. Charles, MO). The intra-assay coefficient of variation was 3.7%–7.5% for leptin and 1.8%–3.6% for adiponectin. Plasma PAI-1 was measured by a two-site enzyme-linked immunosorbent assay (ELISA; Collen Laboratory, Belgium) with a coefficient of variation of 3.5%. Serum IL-6 and plasma TNF-{alpha} were measured by Quantikine HS ELISA kits (R&D Systems, Minneapolis, MN). The coefficients of variation were 10.3 for IL-6 and 16% for TNF-{alpha}, respectively. Plasma levels of CRP were measured using ELISA with anti-CRP antibodies (Calbiochem, San Diego, CA) with a coefficient of variation of 8.0%.

Statistical Analyses
Differences in continuous variables of sociodemographics, body composition and adipokines between individuals with and without metabolic syndrome, or each metabolic syndrome component, were evaluated by the t test for normally distributed variables, or by the Wilcoxon rank-sum test for variables that were not normally distributed. Differences in categorical sociodemographic variables between those with and without metabolic syndrome were evaluated by the chi-square test. Because data for physical activity and adipokines were not normally distributed, median values with interquartile ranges were reported, and log-transformed values were used for the following analyses. Adipokines were compared across individuals with 0, 1, 2, 3, 4, and 5 metabolic syndrome risk components, and the p values for trend were assessed using linear regression. Logistic regression was used to evaluate the probability of metabolic syndrome as a function of each adipokine after adjusting for different factors. Odds ratios and 95% confidence intervals (CI) were used to express the odds ratios of metabolic syndrome. To permit direct comparison between adipokines, odds were evaluated per standard deviation in adipokine increment. Finally, adipokines were compared using t test between individuals with and without metabolic syndrome separately in percent fat tertiles by adjusting for different factors, and using analysis of variance across percent fat tertiles in those with and without metabolic syndrome by adjusting for different factors.


   RESULTS
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Discussion
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Of the 1914 participants with complete data and without prevalent cardiovascular disease or diabetes at the baseline visit of the Health ABC Study, 666 (34.8%) had the metabolic syndrome (Table 1). The prevalence of metabolic syndrome was higher in women and whites, and lower in current smokers. Individuals with the metabolic syndrome had higher body weight, BMI, fat mass, lean mass, percent body fat, and abdominal subcutaneous and visceral fat area compared to those without metabolic syndrome. In addition, those with metabolic syndrome had higher circulating levels of leptin, PAI-1, IL-6, TNF-{alpha}, and CRP, and lower levels of adiponectin.


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  		Table 1. Sociodemographics, Body Composition, and Adipokines in Older Individuals With (MS+) and Without (MS–) the Metabolic Syndrome.

 
Circulating levels of adipokines were also compared across individuals with a different number of metabolic syndrome risk components (Table 2). The numbers of individuals with 0, 1, 2, 3, 4, and 5 risk components were 140 (7.3%), 498 (26.0%), 610 (31.9%), 420 (21.9%), 193 (10.1%), and 53 (2.8%), respectively. There was a significant linear trend for higher levels of leptin, PAI-1, IL-6, TNF-{alpha}, and CRP, and lower levels of adiponectin, with increasing number of metabolic syndrome components.


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  		Table 2. Association Between Adipokines With the Number of Metabolic Syndrome Components.

 
The odds ratios of having metabolic syndrome as a function of each adipokine before and after adjustment for several factors are shown in Table 3. In the model adjusted for age, gender, race, and site (Model 1), metabolic syndrome was significantly associated with increments in all adipokines, but it was more strongly linked with leptin (2.63 [2.24–3.08]), PAI-1 (2.26 [2.01–2.54]), and adiponectin (0.47 [0.42–0.53]). Adjustment for all sociodemographics (age, race, gender, site, education, alcohol use, smoking status, and physical activity) only slightly attenuated the associations between metabolic syndrome and adipokines (Model 2). The associations remained significant after additional adjustment for height and fat mass (Model 3), or height and visceral fat area (Model 4), although the odds ratios were attenuated. Moreover, the associations were still significant after adjustment for height, fat mass, and visceral fat area (Model 5). The association of metabolic syndrome to leptin was closer between Models 3 and 5, suggesting that this association was affected mostly by total fat mass. The association of metabolic syndrome to adiponectin, PAI-1, IL-6, and TNF-{alpha} was similar between Models 4 and 5, indicating that those associations were influenced more by visceral fat area. The association between metabolic syndrome and CRP was about equally influenced by body fat mass and visceral fat area. The presence of metabolic syndrome was more strongly linked with levels of adiponectin, PAI-1, and TNF-{alpha} compared to other adipokines, independent of total and visceral adiposity.


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  		Table 3. Odds Ratios for Metabolic Syndrome Associated With Adipokines After Adjustment for Different Factors.

 
Circulating levels of adipokines were compared between individuals with and without the metabolic syndrome within tertiles of percent body fat. The mean percent body fat for each tertile was 25.3 ± 3.6%, 34.4 ± 2.5%, and 43.3 ± 3.2%, respectively. After adjustment for all sociodemographics, levels of leptin, PAI-1, IL-6, TNF-{alpha}, and CRP were higher or tended to be higher, and levels of adiponectin were lower in those with metabolic syndrome in all three adiposity tertiles (Figure 1). In addition, adipokines were compared among different percent body fat tertiles in individuals with and without the metabolic syndrome, after adjustment for sociodemographics. Levels of leptin, PAI-1, IL-6, and CRP were significantly higher with an increase in percent fat tertile in both individuals with and without the metabolic syndrome. Levels of TNF-{alpha} were elevated, and levels of adiponectin were lower, with a higher percent fat tertile only in individuals without the metabolic syndrome.


Figure 01
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  		Figure 1. Adipokines in older individuals with the metabolic syndrome (MS+, filled bars) and without (MS–, open bars) across percent fat tertiles. Expressed as median (25%, 75%). p values were after adjustment for sociodemographics (age, race, gender, site, education, alcohol use, smoking, and physical activity). Percent body fat tertile 1: <30.2% (MS–: n = 524, MS+: n = 114); tertile 2: 30.2%–38.7% (MS–: n = 405, MS+: n = 233); tertile 3: >38.7% (MS–: n = 319, MS+: n = 319). *p <.05; {dagger}p <.01; §p <.0001 compared with MS–

 

   DISCUSSION
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 Methods
 Results
 Discussion
References
 
These findings show that the presence and severity (number of components) of the metabolic syndrome are highly associated with circulating levels of adipokines in well-functioning older adults 70–79 years old. The association between the presence of metabolic syndrome and these adipokines is partially attenuated by fat mass and visceral fat area, but remains significant after adjustment for these adiposity measures. In addition, this association is present in a wide range of adiposity in these older individuals, including in those with normal percent fat (<30%).

Previous studies indicate that both the presence and severity of metabolic syndrome are associated with circulating levels of various inflammatory markers and cytokines in different populations, including healthy women (18), women with suspected myocardial ischemia (19), healthy Japanese men (20), individuals with type 2 diabetes (21), and obese individuals (16,22–25). Most of these studies show that the presence of metabolic syndrome or number of metabolic syndrome components is positively linked with levels of adipokines or inflammatory markers, such as IL-6 (24), TNF-{alpha} (22), PAI-1 (21,25), and CRP (18–21,24,25), and is inversely related to levels of anti-inflammatory cytokines, such as adiponectin (20,22,24,25) and IL-10 (23,24). Some studies did not find such a relationship between the metabolic syndrome and CRP, IL-6, or TNF-{alpha}, possibly due to a small sample size (16), or special study population (20). Most of these studies were conducted in young or middle-aged individuals. Whether the metabolic syndrome is linked with adipokines in well-functioning elderly persons, especially those during their late life, has not been reported elsewhere. Therefore, our findings are of importance for linking circulating levels of adipokines and metabolic syndrome in a population of older adults in whom there appeared no overt disease. Indeed, the metabolic syndrome is strongly associated with subclinical atherosclerosis and aortic stiffness (26), and strikingly predicts new onset of diabetes and coronary heart disease (27), which are highly prevalent in older individuals.

Our results also demonstrate that, in older adults, the association of metabolic syndrome to circulating adipokines is attenuated by, but independent of, total or visceral adiposity. Adipose tissue secrets a number of cytokines that may contribute to circulating levels of these cytokines. Other cell types, such as muscular cells or mononuclear cells, also produce these cytokines (28,29). The role of muscle-derived cytokines is still not entirely known. A possible effect of muscle-derived cytokines, such as proinflammatory cytokine IL-6, is to stimulate adipose tissue lipolysis, in response to muscle contractions during physical exercise (29). Interestingly, expression levels of IL-6 and TNF-{alpha} from circulating mononuclear cells are elevated in obesity, which may contribute largely to circulating inflammation. However, whether this part of cytokine production is proportional to the extent of adiposity still needs to be further studied (28). In addition, the role of adipose tissue in inflammation may not be limited to adipose tissue mass. Variation in cytokine gene expression from adipose tissue may also be an important factor. Visceral adipose tissue, for example, may release higher levels of proinflammatory (8,9) and prothrombotic cytokines (10), and lower levels of anti-inflammatory cytokines (11), than subcutaneous adipose tissue.

Previous findings in newly diagnosed type 2 diabetics support that the association between metabolic syndrome and circulating CRP is dependent on BMI; however, the metabolic syndrome is still associated with circulating PAI-1 after adjustment for BMI (21). Another study conducted in women with suspected myocardial ischemia further indicates that the circulating inflammatory marker CRP is more closely linked with metabolic syndrome than BMI is, and that metabolic syndrome, but not BMI, predicts future cardiovascular risk (30). The authors suggest that, although it remains prudent to recommend weight loss to overweight and obese individuals, control of other modifiable risk factors are important to prevent transition to the metabolic syndrome in nonobese individuals. In the current investigation, we found that the association between the metabolic syndrome and adipokines was present across a wide range of adiposity, including in those with normal percent body fat. These findings further indicate that weight loss alone may not be the most effective intervention to affect adipokines and reduce metabolic risk in all persons. Genetic and other behavioral factors may play important roles in the link between metabolic syndrome and cytokines. Indeed, before reversal of obesity, even a short-term diet and exercise intervention reduces inflammation and metabolic risk in individuals with the metabolic syndrome (31). Moreover, although we adjusted for the amount of physical activity, data on the type, intensity, and duration of physical exercise were not collected and adjusted. Therefore, future studies need to consider influence of these factors on the relationship between metabolic syndrome and these adipokines.

Summary
The metabolic syndrome is associated with circulating adipokines in well-functioning older adults aged 70–79 years old. This association is independent of percent body fat and visceral adiposity, and is present across a wide range of adiposity in these older individuals. Future studies are needed to identify other genetic or behavior risk factors that may contribute to this association and the best strategy for lowering inflammation and the prevalence of metabolic syndrome in older adults.


   Acknowledgments
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The Health ABC Study was funded through the National Institute on Aging, contracts N01–AG-62101, N01-AG-62103, and N01-AG-62106. This study was also supported in part by the Intramural Research Program of the National Institute on Aging. Drs. You, Nicklas, Ding, and Kritchevsky were supported by the Wake Forest University Claude D. Pepper Older Americans Independence Center (National Institute on Aging grant P30–AG-21332), and Drs. You and Nicklas were also supported by National Institutes of Health grant R01-AG/DK-20583.


   Footnotes
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Decision Editor: Luigi Ferrucci, MD, PhD

Received April 11, 2007

Accepted June 28, 2007


   References
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