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Keywords:

  • metabolic syndrome;
  • oxidative stress;
  • inflammation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Objective: Both obesity and the metabolic syndrome (MetS) have been independently linked with increased oxidative and inflammatory stress. This study tested the hypothesis that obesity with MetS is associated with greater oxidative and inflammatory burden compared with obesity alone.

Research Methods and Procedures: Forty-eight normal-weight and 40 obese (20 without MetS; 20 with MetS) adults were studied. MetS was defined according to National Cholesterol Education Program Adult Treatment Panel III criteria. Plasma concentrations of oxidized low-density lipoprotein, C-reactive protein, tumor necrosis factor-α, interleukin (IL)-6, and IL-18 were determined by enzyme immunoassay.

Results: Plasma biomarkers of oxidative stress and inflammation were lowest in normal-weight controls. Of note, obese MetS adults demonstrated significantly higher plasma concentrations of oxidized low-density lipoprotein (62.3 ± 3.2 vs. 54.0 ± 4.0 U/L; p < 0.05), C-reactive protein (3.0 ± 0.6 vs. 1.5 ± 0.3 mg/L; p < 0.01), tumor necrosis factor-α (2.1 ± 0.1 vs. 1.6 ± 0.1 pg/mL; p < 0.05), IL-6 (2.8 ± 0.4 vs. 1.4 ± 0.2 pg/mL; p < 0.01), and IL-18 (253 ± 16 vs. 199 ± 16 pg/mL; p < 0.01), compared with obese adults without MetS.

Discussion: These results suggest that MetS heightens oxidative stress and inflammatory burden in obese adults. Increased oxidative and inflammatory stress may contribute to the greater risk of coronary heart disease and cerebrovascular disease in obese adults with MetS.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Increased oxidative stress and inflammatory stress are recognized as playing an important role in the initiation and progression of atherosclerotic vascular disease (1, 2). For example, oxidized low-density lipoprotein (ox-LDL),1 a marker of oxidative stress, is elevated in subjects with established coronary heart disease (CHD) (1) and is a prognostic marker for the progression of subclinical atherosclerosis (3). Furthermore, elevated pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α (4), interleukin (IL)-6 (5) and IL-18 (6), as well as C-reactive protein (CRP) (7), are markers of systemic inflammation and strong determinants of future atherosclerotic events.

Obesity is associated with increased circulating markers of oxidative stress and low-grade inflammation (8, 9). The metabolic syndrome (MetS), which often accompanies obesity, has also been independently linked with increased oxidative stress and inflammatory burden (10, 11). Importantly, the risk for CHD is markedly greater in obese individuals with MetS compared with those without it (12). A potential mechanism underlying the increased cardiovascular risk in obese adults with MetS may be augmented oxidative stress and inflammatory burden. However, the combined influence of obesity and MetS per se on plasma biomarkers of oxidative and inflammatory stress in otherwise healthy adults is unknown. Accordingly, we tested the hypothesis that obesity with MetS is associated with greater oxidative stress and inflammatory burden compared with obesity alone.

Research Methods and Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Eighty-eight sedentary adults (ages 45 to 75 years) were studied: 48 normal-weight and 40 obese subjects (20 without MetS and 20 with MetS). MetS was diagnosed according to National Cholesterol Education Program Adult Treatment Panel III criteria (13). All subjects were non-smokers, non-medicated, non-diabetic, and free of overt cardiovascular disease as assessed by medical history, physical examination, resting and maximal exercise electrocardiograms, and fasting blood chemistries. All women were at least 1 year postmenopausal and had never taken or had discontinued use of hormone replacement therapy at least 1 year before the start of the study. Before participation, the subjects provided written informed consent according to the guidelines of the University of Colorado at Boulder.

Body mass was measured using a medical beam balance (Detecto, Webb City, MO). Percent body fat was determined by DXA (Lunar Radiation, Madison, WI). BMI and waist circumference were measured according to standard guidelines. Maximal oxygen consumption was determined by using online computer-assisted open-circuit spirometry during incremental exercise on a motorized treadmill. Fasting plasma lipid and lipoprotein, glucose, and insulin concentrations were determined using standard techniques. Plasma concentrations of ox-LDL were determined by enzyme immunoassay (ALPCO Diagnostics, Windham, NH). TNF-α, IL-6, IL-18, and high-sensitivity CRP were determined by enzyme immunoassay (R&D Systems, Minneapolis, MN). Inter- and intra-assay variability for all assays were <7% and 8%, respectively.

Group differences were determined by ANOVA and, when appropriate, post hoc testing using the Newman-Keuls method. There were no significant sex differences in any of the key outcome variables; therefore, the data were pooled and presented together. Because of the skewed distribution of plasma CRP concentrations, the data were log-transformed to satisfy the basic assumptions of parametric testing. However, the absolute values for CRP are presented to facilitate clinical interpretation. All data are expressed as means ± standard error of the mean. Statistical significance was set at p < 0.05.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Selected subject characteristics are shown in Table 1. All indices of adiposity were higher (p < 0.01) in obese adults compared with normal-weight controls. Of note, there were no differences in measures of adiposity and aerobic fitness between the obese adults with MetS and the obese adults without MetS. However, plasma high-density lipoprotein was lowest and triglycerides, glucose, insulin, and homeostasis model assessment of insulin resistance (HOMAIR) were highest (all p < 0.05) in obese MetS adults.

Table 1.  Selected subject characteristics
VariableNormal-weight (n = 48)Obese/no MetS (n = 20)Obese/MetS (n = 20)
  • MetS, metabolic syndrome; Vo2 max, maximal oxygen consumption; BP, blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; HOMAIR, homeostasis model of insulin resistance. Values are means ± standard error of the mean.

  • *

    p < 0.05 vs. normal-weight subjects.

  • p < 0.05 vs. obese subjects without MetS.

Age (years)56 ± 157 ± 258 ± 1
Sex (M/F)24/2413/713/7
Body mass (kg)68.0 ± 1.488.9 ± 2.1*90.8 ± 2.5*
BMI (kg/m2)22.9 ± 0.330.0 ± 0.5*30.7 ± 0.6*
Body fat (%)26.5 ± 1.234.4 ± 1.9*37.5 ± 1.6*
Waist circumference (cm)80.1 ± 1.2100.2 ± 2.1*104.0 ± 1.8*
Vo2 max (L/min)2.3 ± 0.12.7 ± 0.22.4 ± 0.2
Systolic BP (mm Hg)117 ± 1124 ± 2*125 ± 2*
Diastolic BP (mm Hg)75 ± 181 ± 1*80 ± 1*
Total cholesterol (mM)4.9 ± 0.15.0 ± 0.15.2 ± 0.2
LDL-cholesterol (mM)3.1 ± 0.13.2 ± 0.23.3 ± 0.2
HDL-cholesterol (mM)1.4 ± 0.11.3 ± 0.11.0 ± 0.1*
Triglycerides (mM)0.9 ± 0.11.2 ± 0.1*1.9 ± 0.2*
Glucose (mM)4.9 ± 0.15.0 ± 0.15.3 ± 0.1*
Insulin (pM)25.8 ± 1.836.0 ± 4.2*54.6 ± 4.8*
HOMAIR1.0 ± 0.11.3 ± 0.2*2.2 ± 0.2*

Plasma oxidative and inflammatory markers are shown in Figure 1. Plasma ox-LDL (45.1 ± 1.8 U/L), high-sensitivity CRP (0.9 ± 0.2 mg/L), TNF-α (1.5 ± 0.1 pg/mL), and IL-18 (189 ± 8 pg/mL) were lowest in normal-weight controls. Obese MetS adults demonstrated significantly higher plasma concentrations of ox-LDL (62.3 ± 3.2 vs. 54.0 ± 4.0 U/L), high-sensitivity CRP (3.0 ± 0.6 vs. 1.5 ± 0.3 mg/L), TNF-α (2.1 ± 0.1 vs. 1.6 ± 0.1 pg/mL), IL-6 (2.8 ± 0.4 vs. 1.4 ± 0.2 pg/mL), and IL-18 (253 ± 16 vs. 199 ± 16 pg/mL) compared with obese adults without MetS.

image

Figure 1. Plasma concentrations of CRP, TNF-α, IL-6, IL-18, and ox-LDL in normal-weight adults, obese adults without MetS, and obese adults with MetS. Values are means ± standard error of the mean. * p < 0.05 vs. normal-weight adults; † p < 0.05 vs. obese adults without MetS.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

The results of the present study suggest that the presence of MetS exacerbates oxidative and inflammatory stress in obese adults. Indeed, we observed significantly higher systemic markers of oxidative stress and low-grade chronic inflammation in obese adults with MetS compared with obese adults free of MetS. Our findings are consistent with previous studies demonstrating that obesity and MetS are independently associated with increased oxidative stress and inflammatory burden (8, 9, 10, 11). Importantly, however, to our knowledge, this is the first study to demonstrate synergistic effects of obesity and MetS on biomarkers of oxidative stress and inflammation in adults free of overt cardiovascular disease or diabetes.

The mechanisms responsible for the heightened oxidative and inflammatory state in obese adults with MetS are unclear. Adipose tissue is an important mediator of oxidative stress and inflammation, contributing to the production of reactive oxygen species and pro-inflammatory cytokines, including TNF-α, IL-6, and IL-18 (14). Moreover, expression and secretion of these inflammatory mediators increase in proportion to adiposity (15) and are largely determined by body fat distribution. For example, excess visceral fat accumulation, not subcutaneous fat, is associated with greater production of TNF-α (16). However, we do not believe that adiposity is the primary factor underlying the observed differences between the obese groups. Indeed, we observed no influence of uncomplicated obesity on plasma concentrations of TNF-α, IL-6, and IL-18. These factors were elevated only in the obese adults with MetS. A seminal feature of the present study was the similar anthropometric profile (no differences in body mass, BMI, or waist circumference) of the obese adults with and without MetS. Thus, it is logical to suggest that the independent or combined effects of the constellation of risk factors associated with MetS contributed to the greater pro-oxidative, pro-inflammatory state (2). For example, insulin resistance has been reported to exert a greater modulatory influence on CRP concentrations than adiposity (17). In the present study, HOMAIR was 70% higher in the obese MetS adults, and we observed a positive univariate relationship between HOMAIR and CRP in our obese population (r = 0.41, p < 0.05). However, it should be noted that it has also been postulated that chronic low-grade inflammation may underlie the pathogenesis of insulin resistance, demonstrating the complexity of the link between inflammation and MetS. It is also possible that oxidative stress may exacerbate the pro-inflammatory condition with MetS. Reactive oxygen species activate redox-sensitive transcription factors, particularly nuclear factor κB, inducing the expression of pro-inflammatory cytokines including TNF-α and IL-6 (18).

The primary limitation of the present study is its cross-sectional design and the inherent possibility that genetic and/or lifestyle factors may have influenced the results of our group comparisons. However, in an effort to minimize the influence of lifestyle behaviors, we studied subjects of similar age who were non-smokers, who were not currently taking medication that could influence inflammatory and oxidative markers (i.e., statins), and who did not differ in habitual physical activity. In addition, we used strict inclusion criteria to eliminate the confounding effects of underlying cardiovascular and metabolic disease.

From a clinical perspective, it is important to emphasize that the obese MetS subjects in the present study demonstrated hemodynamic and metabolic characteristics that only marginally met National Cholesterol Education Program Adult Treatment Panel III criteria. Nevertheless, the presence of MetS had a significant impact on biomarkers of oxidative stress and systemic inflammation. Enhanced oxidative and inflammatory stress may contribute to the greater risk of CHD and cerebrovascular disease in obese adults with MetS. Future studies are needed to elucidate the mechanisms responsible for the pro-oxidative and pro-inflammatory phenotype in this at risk and largely clinically untreated population.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

This study was supported by NIH Grants HL068030, DK062061, HL076434, and M01 RR00051 and an American Diabetes Association Clinical Research Award. The authors thank Yoli Casas and Heather Irmiger for their technical assistance and the subjects who participated in the study.

Footnotes
  • 1

    Nonstandard abbreviations: ox-LDL, oxidized low-density lipoprotein; CHD, coronary heart disease; TNF-α, tumor necrosis factor-α IL, interleukin; CRP, C-reactive protein; MetS, metabolic syndrome; HOMAIR, homeostasis model assessment of insulin resistance.

  • The costs of publication of this article were defrayed, in part, by the payment of page charges. This article must, therefore, be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  • 1
    Toshima, S., Hasegawa, A., Kurabayashi, M., et al (2000) Circulating oxidized low density lipoprotein levels: a biochemical risk marker for coronary heart disease. Arterioscler Thromb Vasc Biol. 20: 22432247.
  • 2
    Libby, P., Ridker, P. M., Maseri, A. (2002) Inflammation and atherosclerosis. Circulation. 105: 11351143.
  • 3
    Wallenfeldt, K., Fagerberg, B., Wikstrand, J., et al (2004) Oxidized low-density lipoprotein in plasma is a prognostic marker of subclinical atherosclerosis development in clinically healthy men. J Intern Med. 256: 413420.
  • 4
    Ridker, P. M., Rifai, N., Stampfer, M. J., et al (2000) Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 101: 17671772.
  • 5
    Ridker, P. M., Buring, J. E., Shih, J., et al (1998) Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 19621967.
  • 6
    Blankenberg, S., Luc, G., Ducimetiere, P., et al (2003) Interleukin-18 and the risk of coronary heart disease in European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation 24532459.
  • 7
    Koenig, W., Sund, M., Frohlich, M., et al (1999) C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men. Circulation. 99: 237242.
  • 8
    Keaney, J. F., Larson, M. G., Vasan, R. S., et al (2003) Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study. Arterioscler Thromb Vasc Biol. 23: 434439.
  • 9
    Festa, A., D'Agostino, R., Jr, Williams, K., et al (2001) The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord. 25: 14071415.
  • 10
    Hansel, B., Giral, P., Nobecourt, E., et al (2004) Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity. J Clin Endocrinol Metab. 89: 49634971.
  • 11
    Festa, A., D'Agostino, R., Jr, Howard, G., et al (2000) Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 102: 4247.
  • 12
    Lakka, H. M., Laaksonen, D. E., Lakka, T. A., et al (2002) The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 288: 27092716.
  • 13
    Grundy, S. M., Brewer, H. B., Jr, Cleeman, J. I., et al (2004) Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 109: 433438.
  • 14
    Mohamed-Ali, V., Pinkney, J. H., Coppack, SW (1998) Adipose tissue as an endocrine and paracrine organ. Int J Obes Relat Metab Disord. 22: 11451158.
  • 15
    Kern, P. A., Ranganathan, S., Li, C., et al (2001) Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 280: E745E751.
  • 16
    Bertin, E., Nguyen, P., Guenounou, M., et al (2000) Plasma levels of tumor necrosis factor-alpha (TNF-alpha) are essentially dependent on visceral fat amount in type 2 diabetic patients. Diabetes Metab. 26: 178182.
  • 17
    McLaughlin, T., Abbasi, F., Lamendola, C., et al (2002) Differentiation between obesity and insulin resistance in the association with C-reactive protein. Circulation. 106: 29082912.
  • 18
    Lavrovsky, Y., Chatterjee, B., Clark, R. A., et al (2000) Role of redox-regulated transcription factors in inflammation, aging and age-related diseases. Exp Gerontol. 35: 521532.