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Original Article |
Center for Obesity Management, Department of Geriatrics and Metabolic Diseases, Chair of Plastic and Reconstructive Surgery, Second University of Naples, 80138 Naples, Italy
Address all correspondence and requests for reprints to: Dr. Katherine Esposito, Department of Geriatrics and Metabolic Diseases, Second University of Naples, Piazza L. Miraglia, 80138 Naples, Italy. E-mail: . katherine.esposito{at}unina2.it
Abstract
Obesity is associated with an increased risk of developing atherosclerosis, which may be mediated, at least in part, by increased secretion of proinflammatory cytokines by adipose tissue. We examined the hypothesis that circulating levels of IL-18 were elevated in obese women and would be reduced by weight loss. In a sample of 40 obese (body mass index, 36.4 ± 3.1 kg/m2) women we found that plasma IL-18 levels were higher than in 40 normal weight control women (P < 0.01) and were positively associated with body weight (r = 0.46; P < 0.01) and visceral fat (waist to hip ratio; r = 0.39; P < 0.01). Caloric restriction-induced weight loss (
10% of original weight) over 1 yr reduced IL-18 levels from 247 (204/309) to 147 (111/210) pg/ml (medians and 25%/75%; P < 0.01), positively associated with changes in body mass index and waist to hip ratio. In obese women, IL-18 levels are associated with body weight and abdominal fat deposition; weight loss is an important intervention to reduce IL-18 levels. IL-18 may be a novel cytokine operating in human obesity.
OBESITY IS A common condition on every continent. National surveys in the United States have shown a prevalence of obesity of 20% in men and 25% in women (1). The striking increase in prevalence in the last 2 decades of the past century also indicates that a population-wide increase in obesity may occur over a short period of time. Visceral obesity is an important predictor of cardiovascular disease (2). Visceral fat is a key regulator of inflammation, as it secretes proinflammatory cytokines that may be relevant to the process of atherogenesis (3). In this context, TNF
and IL-6 seem to play a major role, because they are expressed and released by adipose tissue (4, 5), can influence endothelial function (6), and induce endothelial expression of chemokines and adhesion molecules (7), which are central in the early stage of the atherogenetic process (8). Atherosclerosis is now recognized as a disorder characterized by a chronic alteration of inflammatory functions, and key markers of inflammation, including IL-6 and TNF-, and several adhesion molecules have been linked to the future occurrence of myocardial infarction and stroke in both healthy populations and those with known coronary disease (9).
IL-18 is a potent proinflammatory cytokine with potential atherogenetic properties through effects on IL-6, TNF-, and interferon-
(10). Until now, there have been no reported studies that evaluated circulating IL-18 levels in human obesity. The aims of the present study were to determine whether circulating levels of IL-18 are elevated in obese women and whether they could be reduced by a substantial decrease in body weight.
Subjects and Methods
We studied 40 obese and 40 age-matched, normal weight, premenopausal women, aged 25–40 yr. Obese women were recruited from those attending the center for obesity management and were followed as out-patients; normal weight women were recruited from the medical and paramedical staff of our department and volunteered to serve as the control group. All women were free from type 2 diabetes, hypertension, cardiovascular disease, and alcohol abuse; none smoked or took any drug. All had normal glucose tolerance, as evidenced by a 2-h postload plasma glucose level below 7.8 mmol/liter. Each woman gave informed written consent to participate in this study, which was approved by the institutional committee of ethical practice of our institution.
Obese women entered into a medically supervised weight loss program aimed at reducing body weight to 90% of baseline. The program consisted of a 1300 kcal/d diet (55% carbohydrate, 30% lipid, and 15% protein) associated with behavioral and nutritional counseling. Women were in the weight loss program for 12 months and were followed on an out-patient basis at 1-month intervals.
All women were studied after a 14-h overnight fast, within the first week after the end of menstrual bleeding and were required to refrain from drinking alcohol in the previous 10 d. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. The waist to hip ratio (WHR) was calculated as waist circumference in centimeters divided by hip circumference in centimeters. Routine chemical analyses were assessed in the hospital’s chemistry laboratory. Plasma insulin levels were assayed by RIA (Ares Serono, Milan, Italy). Serum samples for IL-18 were stored at -80 C and were assayed in duplicate with an immunosorbent kit (R\|[amp ]\|D Systems, Inc., Minneapolis, MN). Dilution curves of serum samples were parallel those of standard. Intra- and interassay coefficients of variations were 4% and 6%, respectively; the detection limit was 3 pg/ml.
Data are presented as the group mean (SD), except for IL-18, values of which are presented as the median (25%/75%). For a desired value of P = 0.05 and 80% power to detect an actual difference, a sample size of 20/group was considered satisfactory. A preliminary ANOVA was used to assess the significance between and within groups. One-sample t tests were used to compare values obtained before and after weight loss, and two-samples t tests were used for between-group comparisons. Pearson’s simple correlation allowed studying the association between 2 variables. Multivariate regression analysis tested the independent association and contribution of changes in BMI and WHR with the dependent variable (IL-18). P < 0.05 was considered significant. All calculations were made on an IBM PC computer (SPSS, Inc., Chicago, IL; version 9.0).
Results
The characteristics of the study women are shown in Table 1
. Compared with nonobese women, obese women had higher fasting glucose and insulin concentrations; by contrast, lipid levels were not different between the two groups. IL-18 concentrations were higher in obese women than in control women (Table 1 and Fig. 1), although there was overlap between values. The relationships between plasma IL-18 levels and metabolic parameters are shown in Table 2. Plasma IL-18 levels were positively associated with body weight, BMI, and WHR. Associations between IL-18 levels and variables of the lipid profile were not significant. We also found a significant association between IL-18 and fasting insulin levels. Thus, elevated IL-18 levels were observed primarily in women who were more obese and had more visceral fat and higher insulin levels. To examine independent predictors of IL-18 levels, we performed stepwise multiple regression analyses: the best predictors of IL-18 levels were BMI and WHR, which explained 36% of the variance (P < 0.01).
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). Weight loss also induced a significant reduction in serum IL-18 levels: the magnitude and significance of the weight-loss-induced difference were similar whether parametric (paired t test) or nonparametric (Wilcoxon matched test, not shown) tests were used. Changes in BMI (r = 0.44; P < 0.01) and WHR (r = 0.34; P < 0.02) were associated with reductions in serum IL-18 levels. For evaluating the independent association of changes in IL-18 levels with changes in body weight, a multivariate analysis was performed in which the IL-18 level was the dependent variable, and BMI, WHR, and plasma glucose, insulin, and triglyceride levels were the independent variables. Changes in BMI, WHR, and insulin levels explained 22%, 19%, and 11%, respectively, of the variability in IL-18 levels. Discussion
This is the first demonstration that circulating IL-18 levels are elevated in human obesity and that weight loss is associated with proportional reductions in IL-18 levels. IL-18 is a pleiotropic cytokine acting in both acquired and innate immunity (10). Beside acting as a proinflammatory cytokine by inducing the expression of adhesion molecules, IL-18 is able to stimulate the production of granulocyte-macrophage colony-stimulating factor, TNF, and inducible nitric oxide synthase by mononuclear and mesenchymal cells (10). Interestingly, increased circulating levels of adhesion molecules have been found to be elevated in nondiabetic obese men (11) and women (12); even in diabetes mellitus, the level of adiposity is a significant predictor of plasma levels of adhesion molecules (13, 14). Moreover, circulating concentrations of TNF have been found to be associated with BMI (2, 12).
Until now, IL-18 secretion from adipose tissue has never been reported; however, the relation we found among IL-18 levels, body weight, and visceral adiposity as well as between changes in body weight and parallel changes in IL-18 levels after weight loss suggest that a likely site for IL-18 production may be the adipose tissue.
Obesity is associated with an increased risk of developing atherosclerosis, which may be mediated, at least in part, by increased secretion of proinflammatory cytokines by adipose tissue. For example, both IL-6 and TNF are released by adipose tissue (3) and can induce endothelial expression of chemokines and adhesion molecules (7), which are central in the early stage of the atherogenetic process (8). Moreover, prospective epidemiological studies have found increased vascular risk in association with increased levels of both IL-6 and TNF (15, 16, 17). As IL-18 induces the production of TNF, which, in turn, promotes the synthesis of IL-6 (18), it could be speculated that IL-18 may be involved in the increased cardiovascular risk of the obese patient. Consistent with this possibility, in human atheroma in situ, IL-18 signaling evokes effectors involved in atherogenesis, such as IL-6, intracellular adhesion molecule-1, and matrix metalloproteinases 1, 9, and 13 (19); moreover, higher levels of IL-18 mRNA have been found in unstable than stable atherosclerotic plaques, suggesting a role for IL-18 in plaque destabilization (20).
From a clinical perspective, it is reassuring that lifestyle changes can so effectively reduce rates of both atherosclerosis and type 2 diabetes in the population (9). In particular, weight loss seems to represent a safe method for down-regulating an individual’s inflammatory status. Both short-term (12 wk) and long-term (12 months) intervention studies aimed at evaluating the effect of weight loss on circulating inflammatory markers have found that weight reduction averaging from 5–15% of initial body weight, resulted in significant decrease in circulating C-reactive protein, IL-6, TNF, and adhesion molecule levels (12, 21, 22, 23).
This study shows that in obese women, IL-18 levels are associated with body weight and abdominal fat deposition. These results suggest a novel paracrine pathway operating in human obesity and demonstrate that weight loss is an important intervention to reduce IL-18 levels.
Acknowledgments
Footnotes
Abbreviations: BMI, Body mass index; WHR, waist to hip ratio.
Received March 31, 2002.
Accepted May 15, 2002.
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