HORMONES 2006,5(3):192-199
Research Paper
Plasma Interleukin-6 levels, glutathione peroxidase and isoprostane in obese women before and after weight loss. Association with cardiovascular risk factors
Maria Bougoulia, Athanassios Triantos, George Koliakos

Biochemistry Department, Aristotele University Medical School, Thessaloniki, Greece


OBJECTIVE: To evaluate the levels of Interleukin-6 (IL-6), glutathione peroxidase and iso­prostane in obese women and their association with markers of cardiovascular risk factors before and after weight loss. DESIGN: 36 healthy obese women of reproductive age (group A: age (mean ±SD) 35.4 ± 9.2 years, Body Mass Index (BMI) 38.5±7 kg/m2) and 30 healthy, normal weight women (group B: age mean ±SD 34.9±7.4y., BMI 24±1.1 kg/m2) were included in the study. Glucose tolerance was normal in all participating women. Il-6, glutathione perox­idase and isoprostane, C-Reactive Protein (CRP), insulin, fasting plasma glucose, HOMA-IR as well as the lipid profile were evaluated. Body weight, BMI, Waist to Hip ratio (W/H) ratio, Waist Circumference (WC), %free fat mass and the %fat mass were also measured. A hypo-caloric diet was prescribed for the obese women and all participants were re-examined after six months. RESULTS: In obese women after weight loss, anthropometric obesity markers (BMI, W/H ratio), %fat, lipid profile, insulin levels and inflamation indices such as IL-6 and CRP, the oxidative stress index isoprostane, as well as glutathione peroxidase were signifi­cantly ameliorated. The levels of serum glutathione peroxidase activity were negatively corre­lated with IL-6 levels and were significantly increased after weight reduction. In obese women there was an association between IL-6 levels and the values of %fat, %free fat mass, insulin and HOMA-IR before and after weight loss. CONCLUSIONS: Weight loss is related to reduc­tion of oxidative stress and inflammation; this beneficial effect could possibly be translated into reduction of cardiovascular risk in obese individuals.


Body mass index, C-reactive protein, Glutathione peroxidase, Interleukin-6, Iso­prostane, Obesity

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Obesity is the most common metabolic disorder in developing countries and is characterized by a re­duction in insulin sensitivity, both in animal models and in humans.1 Obesity has been associated with increased cardiovascular morbidity and mortality2-4 and is now considered a major independent risk fac­tor for coronary heart disease.5 Furthermore, the degree of abdominal adiposity conveys an indepen­dent prediction of risk beyond body mass index (BMI) for cardiovascular pathology.4,6,7 Vascular endothelial dysfunction (VED) plays a pivotal role in the pathogenesis of atherosclerosis8 and enhanc­es the risk for future cardiovascular events. The pres­ence of VED has been demonstrated in overweight patients with insulin resistance9 and with visceral obesity.9,10 Therefore, VED may be an important link between obesity per se and heightened cardiovas­cular risk. However, the molecular mechanisms in­volved in obesity-related insulin resistance are not yet well understood.11 It has been clearly demon­strated that adipocytes are able to synthesize and secrete several cytokines, such as leptin,12 tumor ne­crosis factor (TNFα)13 and interleukin-6 (IL-6).14 Re­cently an attractive hypothesis has emerged propos­ing that cytokines produced by adipose tissue may be responsible for insulin resistance in obesity.2-5

IL-6 is a cytokine produced by different cell types, including immune and adipose tissue cells, and me­diates inflammatory responses. Unlike other cyto­kines, IL-6 is distinct in that its major effects take place at sites distant from its origin. For this reason IL-6 has come to be known as "the endocrine cy­tokine". Circulating IL-6 levels constitute a signifi­cant proatherogenic cytokine.

The role of chronic inflammation in atheroscle­rosis has become well established during the past decade. Numerous epidemiological studies have demonstrated an association of CRP levels with in­creased risk of myocardial infarction (MI), stroke, sudden cardiovascular death and peripheral vascu­lar disease.15 Furthermore, the synthesis of CRP by the liver has been shown to be largely regulated by IL-6.15,16

Recently reported population-based data from the Women.s Health Study demonstrated that a sin­gle nonfasting measurement of CRP1 is a stronger predictor of future cardiovascular events than LDL cholesterol,2 identifies at-risk individuals with low LDL cholesterol levels and3 adds prognostic infor­mation to the currently used Framingham risk algo­rithm.17

It has recently been reported that F2 isoprostanes are the most reliable indicators of oxidative stress, although their role in pathophysiologic processes is unknown.18 The measurement of F2 isoprostanes may represent an important development in the as­sessment of free radical generation and oxidative stress in vivo. Glutathione peroxidase is an antioxi­dant enzyme that reduces hydrogen peroxide and lipid peroxides. In the reduced state, glutathione (GSH) is an indirect indicator of oxidative stress. GSH may also be an important antiatherogenic agent, is present in human plasma and intracellu­larly, has antioxidant properties by inhibiting free radical formation and generally functions as a re­dox buffer.19

The above data underline the need for further clarification of the metabolic and endocrine func­tion of adipose tissue in obese subjects. We thus sought to investigate the relationships between cy­tokines, proinflammatory products and oxidative stress, as well as their relation to cardiovascular risk factor in obese women and their possible modifica­tion by weight reduction.


Thirty-six obese women of reproductive age (group A: mean ±SD age 35.4±9.2yr, BMI 38.5±7 kg/m2) and 30 normal weight women (group B: mean ±SD age 34.9±7.4yr, BMI 24±1.1 kg/m2) were stud­ied. All participants were informed about the ob­jectives of the study and volunteered to participate. All individuals included in the study (groups A and B) had two menses in the 3 months before the test­ing and displayed a normal response to oral glucose tolerance test (OGTT).

Additional exclusion criteria included diabetes mellitus, hormone replacement therapy, pregnan­cy, lactation, psychiatric or neurological disorders, alcohol abuse, a history or the presence of malig­nancy, coronary heart disease and cerebrovascular disease. Continuing use of antihypertensive medi­cation was permitted provided that the dose had been stable for at least 3 months before entry into the study.

None of the subjects was taking any medication known to influence lipid metabolism. Apart from obesity, all obese subjects were in good health and had maintained stable body weight for at least 12 months prior to entering the study. None was en­gaged in any type of exercise program or was exces­sively sedentary. All participants underwent physi­cal examination, measurement of fat mass and com­plete biochemical investigations.

Anthropometric parameters such as Body Weight (BW), height, BMI, Waist Circumference (WC), Waist to Hip ratio (W/H) and %Body fat as well %Free fat mass (FFM) were also evaluated.

Weight in Kg was determined using a standard beam-balance scale and with the subjects barefoot and wearing light indoor clothing. Height in centi­meters was measured using a meter rule built into the scale. BMI was calculated by dividing weight in Kg by height in meters squared. Obesity was defined as a BMI value greater than 30 kg/m2. Waist cir­cumference was measured with a flexible measur­ing tape, taking as a reference the midway line be­tween the costal inferior border and the iliac crest. Body fat mass was evaluated by a bioelectric imped­ance analysis device (Bodystat Ltd, Isle of Man, Bodystat 1500).

Morning fasting blood samples were obtained both at entrance to the study and after the treat­ment period. All biochemical measurements were performed on frozen plasma samples obtained by centrifugation of the freshly drawn blood (3000 Xg for 20 min at 4°C) and subsequent storage at -70°C.

The tests included measurement of insulin, IL­6, CRP, glutathione peroxidase activity and isopros­tane.

Bio-electrical impedance analysis (BIA), a meth­od that measures the impedance or opposition to the flow of an electric current through the body flu­ids, was evaluated as follows: a small constant cur­rent, typically 400 uA at a fixed frequency, usually 50 kHz, passed between electrodes spanning the body and the voltage drop between electrodes pro­vided a measure of impedance.

Prediction equations, previously generated by correlating impedance measures against an indepen­dent estimate of TBW, were used subsequently to convert measured impedance to a corresponding estimate of TBW. Lean body mass was then calcu­lated from this estimate using an assumed hydra­tion fraction for lean tissue. Fat mass was calculat­ed as the difference between body weight and lean body mass.20,21

OGTT was performed as follows: all subjects in­gested a 75g glucose solution after an overnight fast. Serum samples were collected before and 30, 60, 90 and 120 min after the glucose load. The criteria de­veloped by the World Health Organization Expert Committee on Diabetes Mellitus were used to de­termine whether a subject was not diabetic (2-h glu­cose concentration <140 mg/dl).22 Insulin resistance was calculated based on homeostasis model assess­ment (HOMA-IR) index. The homeostasis model assessment (HOMA) has been suggested as a meth­od to assess IR and is calculated using the formula HOMA-IR=fasting insulin (units/ml) x fasting glu­cose (mmol/l)/22.5).23

Obese women were subscribed a hypocaloric diet according to the following calculation: [18-40 y= 0.0621x weight in Kg+2.0357=-mJ/day x 240=- -Kcal/day, adjusting with daily activities: --Kcal/ day x-coefficient of daily activities=--Kcal/day, in order to have hypocaloric diet --Kcal/day­600Kcal/day].24 The energy distribution of this diet was 50% carbohydrates, 30% fat and 20% protein and the duration of dietary intervention was 6 months.

Serum glucose levels were measured using the chromatographic method (bioanalyzer Wako Che­micals GmbH), cholesterol, triglyceride and HDL were measured by standardized laboratory methods and LDL-cholesterol level was calculated with the Friedewald formula. Insulin by immunoradiomet­ric assay using a Sorin-Biomedica Kit (Saluggia, Ita­ly). The lower limits of detection for insulin was 0.3 µIU/ml while inter-assay and intra-assay coefficients of variation (CV) were 6.9 and 6.4%, respectively. Normal range for our laboratory is 2-25 µIU/ml.

IL-6 levels were determined by enzyme-linked immunosorbent assay (Quantikine High Sensitivity IL-6; R&D Systems, Oxford, UK). The sensitivity of this assay was 0.70 pg/mL IL-6. Plasma levels of peroxidase of glutathione were determined by use of an enzymatic assay (BIOXYTECH of company OxisResearch, Inc Portland, USA) that allows a re­covery of GSH >90% and has no appreciable inter­ference with other thiols present in the plasma or in the reactive mixture; meanwhile, levels of isopros­tane (8-iso-PGF2) were determined using the en­zymatic method elisa by Assay Designs' Corre­late-EIA™ Direct 8-iso-Prostaglandin F2kit.

Statistical methods

For statistical analysis the statistical package SPSS 11.5. (SPSS, Chicago, IL, USA) was used. Results are expressed as mean ± standard devia­tion (SD). Normality was assessed by the Kolmog­orov-Smirnov test. The unpaired Student-t test was used for comparisons between normal and obese individuals. The paired Student-t test was used for comparisons between baseline and 6 months of treatment in obese women. For correlations the Pearson correlation coefficient was used. P-values
<0.05 were considered statistically significant.


The results of this study showed significant dif­ferences between group A and group B with regard to the anthropometric parameters %body fat and %free fat mass (p <0.001) but not the age (Table 1 ).

The mean values of cholesterol, triglycerides and LDL cholesterol were not significantly different be­tween the obese and the controls, whereas HDL lev­els were significantly lower in the obese group than in the normal weight group (Table 2) .

The mean values of CRP, insulin, IL-6, HOMA­IR and isoprostane were significantly higher in the obese women as compared to the normal weight controls (p<0.001) (Table 2)).

Glutathione peroxidase was significantly lower in the obese women than in the controls (p<0.001) (Table 2)).

The biochemical and hormonal values as well as anthropometric indices in the obese women before and after weight reduction are presented in Table 3 .

The mean weight, BMI, W/H ratio, waist circum­ference, %, body fat, cholesterol, triglycerides, CRP, insulin, HOMA-IR, interleukin-6 and isoprostane were significantly reduced after weight loss (p<0.001), whereas glutathione peroxidase was sig­nificantly increased after weight reduction (p <0.001).

The data presented in Table 4 indicate a posi­tive correlation of BMI (group A) with W/H ratio (r=0.652, p<0.001), insulin (r=0.501, p<0.002), %fat (r=0.870, p<0.001), HOMA-IR (r=0.545, p<0.001), and glutathione (r=0.331, p<0.049), whereas it was negatively correlated with %free fat mass (r= -0.789, p<0.001) before weight reduction.

Table 5 shows a positive correlation of W/H ra­tio in group A with BMI (r=0.652, p=<0.001), %fat (r=0.627, p<0. 001) and a negative one of W/H ra­tio with %FFM (r= -0.561, p<0.001) and LDL (r= -0.45, p<0.039) before weight loss.

Insulin levels of the obese women were positive­ly correlated with BMI (r=0.381, p<0.022) and HOMA-IR (r=0.973, p<0.001) after weight loss as shown in Table 6 .

IL-6 levels of the obese women (group A) corre­lated positively with %body fat (r=0.275, p<0.020), HOMA-IR (r=0.484, p<0.003) insulin (r=0.470, p<0.004) and negatively with %FFM (r=-0.279, p<0.019) and glutathione (r=-0.340, p<0.046) af­ter weight loss (Table 7 , Figure 1)

Figure 1.
Correlation of IL-6 with HOMA-IR after weight re­duction in group A.

%Body fat correlated positively with BMI (r= 0.709, p<0.001), WC (r=0.400, p<0.001), insulin (r=0.388, p<0.001),CRP (r=0.382, p<0.001), IL-6 (r=0.275, p<0.020) and negatively with %FFM (r= -0.875, p<0.001) and HDL (r=-0.262, p<0.027) after weight loss (Table 8) .


Obesity is associated with an increased risk of developing cardiovascular diseases.2,4 The metabo­lic consequences of obesity can promote the pro­cess of atherosclerosis influencing endothelial func­tion as well as the mechanisms of oxidative stress.9,10 In our study the levels of adipose tissue related cy­tokines, oxidative and antioxidative substances were evaluated in obese women (group A) before and after weight reduction and in normal weight wom­en (group B).

The obese women also presented visceral obesi­ty as indicated by the values of WC and W/H ratio (108.9cm and 0.9cm, respectively) (Table 1). The women in group A had lower HDL values than those in group B with no difference in total cholesterol, LDL-cholesterol or triglycerides.

BMI values in group A correlated positively with W/H ratio, WC, %body fat, insulin, HOMA-IR, cholesterol, triglycerides, CRP and glutathione per­oxidase activity and negatively with %free fat mass (Table 4). %Body fat was positively correlated with BMI, WC, plasma insulin concentration, CRP and IL-6. The latter correlation is a predictable relation­ship between the total body fat and risk factors, which are believed to be responsible for the chronic endothelial inflammation.15-17 Fernandez-Real J.M. et al reported that the omental adipose tissue pro­duces 3-fold higher levels of IL-6 than subcutane­ous adipose tissue and this is the major mediator of inflammation, which induces the hepatic synthesis of CRP.25 The findings of Lemieux et al26 and Forou­hi et al27 l, suggested that fat distribution correlated with CPR levels as well as with other markers, such as BMI and WC. Although these studies show that there is a correlation between the low levels of in­flammatory markers and the low body and splach­nic adiposse tissue, the influence of weight reduc­tion in the obese on the levels of these markers has not previously been studied. Previous studies have also suggested that CRP can predict future cardio­vascular events independently of other more tradi­tional cardiovascular risk factors, such as plasma lip­id levels.28-31 One possible link between subclinical inflammation and cardiovascular disease (CVD) may be insulin resistance. In the study of Festa et al, 1008 nondiabetic individuals were evaluated. In this study CRP levels were significantly correlated with cardiovascular risk factors.33 Increased fasting levels of insulin and HOMA-IR seem to be mainly related with the levels of the important proinflam­matory cytokine IL-6.34,36 This is in accordance with our results of increased levels of insulin, HOMA­IR and IL-6 in the obese group (A). Furthermore, fasting hyperinsulinemia is related with the produc­tion of free radicals.37-39 The data of the present study indicate that serum CRP as well as IL-6 circulating levels decreased during weight loss, supporting the beneficial effect of weight reduction on cardiovas­cular risk factor. Our data are in accordance with other studies, indicating a possible link between adipose tissue and secretion of IL-6.1 In our study IL-6 levels as well as isoprostane were significantly higher and glutathione peroxidase significantly lower in obese subjects compared to controls (group A) (Table 2)). Furthermore, IL-6 levels positively cor­related with isoprostane and negatively with glu­tathione peroxidase in the obese, a finding which has not been previously described (Table 7). After weight reduction the levels of insulin, CRP, IL-6 and isoprostane significantly decreased, whereas glu­tathione peroxidase significantly increased.

These results are in accordance with the benefi­cial effect of weight loss considering that increased glutathione peroxidase activity protects tissues from oxidative stress injury (Table 3). Accordingly, it is suggested that the improvement of inflammation factors results in a decrease of cellular destruction and protects from CVD. In other words, low values of glutathione peroxidase along with higher levels of isoprostane in obese women indicate defective protection mechanisms against atherosclerosis and oxidative stress. In obese women despite the im­provement in BMI values (from 38.5 to 30.93 kg/m2 p <0.001), following therapeutic interventions, the levels of IL-6, insulin and antioxidative substances did not reach levels similar to the controls. It can be speculated that normalization of these parameters requires either greater BMI reduction and/or a long­er period of dietary intervention. However, the ap­proximately 20% decrease in body weight and the reduction in adiposity, as was reflected in the de­creased ratio of fat to free-fat mass in group A, was associated with an improvement in all adverse pa­rameters measured in this study.

It seems that adipose tissue produces peptides and cytokines which alter not only the hormonal milieu but also certain biochemical parameters and oxidative stress. The results of this study demon­strate that the elevated circulating IL-6, isoprostane and CRP levels and the decreased levels of glu­tathione peroxidase found in obese women corre­lated significantly with a number of cardiovascular risks factors and were ameliorated by weight reduc­tion.

In conclusion, the data of the present study indi­cate that individuals with high BMI and central obe­sity have increased levels of markers associated with insulin resistance, vascular inflammation, oxidative stress and atherosclerosis. Weight reduction can improve all these parameters and, therefore, a pos­sible reduction of the metabolic and cardiovascular morbidity of obesity is expected.


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Address correspondence and requests for reprints to:
Maria Bougoulia MD, 4 Imeras Str., Kalamaria, 55132,
Thessaloniki, e-mail: mariabougoulia@hotmail.com

Received 11-04-06, Revised 28-05-06, Accepted 20-06-06