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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2191
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 5 1931-1938
Copyright © 2008 by The Endocrine Society

Visceral Obesity and Plasma Glucose-Insulin Homeostasis: Contributions of Interleukin-6 and Tumor Necrosis Factor-{alpha} in Men

Amélie Cartier, Isabelle Lemieux, Natalie Alméras, Angelo Tremblay, Jean Bergeron and Jean-Pierre Després

Québec Heart Institute (A.C., I.L., N.A., J.-P.D.), Hôpital Laval Research Centre, Hôpital Laval, Québec, Canada G1V 4G5; Department of Anatomy and Physiology (A.C.) and Division of Kinesiology (A.T., J.-P.D.), Department of Social and Preventive Medicine, Université Laval, Québec, Canada G1K 7P4; and Lipid Research Centre (J.B.), Centre Hospitalier de l’Université Laval Research Centre, Québec, Canada G1V 4G2

Address all correspondence and requests for reprints to: Jean-Pierre Després, Ph.D., F.A.H.A., Director of Research, Québec Heart Institute, Hôpital Laval Research Centre, Hôpital Laval, 2725, Chemin Sainte-Foy, Pavilion Marguerite-D’Youville, 4th Floor, Québec, Canada G1V 4G5. E-mail: jean-pierre.despres{at}crhl.ulaval.ca.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Objective: This study examined the relationships of two inflammatory cytokines, IL-6 and TNF-{alpha}, to visceral adiposity and indices of plasma glucose-insulin homeostasis.

Research Design and Methods: Plasma levels of IL-6 and TNF-{alpha} were measured in 189 untreated asymptomatic men (aged 43.7 ± 7.8 yr; body mass index 29.0 ± 4.3 kg/m2; waist girth 98.6 ± 10.3 cm).

Results: Significant and positive associations were found between both cytokines with adiposity and adipose tissue distribution indices (0.15 ≤ r < 0.32; P < 0.05) as well as plasma glucose-insulin homeostasis variables (0.22 ≤ r < 0.28; P <0.05). Comparison of two subgroups, each composed of 32 overweight men (≥25 kg/m2) with similar body mass index values (28.7 kg/m2 in both groups) but with markedly different levels of visceral adipose tissue (< vs. ≥ 130 cm2), revealed significant differences only for IL-6 levels (1.42 ± 1.15 vs. 0.86 ± 0.52 pg/ml; P < 0.02 for men with high vs. low visceral adipose tissue, respectively). Finally, when subjects were stratified on the basis of their respective concentrations of IL-6 and TNF-{alpha} (using the 50th percentile of their overall distribution), an ANOVA revealed an independent contribution of IL-6 to the variation of fasting insulin (P < 0.01) and each of these two cytokines to the variation of insulin levels measured after a 75-g oral glucose challenge (P <0.01 for IL-6 and P < 0.05 for TNF-{alpha}).

Conclusions: Because IL-6 appeared to be clearly associated with visceral adiposity, TNF-{alpha} rather showed associations with indices of total body fatness. Thus, TNF-{alpha} may contribute to the insulin resistance of overall obesity, whereas IL-6 may be one of the mediators of the hyperinsulinemic state specifically related to excess visceral adiposity.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
It is now more and more recognized that inflammation is an important component of not only cardiovascular disease (1) but also type 2 diabetes (2). In fact, many studies have reported that inflammation is associated with insulin resistance (3) and could even predict type 2 diabetes (4, 5).

Several lines of evidence suggest that TNF-{alpha} and IL-6 are involved in the obesity-related insulin resistance. For instance, it has been observed in animals and humans that obesity is associated with an overexpression of both TNF-{alpha} and IL-6 as well as other proinflammatory cytokines in adipose tissue (AT) (6). In that regard, it has been recently documented that such overexpression of proinflammatory molecules by the AT in the context of obesity could be due to macrophage infiltration (7). Although it is unclear how adipose TNF-{alpha} and IL-6 expression may cause insulin resistance, they have been both demonstrated to interfere with insulin signaling (8, 9). Moreover, TNF-{alpha} (10) and IL-6 (11) are also known to promote lipolysis and secretion of free fatty acids (FFAs) from AT into the circulation, which also contribute to insulin resistance and an increase in hepatic glucose production. It has been proposed that TNF-{alpha} acts locally at the site of AT through autocrine/paracrine mechanisms having effects on insulin resistance and inducing IL-6, whereas IL-6 rather appears to be released systemically by the AT acting more as an endocrine signal that induces the hepatic acute-phase response or insulin resistance in the skeletal muscle (12).

Because these two cytokines seem to be linked to the insulin-resistant state of abdominal obesity, the aim of the present study was to verify whether circulating levels of TNF-{alpha} and IL-6 would be related to indices of total and visceral adiposity as well as indices of plasma glucose-insulin homeostasis. Mostly we were interested to test the potentially additive contribution of plasma TNF-{alpha} and IL-6 levels to the variation in indices of plasma glucose-insulin homeostasis. Finally, we investigated the respective contributions of each cytokine to the variation in indices of plasma glucose-insulin homeostasis beyond what is explained by visceral adiposity.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

A sample of 189 apparently healthy adult men [aged 43.7 ± 7.8 (mean ± SD) yr] from the Québec city metropolitan area were recruited through the media and selected to cover a wide range of body fatness values [body mass index (BMI) ranged from 18.7 to 39.7 kg/m2]. All subjects gave written consent to participate in the present study, which was approved by the Medical Ethics Committee of Université Laval. Men with diabetes or coronary heart disease as well as smokers and morbidly obese individuals were excluded. None of the subjects were on medication known to affect insulin action or plasma lipoprotein-lipid levels. No subjects were on antiinflammatory drugs either before or at the time of the study. Individuals using aspirin as a chronic medication were excluded from the study. Subjects were not allowed to take any medication for at least 24 h before any metabolic investigation.

Body composition and anthropometric measurements

The hydrostatic weighing technique (13) was used to measure body density, which represented the mean of six measurements. Pulmonary residual volume was measured before immersion in the hydrostatic tank, with use of the helium dilution method of Meneely and Kaltreider (14). Percent body fat was derived from body density by using the equation of Siri (15). Fat mass was obtained by multiplying body weight by percent body fat. Height, body weight (16), and waist circumference (17) were measured following standardized procedures.

Computed tomography

Visceral AT accumulation was assessed by computed tomography, which was performed with a Somatom DRH scanner (Siemens, Erlanger, Germany), using previously described procedures (18). Briefly, each subject was examined while being in the supine position with both arms stretched above the head. The scan was performed at the abdominal level (between L4 and L5 vertebrae) by use of an abdominal scout radiograph to standardize the position of the scan to the nearest millimeter. Total AT area was calculated by delineating the abdominal scan with a graph pen and then computing the AT surface with an attenuation range of –190 to –30 Hounsfield units (18). The abdominal visceral AT area was measured by drawing a line within the muscle wall surrounding the abdominal cavity. The abdominal sc AT area was calculated by subtracting the visceral AT area from the total abdominal AT area.

Oral glucose tolerance test (OGTT)

A 75-g OGTT was performed in the morning after an overnight fast. Blood samples were collected in EDTA-containing tubes through a venous catheter placed in an antecubital vein at –15, 0, 15, 30, 45, 60, 90, 120, 150, and 180 min for the determination of plasma glucose and insulin concentrations. Plasma glucose was measured enzymatically (19), whereas plasma insulin was measured by RIA with polyethylene glycol separation (20). The total glucose and insulin areas under the curve during the OGTT were determined by the trapezoid method. An additional insulin resistance variable was calculated with the homeostasis model assessment (HOMA) index formula: HOMA index = (fasting insulin x fasting glucose)/22.5.

Determination of plasma TNF-{alpha} and IL-6 concentrations

Fasting plasma IL-6 and TNF-{alpha} concentrations were assessed on deeply frozen plasma samples (–80 C) and were measured by a high-sensitivity ELISA for human TNF-{alpha} and IL-6 (R&D Systems Inc., Minneapolis, MN). The intra- and interassay coefficients of variation were less than 10% for both cytokines.

Statistical analyses

Data are presented in the Table 1Go as mean ± SD or as median (interquartile range) for skewed variables. Because TNF-{alpha} and IL-6 data followed a log-normal distribution, a logarithmic transformation was used for these variables. Spearman correlations were used to compute relationships among variables. Two subgroups of subjects were individually matched for BMI (≥25 kg/m2) but with high vs. low levels of visceral AT (< vs. ≥ 130 cm2; n = 32) and then compared with a subgroup of nonobese men (BMI < 25 kg/m2). Group differences were analyzed using one- or two-way ANOVA with interactive effect. Multiple regression analyses were computed to sort out the independent and respective contributions of adiposity and circulating TNF-{alpha} and IL-6 concentrations to the variance in indices of plasma glucose-insulin homeostasis. Normality and variance assumptions were verified using the Shapiro-Wilk’s test and Brown and Foresythe’s test, respectively. Results were declared significant at the level of 0.05 or less. All analyses were performed with the SAS statistical package (SAS Institute, Cary, NC).


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  		TABLE 1. Anthropometric and metabolic characteristics of the total sample and a subsample paired for BMI of the study

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Overall, subjects covered a wide range of age, BMI, and body fat distribution variables (Table 1Go). The average BMI value was 29.0 ± 4.3 kg/m2 and corresponded to a waist girth of 98.6 ± 10.3 cm. The median values and interquartile ranges of plasma IL-6 and TNF-{alpha} levels were 0.85 (0.63, 1.24) and 1.16 (0.90, 1.42) pg/ml, respectively.

Overall, circulating IL-6 or TNF-{alpha} were significantly and positively correlated with total adiposity indices such as the following: BMI (r = 0.26, P < 0.001; r = 0.30, P < 0.0001); fat mass (r = 0.27, P < 0.001; r = 0.32, P < 0.0001); and variables of abdominal adiposity such as waist girth (r = 0.26, P < 0.001; r = 0.30, P < 0.0001), visceral AT (r = 0.29, P < 0.0001; r = 0.16, P < 0.05), sc AT (r = 0.23, P < 0.005; r = 0.31, P < 0.0001), and total AT (r = 0.28, P < 0.0001; r=0.28, P < 0.0001). Accordingly, significant and positive correlations were found between circulating IL-6 or TNF-{alpha} and fasting insulin levels (r = 0.28, P < 0.0001; r = 0.26, P < 0.001) and area under the curve of plasma insulin (r = 0.27, P < 0.001; r = 0.22, P < 0.05). Figure 1Go illustrates the relationship between quartiles of adiponectin, IL-6, TNF-{alpha}, and visceral AT with homeostasis model assessment (HOMA) index.


Figure 1
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  		FIG. 1. HOMA index values across quartiles of visceral AT (A), plasma adiponectin (B), IL-6 (C), and TNF-{alpha} (D) levels. 1 and 2, Significantly different from the corresponding subgroups (P < 0.05). HOMA index = (fasting insulin x fasting glucose)/22.5.

 
To investigate the contribution of visceral AT to the circulating levels of IL-6 and TNF-{alpha}, two subgroups (n = 32 in each group) of overweight men (BMI ≥ 25 kg/m2) were individually matched for similar BMI values but with high vs. low levels of visceral AT (< vs. ≥ 130 cm2) and then compared with lean subjects (with both BMI < 25 kg/m2 and visceral AT < 130 cm2; n = 28) (Fig. 2Go). This analysis revealed that among overweight/obese men (BMI ≥ 25 kg/m2), individuals characterized by a high accumulation of visceral AT had elevated plasma IL-6 concentrations (P < 0.05), compared with men with low visceral AT and lean controls (P < 0.05). As for circulating TNF-{alpha} levels, there were no differences between the two overweight/obese subgroups characterized by low or high levels of visceral AT because both had elevated plasma TNF-{alpha} concentrations, compared with lean controls (Fig. 2Go).


Figure 2
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  		FIG. 2. A, Circulating IL-6 concentrations in 28 nonobese men (1 ) and two subgroups of 32 overweight men, each individually matched for similar BMI but with low (2 ) or high (3 ) visceral AT accumulation. B, Circulating TNF-{alpha} concentrations in 28 nonobese men (1 ) and two subgroups of 32 overweight men, each individually matched for similar BMI but with low (2 ) or high (3 ) visceral AT accumulation. 1 and 2, Significantly different from the corresponding subgroups (P < 0.05).

 
We then stratified our sample of men on the basis of the 50th percentile of their plasma IL-6 and TNF-{alpha} concentrations. A two-way ANOVA (with an interaction term) was performed to examine the respective contributions of each cytokine to the variation in indices of plasma glucose-insulin homeostasis (Fig. 3Go). Irrespective of TNF-{alpha} levels (< or ≥ 1.16 pg/ml), men characterized by elevated IL-6 concentrations (≥0.85 pg/ml, subgroups 3 and 4) showed significantly higher levels of fasting insulin (Fig. 3AGo), compared with subgroup 1 (P < 0.01). Plasma levels of both cytokines (IL-6: P < 0.01 and TNF-{alpha}: P < 0.05) were significantly related to the area under the curve of plasma insulin levels (Fig. 3BGo) measured during the OGTT. However, the interaction term was not significant, suggesting that the presence of both elevated IL-6 and TNF-{alpha} did not have a multiplicative effect on the area under the curve of plasma insulin. As for the insulin-sensitivity index (HOMA), only plasma IL-6 levels contributed to the variation in this parameter (Fig. 3CGo) (P < 0.01). The subgroup (subgroup 4) characterized by higher IL-6 and TNF-{alpha} levels had a significantly higher HOMA index, compared with subgroup 1. Concerning adiponectin levels (Fig. 3DGo), there were no significant contribution of either TNF-{alpha} or IL-6 and no significant differences between each subgroup.


Figure 3
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  		FIG. 3. Respective contributions of TNF-{alpha} and IL-6 levels to the variance in metabolic risk variables [fasting insulin (A), area under the curve of plasma insulin (B), HOMA index (C), and adiponectin (D)] in the different subgroups (1 2 3 4 ) classified on the basis of the 50th percentile of plasma IL-6 and TNF-{alpha}. 1, Significantly different from the corresponding subgroup (P < 0.05). HOMA index = (fasting insulin x fasting glucose)/22.5.

 
Moreover, to examine the potentially additional contribution of each cytokine to the variance in metabolic risk variables beyond what could be explained by visceral adiposity, 2 x 2 ANOVAs were conducted in which subjects were classified into those having either low or elevated visceral adiposity (using the median of the distribution corresponding to < or ≥ 158 cm2) and further classified on the basis of low or high levels of circulating IL-6 (< or ≥ 0.85 pg/ml) or TNF-{alpha} (< or ≥ 1.16 pg/ml) and also with the use of the 50th percentile of the distribution of these variables. Figure 4Go shows that although visceral AT significantly contributed (P < 0.0001) to the variation in fasting insulin (Fig. 4AGo), the area under the curve of plasma insulin (Fig. 4BGo), and the HOMA index (Fig. 4CGo), both circulating IL-6 and TNF-{alpha} levels also significantly and independently contributed to the variation in fasting and post-OGTT insulin levels as well as the variance in the HOMA index. The interaction term between IL-6 concentrations and visceral AT was not significant for both insulin variables; however, the interaction term between circulating TNF-{alpha} levels and visceral AT was significant, suggesting a multiplicative effect of these variables on fasting plasma insulin levels and the HOMA index.


Figure 4
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  		FIG. 4. Respective contributions of either TNF-{alpha} or IL-6 levels and visceral AT to the variance in metabolic risk variables [fasting insulin (A), area under the curve of plasma insulin (B), and HOMA index (C)] in the different subgroups (1 2 3 4 ) classified on the basis of the 50th percentile of visceral AT and either plasma IL-6 or TNF-{alpha}. 1, 2, and 3, Significantly different from the corresponding subgroups (P < 0.05). HOMA index = (fasting insulin x fasting glucose)/22.5.

 
Finally, multiple regression analyses were also conducted to sort out the independent contribution of visceral AT and circulating IL-6, TNF-{alpha}, and adiponectin levels (model 1) to the variance in indices of plasma glucose-insulin homeostasis (Table 2Go). This analysis revealed that visceral AT and circulating IL-6 as well as adiponectin concentrations explained 27.4% (P < 0.05) of the variation in fasting insulin levels. Regarding the area under the curve of plasma insulin, the analysis revealed that visceral AT, circulating IL-6, and adiponectin concentrations explained 34.4% (P < 0.05) of its variance. On the other hand, only visceral AT weakly contributed to the variance in fasting glucose (2.1%; P < 0.05). Visceral AT and adiponectin contributed both independently to the area under the curve of plasma glucose (13.7%; P < 0.05). In a second model excluding visceral adiposity and including only adipokines, such as circulating IL-6, TNF-{alpha}, and adiponectin levels, indices of plasma glucose-insulin homeostasis were explained mostly by adiponectin and IL-6 (Table 2Go) with no contribution of TNF-{alpha} to the variation of these parameters.


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  		TABLE 2. Multiple regression analyses for relative contributions of fat distribution and inflammatory cytokines to variance in indices of plasma glucose-insulin homeostasis

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study, we examined the relationships between circulating IL-6 and TNF-{alpha} concentrations and direct measures of total and abdominal adiposity as well as indices of plasma glucose-insulin homeostasis. Although IL-6 and TNF-{alpha} were significantly correlated with total adiposity indices such as BMI and fat mass, IL-6 levels were mostly associated with visceral adiposity, compared with TNF-{alpha} levels, which appeared to be more related to sc fatness. In concordance with our results, Park et al. (21) found that circulating IL-6 levels but not TNF-{alpha} concentrations were significantly associated with visceral adiposity. These data are also consistent with the recently published work of Fontana et al. (22) who reported, in massively obese subjects, that plasma IL-6 concentrations were much higher in the portal vein than systemic arterial blood, suggesting that visceral fat is an important source of IL-6 production in obese people. Another recent study reported a significant decrease in circulating IL-6 along with a decrease in visceral AT and waist circumference in lean and obese subjects as well as in patients with type 2 diabetes who underwent an exercise program without weight loss (23). All these findings support the notion that in addition to overall obesity, the accumulation of visceral AT is a key factor responsible for the up-regulation of low-grade chronic inflammation, which could be a consequence of increased IL-6 production in obese subjects.

Because visceral adiposity is strongly associated with features of the metabolic syndrome, we investigated whether visceral obesity was the obesity phenotype most likely to be associated with inflammatory markers. For that purpose, we matched individuals on the basis of their BMI but with low vs. high levels of visceral AT. The comparison of overweight/obese men with similar BMI but who substantially differed in their level of visceral AT (low visceral AT: 105 cm2 vs. high visceral AT: 202 cm2) revealed marked differences in plasma IL-6 levels, with viscerally overweight men being characterized by higher IL-6 concentrations than equally overweight men with low levels of visceral AT. On the other hand, plasma TNF-{alpha} concentrations did not differ between the two subgroups of overweight men with low vs. high levels of visceral AT. Results obtained from this matching procedure were in line with the previously reported correlations between visceral AT accumulation and circulating IL-6 levels, whereas TNF-{alpha} showed a weak and barely significant association with visceral adiposity. These results support the fact that circulating IL-6 is associated with obesity (24) and is mostly produced and secreted by visceral AT (25). Previous studies have shown that the amount of TNF-{alpha} mRNA and TNF-{alpha} secretion by AT are enhanced in human obesity (26). However, a lack of depot-related difference in the mRNA expression of TNF-{alpha} has been reported (27, 28). Although controversies remain regarding the origin of the increased circulating TNF-{alpha} concentration in obesity, our study shows, in accordance with the findings of others (29), positive and significant correlations between circulating TNF-{alpha} and total adiposity indices. Moreover, irrespective of visceral AT accumulation, individuals with a BMI of 25 kg/m2 or greater had higher circulating TNF-{alpha} concentrations, compared with individuals with a BMI less than 25 kg/m2.

Both TNF-{alpha} and IL-6 have also been suggested to contribute to obesity-related insulin resistance. In the present study, significant associations were found between either TNF-{alpha} or IL-6 and direct (area under the curve of insulin measured during the OGTT) or indirect (fasting insulin levels or the HOMA index) measures of insulin resistance. These data are consistent with previous studies demonstrating increased levels of TNF-{alpha} among subjects with insulin resistance (30, 31). Hotamisligil et al. (8) suggested that the mechanism by which TNF-{alpha} could induce insulin resistance may primarily involve an altered signaling through the insulin receptor and insulin resistance substrate-1. Other studies observed a significant correlation between circulating IL-6 levels and in vivo insulin resistance (6, 32, 33). It has also been demonstrated that IL-6 promotes insulin resistance by interfering with insulin signaling in the liver (9) and AT (34). However, whereas the relationship between insulin resistance and circulating IL-6 levels is well established, there is little information on an independent association between plasma IL-6 levels and insulin secretion (35). It has been recently demonstrated that plasma IL-6 levels were positively related to first-phase insulin secretion and negatively related to insulin sensitivity in glucose-tolerant subjects (36). Moreover, the relationship between IL-6 and insulin secretion in this previous study appeared to be independent of modulators of insulin secretion such as age, sex, BMI, and insulin sensitivity. In contrast, the relationship between IL-6 and insulin action seemed to be partially mediated by adiposity, a finding consistent with our results.

On the other hand, another factor that may contribute to the link between these markers and insulin resistance is the lipolytic effect of both cytokines. In fact, in vitro studies have demonstrated that IL-6 and TNF-{alpha} increase lipolysis in adipocytes (37, 38). Moreover, it has been demonstrated that the infusion of recombinant human IL-6 into healthy humans increases whole-body lipolysis and FFA oxidation (39, 40). In addition, Wallenius et al. (41) recently demonstrated that an IL-6 knockout mouse became obese, a phenotype that was partially reduced with IL-6 treatment. As for TNF-{alpha}, a recent study reported that a relatively low dose of recombinant human TNF-{alpha} could induce systemic lipolysis and that the skeletal muscle fat metabolism was unaffected (42). Taken together, these results provide evidence supporting the hypothesis that the increased production of IL-6 and TNF-{alpha} by the hypertrophied AT could further stimulate its lipolysis. Such increased lipolysis may contribute to systemic and hepatic insulin resistance by releasing FFAs in the circulation, stimulating the hepatic glucose production and reducing hepatic insulin extraction. Furthermore, it is known that insulin inhibits the release of cytokines, such as IL-6, responsible for the stimulation of acute-phase protein gene expression (43). Moreover, it has been recently demonstrated that insulin has the ability to antagonize IL-6 signaling and the induction of inflammatory proteins such as serum amyloid A3 and haptoglobin in vitro supporting the antiinflammatory properties of insulin (44). Thus, in the presence of an impaired insulin action, insulin would no longer be able to inhibit IL-6 release, inducing a prolonged acute-phase reaction (32). Because both cytokines are potentially linked to insulin resistance and the insulin signaling pathway, we examined the respective and even possibly additive contributions of both cytokines to the variance in indices of plasma glucose-insulin homeostasis. Our results suggest that IL-6, but not TNF-{alpha}, significantly contributed to the variance in fasting insulin. However, both cytokines contributed to the variance of insulin levels measured during the OGTT.

Therefore, because of the significant relationship between hyperinsulinemia and visceral AT, we investigated the respective contributions of IL-6 and TNF-{alpha} to the variance in insulinemia beyond what could be explained by visceral adiposity. Our results revealed independent contributions of IL-6 and TNF-{alpha} to the variance in insulinemia both assessed in the fasting state or during an OGTT. Results of multiple regression analyses revealed that, in addition to the well-known contribution of visceral AT to hyperinsulinemia, circulating IL-6 and adiponectin concentrations also contributed independently to the variance in plasma insulin levels. For instance, we found that visceral AT, IL-6, and adiponectin levels explained 27.4% (P < 0.05) of the variation in fasting insulin and 34.4% (P < 0.05) of the variation in post-OGTT insulin levels. It is clear that IL-6 and adiponectin were independent predictors of insulinemia. However, the strong colinearity with visceral AT could be the reason for the small additive effect of IL-6 and adiponectin to insulin levels. Therefore, in a second model in which we excluded visceral AT, adiponectin (8.6%) had a stronger independent contribution to the variance of insulinemia than IL-6 (5.7%). As for the insulin area, IL-6 (13.2%) and adiponectin (6.3%) contributed independently to its variance. These findings are consistent with the hypothesis that these proinflammatory cytokines secreted by AT could contribute to the link between obesity and insulin resistance (6, 45). Another proposed mechanism is the induction by proinflammatory cytokines of suppressor of cytokine signaling proteins, which are known to alter insulin signaling and which could therefore play a role in mediating cytokine-dependent insulin resistance in the liver and other insulin-responsive tissues (46).

Lastly, it is also important to keep in mind that our results were obtained in white men and cannot be generalized to women or other ethnic groups.

In summary, despite the fact that more studies are needed to understand the mechanisms involved in the relationships reported in the present study, our results indicate that elevated circulating IL-6 and TNF-{alpha} concentrations are both related to hyperinsulinemia beyond the effect of visceral adiposity. However, whereas TNF-{alpha} showed significant associations with total adiposity, IL-6 appeared to be clearly associated with visceral adiposity. Thus, TNF-{alpha} may contribute to the insulin resistance of overall obesity, whereas IL-6 may be one of the mediators of the hyperinsulinemic state more specifically related to excess visceral adiposity. Finally, it is important to keep in mind that other factors such as FFAs and other cytokines could also contribute to an altered plasma glucose-insulin homeostasis. Thus, additional studies will be needed to better understand the link between the inflammatory state associated with abdominal obesity and metabolic complications such as alterations in plasma glucose-insulin homeostasis resulting from an insulin-resistant state.


   Acknowledgments
 
We express our gratitude to the study subjects for their contribution to the present study and to our staff for their dedicated work.


   Footnotes
 
This work was supported by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada. J.-P.D. is the Scientific Director of the International Chair on Cardiometabolic Risk, which is supported by an unrestricted grant awarded to Université Laval by Sanofi Aventis. A.T. is partly funded by the Canada Research Chair in Physical Activity, Nutrition, and Energy Balance. A.C. is a recipient of a scholarship from the Merck Frosst/Canadian Institutes of Health Research Research Chair in Obesity.

Disclosure Statement: All authors have nothing to disclose.

First Published Online March 4, 2008

Abbreviations: AT, Adipose tissue; BMI, body mass index; FFA, free fatty acid; HOMA, homeostasis model assessment; OGTT, oral glucose tolerance test.

Received October 1, 2007.

Accepted February 26, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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