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Adipose Tissue IL-6 Content Correlates with Resistance to Insulin Activation of Glucose Uptake both in Vivo and in Vitro

Service de Biochimie et Hormonologie (J.-P.B., M.M., J.C.), Hôpital Tenon-Rothschild, Assistance Publique-Hôpitaux de Paris (AP-HP), 75020 Paris; INSERM U-402, Faculté de Médecine Saint-Antoine (J.-P.B., J.C.), Université Paris VI, 75012 Paris; Département de Pathologie (J.T.V.N.), Hôpital Henri Mondor, AP-HP et Université Paris XII, 94000 Créteil; Service de Biochimie (C.J., B.H.), Hôpital de la Salpêtrière, AP-HP, 75013 Paris; Service d’Endocrinologie et Métabolisme (E.B.), Hôpital de la Pitié, AP-HP, Paris; Service de Diabétologie et Métabolisme (A.G.), Hôpital de la Pitié, AP-HP, 75013 Paris; and Fédération de Pédiatrie (J.-J.R.), Diabète de l’Enfant et de l’Adolescent, Hôpital Necker-Enfants Malades, AP-HP, 75015 Paris, France

Address all correspondence and requests for reprints to: Dr. Jean-Philippe Bastard, M.D., Ph.D., Service de Biochimie et Hormonologie, Hôpital Tenon, 4 rue de la Chine, 75970, Paris Cedex 20, France. E-mail: . jean-philippe.bastard{at}tnn.ap-hop-paris.fr

Abstract

Obesity and type 2 diabetes are associated with insulin resistance, the mechanisms of which remain poorly understood. A significant correlation between circulating IL-6 level and insulin sensitivity has recently been found in humans. Because adipose tissue could be a significant source of IL-6, we analyzed the relationship between the levels of adipose tissue IL-6 and insulin action in vivo, during a hyperinsulinemic normoglycemic clamp, and in vitro by measuring glucose transport in adipocytes from 12 obese subjects with (n = 7) or without (n = 5) diabetes. We observed an inverse correlation between adipose tissue IL-6 content and maximal insulin-responsiveness measured in vivo (P < 0.02) and in vitro (P < 0.02). Conversely, there was no significant correlation between these two later parameters and adipose tissue leptin or tumor necrosis factor- protein contents. Furthermore, we showed, for the first time, the presence of immunoreactive IL-6 receptors in the plasma membrane of human abdominal sc adipocytes. This suggests that locally secreted IL-6 could act on adipocytes by an autocrine/paracrine mechanism. In conclusion, increased IL-6 production by sc adipose cells might participate to the insulin-resistant state observed in human obesity.

OBESITY AND TYPE 2 diabetes are associated with impaired insulin action on peripheral target tissues (i.e. adipose tissue and skeletal muscle) (1, 2). The mechanisms that could explain such a link are not clearly elucidated, although several cytokines expressed in adipose tissue such as leptin, TNF- and IL-6 could be involved (3). Leptin is primarily produced by adipocytes and has been shown to impair the metabolic action of insulin in isolated rat adipocytes (4). However, more recent studies suggest that leptin improves insulin sensitivity (5, 6). TNF- has been found to induce insulin resistance in vitro, and its expression is high in adipose cells from animal models of insulin resistance (7). In human, increased expression of its gene has been documented in the sc abdominal adipose tissue depot, and studies have shown that the expression or production of this cytokine was directly related to the degree of obesity (8, 9), whereas others did not find such an association (10). More recently, TNF- secretion has been shown to be correlated with insulin resistance measured in vitro (11) and in vivo (12). However, it has been shown that human sc adipose tissue did not release a significant amount of TNF- in vivo (13) and a relationship between adipose-derived TNF- and in vivo insulin sensitivity in human has not been observed in different clinical studies (10, 14, 15). Therefore, the relation between adipose tissue TNF- and insulin resistance remains largely debated in humans.

Otherwise, the sc adipose tissue was shown to secrete large amount of IL-6, and this secretion was correlated with the body mass index (BMI) of the subjects (13). Interestingly, such a correlation between circulating IL-6 levels and BMI was consistently found in different studies, suggesting a link between obesity and circulating IL-6 (12, 16, 17, 18). Moreover, we and others recently observed a significant correlation between circulating IL-6 levels and insulin sensitivity assessed by the fasting insulin resistance index or by an iv glucose tolerance test with minimal model analysis (12, 18, 19). We also showed that circulating IL-6 levels might reflect, at least in part, adipose tissue IL-6 production (18). Therefore, IL-6 might be involved in the resistance to insulin observed in obesity and type 2 diabetes with obesity in humans. However, little is known about IL-6 expression in adipose tissue and its relation with adipose tissue insulin resistance. We thus studied the relationship between adipose tissue IL-6 levels and maximal insulin-stimulated glucose uptake in vivo and in vitro in a group of obese subjects with or without type 2 diabetes.

Subjects and Methods

Subjects

Twenty-four Caucasian volunteers [nine lean nondiabetic (age range, 25–53 yr; BMI, 18.0–25.3 kg/m²), seven nondiabetic obese (age range, 26–58 yr; BMI, 29.1–44.3 kg/m²), and eight type 2 diabetic obese subjects (age range, 41–60 yr; BMI, 28.6–38.7 kg/m²)] participated in this study. In each subject, body weight was stable for at least 12 months before participation in the study, and none was engaged in any type of exercise program or was excessively sedentary. Type 2 diabetic patients were treated by sulfonylurea therapy, which was withdrawn at least 2 wk before the study. None was treated by insulin. All studied subjects were chemically and clinically euthyroid and were without renal or hepatic disease. All of the subjects participated in the clamp study. Blood samples were drawn at 0800 h after an overnight fast, and serum was stored at -80 C until analysis. In addition to the clamp study, insulin-stimulated glucose transport in adipocytes from sc abdominal adipose tissue was assessed in 12 of the obese subjects, diabetic (n = 7) or not (n = 5), and compared with their adipose tissue cytokines content. All subjects gave their written informed consent before their participation in the study, which was approved by the ethical committee of Assistance Publique-Hôpitaux de Paris and performed according to the French legislation (Huriet law).

Glucose clamp

Insulin action was measured in each subject after an overnight fast with the hyperinsulinemic normoglycemic glucose clamp technique as previously described (20). A primed continuous infusion of insulin (Umuline, Lilly, Paris, France) was subsequently given at two different rates (40 and 400 mU/m²·min). The continuous infusion was maintained for 100 min at each insulin infusion rate (20). Plasma glucose was maintained at 4.8 mmol/liter by a variable-rate iv 30% dextrose infusion. The plasma glucose concentration was measured every 5 min (Beckman Glucose Autoanalyzer II, Beckman Coulter, Inc., Fullerton, CA), and the glucose infusion rates (GIRs) were calculated according to established algorithms (21) using a portable PC microcomputer (Toshiba 3100 SX) that automatically controlled the peristaltic pump (Infusomat, Secura Braun, Melsungen, Germany). Plasma glucose was allowed to decrease from hyperglycemic to normoglycemic levels during the first step in diabetic patients, and the glucose infusion was not started until the plasma glucose concentration had declined to 4.8 mmol/liter, which required less than 60 min of insulin infusion. During the second plate, the mean glucose infusion rate in the last 30 min of 400 mU/m²·min insulin infusion was used to assess the maximal whole-body glucose disposal rate expressed as mg/m²·min, an estimate of maximal peripheral insulin action. Blood samples were taken every 10 min throughout the last 30 min of the hyperinsulinemic normoglycemic clamp for plasma insulin measurements.

Adipose tissue preparation

After an overnight fast, percutaneous mini-liposuction of sc abdominal adipose tissue under local anesthesia using 2–5 ml 1% lidocaine was performed as previously described (22). For protein measurements and immunohistochemical study, one adipose tissue specimen was blotted on sterile cloth and cleaned of blood and immediately frozen in liquid nitrogen and stored at -80 C until analysis. For glucose transport, adipocytes were isolated by collagenase digestion as previously reported (23).

Glucose transport

Glucose transport was measured by the method described by Kashiwagi et al. (24) in which the uptake of D-U^-14C-glucose is determined at tracer concentrations. To measure basal and maximally stimulated glucose transport rates, adipose cells were incubated in the absence and presence of insulin (100 nM) for 60 min at 37 C in Krebs-Ringer phosphate buffer (pH 7.4) with 5% BSA. Thereafter, 4.5 µmol/liter of D-U^-14C-glucose (304 µCi/µmol) was added to each tube, and the incubation was continued for 30 min before terminating by centrifugation through dinonylphthalate oil. The glucose transport was expressed as clearance rate in fl/cell·sec.

Immunohistochemistry method

Cryostat sections (6 µm thick) were cut from frozen sc adipose tissue from three of the subjects and stored at -20 C until use. One visceral adipose tissue sample from one obese type 2 diabetic and sc adipose tissue samples from two nonobese nondiabetic subjects obtained during surgery were also studied. After thawing, unfixed slides, as well as slides fixed in cold acetone, were rehydrated by immersion in 20% AB human serum in 0.05 M Tris-buffered saline (pH 7.6), then incubated 1 h at room temperature with the anti-IL-6 receptor (IL-6R) (Santa Cruz Biotechnology, Inc., Tebu, France) at a dilution of 1:50. IL-6R is a rabbit polyclonal IgG specific for an epitope mapping at the carboxy terminus of human IL-6R. The results were verified by using the anti-IL-6R M91, which was kindly gifted by J. Brochier from INSERM U-475 (25). An immunoenzymatic method was performed using alkaline phosphatase-anti-alkaline phosphatase (APAAP) complexes (Dakopatts, Trappes, France). Briefly, slides were successively incubated for 30 min with mouse antirabbit Ig antibody diluted 1:50, rabbit antimouse antibody diluted 1:20, and the APAAP complexes diluted 1:50, respectively. A single amplification was performed by adding sequentially the rabbit antimouse antibody for 10 min and the APAAP complexes for 10 min. Sections were incubated with Fast Red salt-TR-Naphtol AX-TR phosphate (Sigma, Saint-Quentin Fallavier, France) in the presence of levamisole to block endogenous activity, then counterstained with aqueous hematoxylin and mounted in Immumount (Shandon, Cergy-Pontoise, France). A negative control was obtained by omitting the primary antibody.

Cytokine measurements

Serum levels of leptin, TNF, and IL-6 were determined by ELISA (Quantikine leptin, Quantikine High Sensitivity TNF, and Quantikine IL-6, R&D Systems, Oxford, UK). The same ELISA kits were used to determine the immunoreactive leptin, TNF, and IL-6 protein content in adipose tissue samples after homogenization of 200 mg of frozen tissue in 400 µl of a buffer (pH 7.4) containing 10 mmol/liter of Tris-HCl, 250 mmol/liter of sucrose, and a cocktail of protease inhibitors (Complete, Roche Molecular Biochemicals, Burlington, NC) as previously reported (18).

Analytical methods

Venous blood samples were taken between 0800 and 0900 h after an overnight fast. Blood glucose was analyzed with a glucose oxidase method (Beckman Glucose Autoanalyzer II, Beckman Coulter, Inc.). Glycated hemoglobin (HbA1c) concentrations (normal range, 4.0–5.6%) were determined by using the Diamat high-pressure liquid-chromatographic system (Bio-Rad Laboratories, Inc., Ivry sur Seine, France). Serum insulin concentrations were measured using commercial RIA kits (Bi-Insulin IRMA, ERIA-Pasteur, Paris, France; normal range, 5–18 µU/ml). Nonesterified fatty acids (NEFA) were determined with a commercially available kit (NEFAC test; Wako Chemicals, Neuss, Germany). C reactive protein (CRP) was assessed by immuno-nephelometry on Behring Nephelometer 2 (Dade-Behring, La Défense, France).

Statistical analysis

Results are means ± SEM, and statistical significance was determined using ANOVA and the Kruskal-Wallis nonparametric test, followed by a Fisher protected least significant difference test for pair-wise differences. Correlations between factors were identified by Spearman’s nonparametric test. P values of less than 0.05 were considered significant.

Results

Insulin resistance and circulating cytokine levels

The characteristics of the three groups of subjects are summarized in Table 1. When compared with the lean controls, as expected, all obese subjects had higher fasting plasma insulin. The type 2 diabetic group had higher fasting plasma glucose and HbA1c levels than the other two groups. As indicated by the clamp studies (GIRs), the group of type 2 diabetic subjects was more insulin-resistant than the group of obese nondiabetics that was more insulin-resistant than the lean control group. Serum leptin, TNF-, and IL-6 levels are shown in Table 1. We found a 3- and 4-fold increase of IL-6 in obese nondiabetic and type 2 diabetic subjects, respectively, compared with controls, whereas no significant difference was observed between the three groups for TNF-. Serum leptin levels were higher in the nondiabetic obese group, whereas no significant difference was observed between type 2 diabetic and control subjects. In line with the finding for IL-6, serum CRP levels were 4-fold increased in obese subjects whatever their diabetic status.

Insulin resistance and adipose tissue cytokines

Because circulating cytokine levels are in part an indirect indicator of their release by adipose tissue, we directly measured their content in adipose tissue in 12 of the obese subjects, diabetic or not. Mean leptin content was 3.15 ± 0.07 ng/g adipose tissue (2.94–3.70), whereas mean TNF- content was 8.2 ± 1.9 pg/g adipose tissue (1.0–21.2), and mean IL-6 content was 17.5 ± 3.2 pg/g adipose tissue (1.0–31.8). There was no correlation between adipose tissue leptin and either TNF- or IL-6 (data not shown). Similarly, no correlation was found between IL-6 and TNF-. Although not significant, there was a tendency for a correlation between serum and adipose tissue IL-6 within the obese group (r = 0.521; P = 0.08). In these 12 obese subjects, glucose transport in adipocytes was enhanced by 2-fold by insulin from 43 ± 9 fl/cell·sec (7–122) to 92 ± 22 fl/cell·sec (17–284). Insulin-stimulated glucose transport in adipocytes was strongly correlated with the whole-body insulin-stimulated glucose disposal in vivo (r = 0.769; P < 0.02; n = 12).

To further study the relationship between adipocyte cytokines and insulin action both in vivo in whole body and in vitro in adipocytes, we compared the results obtained from either the hyperinsulinemic normoglycemic clamp or glucose transport in adipocytes and the cytokine contents in adipose tissue. Our results showed no correlation between adipose tissue leptin or TNF- and 1) insulin-stimulated glucose disposal in vivo, 2) insulin-stimulated glucose transport in adipocytes, or 3) any of the metabolic parameters measured in this study, i.e. fasting plasma glucose, insulin, NEFA, and HbA1c. Conversely, we found a strong inverse correlation between adipose tissue IL-6 content and 1) insulin-stimulated glucose disposal in vivo (r = -0.750; P < 0.02) (Fig. 1A), 2) basal (r = -0.748; P < 0.02), or 3) insulin-stimulated glucose transport in adipocytes (r = -0.767; P < 0.02) (Fig. 1B). In addition, fasting plasma glucose was correlated with adipose tissue IL-6 content (r = 0.591; P = 0.05). It is interesting to compare these values with those we have obtained previously in lean controls. In control subjects, adipose tissue IL-6 levels were very low (1.5 ± 0.8 pg/g adipose tissue; n = 7), whereas GIR was high (538 ± 29 mg/m²·min; n = 9) (Fig. 1A). Similarly, control insulin-stimulated glucose transport in adipocytes was in the high range (234 ± 90 fl/cell·sec; n = 5) (Fig. 1B).

View larger version (18K): [in this window] [in a new window]   Figure 1. Relationship between adipose tissue IL-6 protein content and GIR during the hyperinsulinemic normoglycemic clamp (A) and maximally insulin-stimulated glucose transport in isolated adipocytes (B) in individual obese subjects. The open circle indicates the mean (± SEM) values for lean control subjects to allow comparison, but these values have not been used in calculating the correlation coefficient rank between the two variables. Correlation was identified using Spearman’s nonparametric test.

Anti-IL-6R immunostaining of adipose tissue revealed a thin positivity delineating adipocytes (Fig. 2, A and C) and a strong positivity of the blood vessel wall (Fig. 2A, top right). This immunostaining disappeared when the primary antibody was omitted for negative control (Fig. 2, B and D). Most adipocytes (60%) showed positive staining, however variable in intensity with the two specific IL-6R antibodies used. Immunostaining was reproducible by using different independent technical procedures. Analysis of different samples revealed that IL-6R was present on the plasma membrane from sc and visceral adipocytes. Although performed with a few numbers of subjects, IL-6R was observed in control, obese nondiabetic, and obese type 2 diabetic subjects (data not shown).

View larger version (146K): [in this window] [in a new window]   Figure 2. Immuno-detection of IL-6 receptor in adipocyte plasma membrane from an obese subject. IL-6 receptor staining is red and counterstained is blue. A and B, There is a thin positive anti-IL-6 receptor immunostaining at the adipocyte plasma membrane and a strong positivity of the blood vessel wall (A, top right) in acetone-fixed adipose tissue sections. B and D, Negative controls.

In the present study, we report that the circulating IL-6 level was highly correlated with insulin responsiveness measured by the gold standard hyperinsulinemic glucose clamp, confirming our previous work (18). This result is also supported by the significant correlation observed between circulating CRP levels and insulin responsiveness, IL-6 being the major inductor of liver CRP synthesis. Interestingly, two recent studies reported such a relationship between circulating IL-6 level and insulin resistance, estimated either by the fasting insulin resistance index in a large population or by using the frequently sampled iv glucose tolerance test with the minimal model analysis in a smaller sample of subjects (13, 19). We found a significant relationship between both serum IL-6 or CRP levels and NEFA levels. This result is in line with the data of Kern et al. (12) suggesting that IL-6 could be related to insulin resistance, resulting in increased lipolysis. This is also supported by the fact that IL-6 is able to stimulate lipolysis in human breast adipocyte (26). Therefore, all together, these data emphasize the potential role played by cytokines from adipose tissue in insulin resistance in human. Because circulating IL-6 level is an indirect indicator of its release by adipose tissue, we investigated the relationship between adipose tissue IL-6 content and insulin action both in vivo and in vitro in humans. A recent study suggested that the relationship between circulating IL-6 and insulin action was mediated through adiposity (27). Accordingly, we observed that adipose tissue IL-6 content was very low in control samples. Therefore, to study the relationship between adipose tissue IL-6 content and insulin resistance independently of obesity, we studied obese subjects with different degrees of insulin resistance. We found a significant correlation between adipose tissue IL-6 content and several metabolic parameters such as fasting plasma glucose, basal and insulin-stimulated glucose transport, and whole-body glucose disposal. These results suggest that IL-6 may play an important role in insulin action in these subjects. Moreover, our results suggested that IL-6 could act locally at the adipocyte level and that IL-6 could impair insulin action. Such an IL-6 action required IL-6 receptor to be present on sc adipocytes, which has never been reported. Interestingly, it has been shown recently that human breast adipocytes express IL-6 receptors (26). By using immunohistochemistry, we demonstrate, for the first time, that IL-6R is present at the plasma membrane level in about 60% of the human abdominal sc adipocytes. These data suggest that, in humans, IL-6 secreted from abdominal sc adipocytes alter their metabolism by an autocrine or paracrine mechanism. However, when human breast adipocytes were differentiated in vitro from precursor cells, only a few percentage expressed IL-6 and IL-6R (2–3%). This could explain the poor inhibitory effect of IL-6 on insulin-stimulated glucose transport reported by Päth et al. (26). Further studies are required to clarify this point. A decreased expression of IL-6 and IL-6R in vitro may be due to the fact that culture conditions do not fully mimic the in vivo situation (26).

It was recently shown that TNF- production and glucose transport were highly correlated in human adipose tissue (11). The authors suggested that one third of the variance in insulin-stimulated glucose transport could be explained by variations in TNF- secretion (11). In another study, a correlation was observed between TNF- secreted in vitro from adipose tissue, but not plasma TNF- level or adipocyte TNF- mRNA, and insulin sensitivity (12). In the present study, we found no correlation between TNF- adipose tissue protein content and either maximally insulin-stimulated glucose transport in adipocytes or whole-body glucose disposal during the hyperinsulinemic glucose clamp. These discrepancies may be explained by the different assays used to measure glucose transport in adipocytes, insulin resistance in vivo, TNF- secretion and expression. Furthermore, Löfgren et al. and Kern et al. (11, 12) did not include type 2 diabetic subjects in their studies. Nevertheless, even if the role of TNF- remains to be clarified, it seems likely that part of the variation in insulin-stimulated glucose transport may be imputed to IL-6 variation in adipose tissue.

Leptin is synthesized and secreted by adipose tissue, and this adipose production may account for about 99% of the circulating leptin level in human (3). Recently, leptin was shown to differently affect insulin sensitivity, whether it was tested in skeletal muscle or in adipocytes of rodents (4, 5, 6). Indeed, leptin improved insulin sensitivity in muscle (5, 6), whereas it impaired insulin action in isolated adipocytes (4). In the present study, we found no significant correlation between adipose tissue leptin protein content and insulin-stimulated glucose uptake in vivo and in vitro. Thus, the role played by leptin in insulin action in humans remains unclear and needs further investigation. Otherwise, our data indicate a strong correlation in obese subjects between IL-6 and insulin resistance in particular at the adipose tissue level, suggesting that IL-6 could modulate insulin signaling. However, little is known about IL-6 action in adipocytes at present. On the basis of the present study, it would be important to delineate the mechanisms whereby IL-6 impedes insulin action in adipocytes. It has been demonstrated recently that TNF- counterregulates the insulin response in 3T3-L1 adipocytes by phosphorylating IRS-1 at Ser³⁰⁷ via the MAPK kinase/ERK pathway (28). Interestingly, IL-6 receptor signaling mediated via the signal transducing subunit gp130 involves several pathways, including the activation of ERK (29). Thus, it might be hypothesized that overproduction of IL-6 from adipose tissue could chronically activate the ERK pathway and induce IRS1 serine phosphorylation, therefore inhibiting insulin signaling. The links between IL-6 and insulin signaling have to be elucidated.

In conclusion, IL-6 might be an important local and systemic factor participating in the insulin-resistant state in human obesity.

Acknowledgments

Footnotes

This study was supported by grants from the Assistance Publique-Hôpitaux de Paris (AP-HP/90-132) and by Merck \|[amp ]\| Co., Inc.–LIPHA Foundation.

Abbreviations: APAAP, Alkaline phosphatase-anti-alkaline phosphatase; BMI, body mass index; CRP, C reactive protein; GIR, glucose infusion rates; HbA1c, glycated hemoglobin; IL-6R, IL-6 receptor ; NEFA, nonesterified fatty acids.

Received October 16, 2001.

Accepted January 16, 2002.

References

1. Garvey WT 1989 Insulin resistance and non insulin-dependent diabetes mellitus: which horse is pulling the cart? Diabetes Metab Rev 5:727–742[Medline]
2. Bonadonna RC, Del Prato S, Saccomani MP, Bonora E, Gulli G, Ferraninni E, Bier D, Cobelli C, De Fronzo RA 1993 Transmembrane glucose transport in skeletal muscle of patients with non-insulin-dependent diabetes. J Clin Invest 92:486–494
3. Mohamed-Ali V, Pinkney JH, Coppack SW 1998 Adipose tissue as an endocrine and paracrine organ. Int J Obes Relat Metab Disord 22:1145–1158[CrossRef][Medline]
4. Müller G, Ertl J, Gerl M, Preibisch G 1997 Leptin impairs metabolic actions of insulin in isolated rat adipocytes. J Biol Chem 272:10585–10593[Abstract/Free Full Text]
5. Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL 1999 Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401:73–76[CrossRef][Medline]
6. Yaspelkis BB, Davis JR, Saberi M, Smith TL, Jazayeri R, Singh M, Fernandez V, Trevino B, Chinookoswong N, Wang J, Shi ZQ, Levin N 2001 Leptin administration improves skeletal muscle insulin responsiveness in diet- induced insulin-resistant rats. Am J Physiol Endocrinol Metab 280:E130–E142
7. Hotamisligil GS 2000 Molecular mechanisms of insulin resistance and the role of the adipocyte. Int J Obes Relat Metab Disord 24(Suppl 4):S23–S27
8. Kern P, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB 1995 The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest 95:2111–2119
9. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM 1995 Increased adipose tissue expression of tumor necrosis factor- in human obesity and insulin resistance. J Clin Invest 95:2409–2415
10. Koistinen HA, Bastard JP, Dusserre E, Ebeling P, Zegari N, Andreelli F, Jardel C, Donner M, Meyer L, Moulin P, Hainque B, Riou JP, Laville M, Koivisto VA, Vidal H 2000 Subcutaneous adipose tissue expression of tumor necrosis factor- is not associated with whole body insulin resistance in obese nondiabetic or in type-2 diabetic subjects. Eur J Clin Invest 30:302–310[CrossRef][Medline]
11. Löfgren P, van Harmelen V, Reynisdottir S, Näslund E, Rydén M, Rössner S, Arner P 2000 Secretion of tumor necrosis factor- shows a strong relationship to insulin-stimulated glucose transport in human adipose tissue. Diabetes 49:688–692[Abstract]
12. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G 2001 Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 280:E745–E751
13. Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Klein S, Yudkin JS, Coppack SW 1997 Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor- in vivo. J Clin Endocrinol Metab 82:4196–4200[Abstract/Free Full Text]
14. Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R 1996 Effects of an engineered human anti-TNF- antibody (CDP571) on insulin sensitivity and glycaemic control in patients with NIDDM. Diabetes 45:881–885[Abstract]
15. Frittitta L, Youngren JF, Sbraccia P, D’Adamo M, Buongiorno A, Vigneri R, Goldfine ID, Trischitta V 1997 Increased adipose tissue PC-1 protein content, but not tumour necrosis factor- gene expression, is associated with a reduction of both whole body insulin sensitivity and insulin receptor tyrosine-kinase activity. Diabetologia 40:282–289[CrossRef][Medline]
16. Vgontzas AN, Papanicolaou DA, Bixler EO, Kales A, Tyson K, Chrousos GP 1997 Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab 82:1313–1316[Abstract/Free Full Text]
17. Vgontzas AN, Papanicolaou DA, Bixler EO, Hopper K, Lotsikas A, Lin HM, Kales A, Chrousos GP 2000 Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 85:1151–1158[Abstract/Free Full Text]
18. Bastard JP, Jardel C, Bruckert E, Blondy P, Capeau J, Laville M, Vidal H, Hainque B 2000 Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab 85:3338–3342[Abstract/Free Full Text]
19. Fernandez-Real JM, Vayreda M, Richart C, Guttierez C, Broch M, Vendrell J, Ricart W 2001 Circulating interleukin-6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab 86:1154–1159[Abstract/Free Full Text]
20. Bastard JP, Bruckert E, Robert JJ, Ankri A, Grimaldi A, Jardel C, Hainque B 1995 Are free fatty acids related to plasma plasminogen activator inhibitor 1 in android obesity? Int J Obes Relat Metab Disord 19:836–838[Medline]
21. De Fronzo RA, Tobin JD, Andres R 1979 Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol Endocrinol Metab 237:E214–E223
22. Bastard JP, Cuevas J, Cohen S, Jardel C, Hainque B 1994 Percutaneous adipose tissue biopsy by mini-liposuction for metabolic studies. JPEN J Parenter Enteral Nutr 18:466–468[Abstract/Free Full Text]
23. Pedersen O, Gliemann J 1981 Hexose transport in human adipocytes: factors influencing the response to insulin and kinetics of methylglucose and glucose transport. Diabetologia 20:630–635[Medline]
24. Kashiwagi A, Verso MA, Andrews J, Vasquez B, Reaven G, Foley JE 1983 In vitro insulin resistance of human adipocytes isolated from subjects with non-insulin-dependent diabetes mellitus. J Clin Invest 72:1246–1254
25. Liautard J, Gaillard JP, Mani JC, Montero-Julian F, Duperray C, Lu ZY, Jourdan M, Klein B, Brailly H, Brochier J 1994 Epitope analysis of human IL-6 receptor gp80 molecule with monoclonal antibodies. Eur Cytokine Netw 5:293–300[Medline]
26. Päth G, Bornstein SR, Gurniak M, Chrousos GP, Scherbaum WA, Hauner H 2001 Human breast adipocytes express interleukin-6 (IL-6) and its receptor system: increased IL-6 production by ß-adrenergic activation and effects of IL-6 on adipocyte function. J Clin Endocrinol Metab 86:2281–2288[Abstract/Free Full Text]
27. Vozarova B, Weyer C, Hanson K, Tataranni PA, Bogardus C, Pratley RE 2001 Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res 9:414–417[Medline]
28. Rui L, Aguirre V, Kim JK, Shulman GI, Lee A, Corbould A, Dunaif A, White MF 2001 Insulin/IGF-1 and TNF- stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest 107:181–189[CrossRef][Medline]
29. Kim H, Baumann H 1999 Dual signaling role of the protein tyrosine phosphatase SHP-2 in regulating expression of acute-phase plasma proteins by interleukin-6 cytokine receptors in hepatic cells. Mol Cell Biol 19:5326–5338[Abstract/Free Full Text]

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				A. Cartier, I. Lemieux, N. Almeras, A. Tremblay, J. Bergeron, and J.-P. Despres Visceral Obesity and Plasma Glucose-Insulin Homeostasis: Contributions of Interleukin-6 and Tumor Necrosis Factor-{alpha} in Men J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1931 - 1938. [Abstract] [Full Text] [PDF]

				D. Wu, Z. Ren, M. Pae, W. Guo, X. Cui, A. H. Merrill, and S. N. Meydani Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue J. Immunol., October 1, 2007; 179(7): 4829 - 4839. [Abstract] [Full Text] [PDF]

				R. A. Johnston, M. Zhu, Y. M. Rivera-Sanchez, F. L. Lu, T. A. Theman, L. Flynt, and S. A. Shore Allergic Airway Responses in Obese Mice Am. J. Respir. Crit. Care Med., October 1, 2007; 176(7): 650 - 658. [Abstract] [Full Text] [PDF]

				K. E. Inouye, H. Shi, J. K. Howard, C. H. Daly, G. M. Lord, B. J. Rollins, and J. S. Flier Absence of CC Chemokine Ligand 2 Does Not Limit Obesity-Associated Infiltration of Macrophages Into Adipose Tissue Diabetes, September 1, 2007; 56(9): 2242 - 2250. [Abstract] [Full Text] [PDF]

				D. M.L. Tsukumo, M. A. Carvalho-Filho, J. B.C. Carvalheira, P. O. Prada, S. M. Hirabara, A. A. Schenka, E. P. Araujo, J. Vassallo, R. Curi, L. A. Velloso, et al. Loss-of-Function Mutation in Toll-Like Receptor 4 Prevents Diet-Induced Obesity and Insulin Resistance Diabetes, August 1, 2007; 56(8): 1986 - 1998. [Abstract] [Full Text] [PDF]

				M. Qatanani and M. A. Lazar Mechanisms of obesity-associated insulin resistance: many choices on the menu Genes & Dev., June 15, 2007; 21(12): 1443 - 1455. [Abstract] [Full Text] [PDF]

				K. Ishizuka, I. Usui, Y. Kanatani, A. Bukhari, J. He, S. Fujisaka, Y. Yamazaki, H. Suzuki, K. Hiratani, M. Ishiki, et al. Chronic Tumor Necrosis Factor-{alpha} Treatment Causes Insulin Resistance via Insulin Receptor Substrate-1 Serine Phosphorylation and Suppressor of Cytokine Signaling-3 Induction in 3T3-L1 Adipocytes Endocrinology, June 1, 2007; 148(6): 2994 - 3003. [Abstract] [Full Text] [PDF]

				S. Glund, A. Deshmukh, Y. C. Long, T. Moller, H. A. Koistinen, K. Caidahl, J. R. Zierath, and A. Krook Interleukin-6 Directly Increases Glucose Metabolism in Resting Human Skeletal Muscle Diabetes, June 1, 2007; 56(6): 1630 - 1637. [Abstract] [Full Text] [PDF]

				M. P Corcoran, S. Lamon-Fava, and R. A Fielding Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise Am. J. Clinical Nutrition, March 1, 2007; 85(3): 662 - 677. [Abstract] [Full Text] [PDF]

				R. A. Mooney COUNTERPOINT: INTERLEUKIN-6 DOES NOT HAVE A BENEFICIAL ROLE IN INSULIN SENSITIVITY AND GLUCOSE HOMEOSTASIS J Appl Physiol, February 1, 2007; 102(2): 816 - 818. [Full Text] [PDF]

				REBUTTAL FROM DRS. PEDERSEN AND FEBBRAIO J Appl Physiol, February 1, 2007; 102(2): 818 - 818. [Full Text] [PDF]

				S. A. Shore Obesity and asthma: lessons from animal models J Appl Physiol, February 1, 2007; 102(2): 516 - 528. [Abstract] [Full Text] [PDF]

				B. K. Pedersen, M. A. Febbraio, and R. A. Mooney Interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis J Appl Physiol, February 1, 2007; 102(2): 814 - 816. [Full Text] [PDF]

				M. Corton, J. I. Botella-Carretero, A. Benguria, G. Villuendas, A. Zaballos, J. L. San Millan, H. F. Escobar-Morreale, and B. Peral Differential Gene Expression Profile in Omental Adipose Tissue in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 328 - 337. [Abstract] [Full Text] [PDF]

				F. L. Lu, R. A. Johnston, L. Flynt, T. A. Theman, R. D. Terry, I. N. Schwartzman, A. Lee, and S. A. Shore Increased pulmonary responses to acute ozone exposure in obese db/db mice Am J Physiol Lung Cell Mol Physiol, May 1, 2006; 290(5): L856 - L865. [Abstract] [Full Text] [PDF]

				M. Mohlig, M. Freudenberg, T. Bobbert, M. Ristow, H. Rochlitz, M. O. Weickert, A. F. H. Pfeiffer, and J. Spranger Acetylsalicylic Acid Improves Lipid-Induced Insulin Resistance in Healthy Men J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 964 - 967. [Abstract] [Full Text] [PDF]

				R. A. Johnston, T. A. Theman, and S. A. Shore Augmented responses to ozone in obese carboxypeptidase E-deficient mice Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R126 - R133. [Abstract] [Full Text] [PDF]

				O. P. Kristiansen and T. Mandrup-Poulsen Interleukin-6 and Diabetes: The Good, the Bad, or the Indifferent? Diabetes, December 1, 2005; 54(suppl_2): S114 - S124. [Abstract] [Full Text] [PDF]

				M. Cardellini, L. Perego, M. D'Adamo, M. A. Marini, C. Procopio, M. L. Hribal, F. Andreozzi, S. Frontoni, M. Giacomelli, M. Paganelli, et al. C-174G Polymorphism in the Promoter of the Interleukin-6 Gene Is Associated With Insulin Resistance Diabetes Care, August 1, 2005; 28(8): 2007 - 2012. [Abstract] [Full Text] [PDF]

				P. J. Klover, A. H. Clementi, and R. A. Mooney Interleukin-6 Depletion Selectively Improves Hepatic Insulin Action in Obesity Endocrinology, August 1, 2005; 146(8): 3417 - 3427. [Abstract] [Full Text] [PDF]

				A. M. W. Petersen and B. K. Pedersen The anti-inflammatory effect of exercise J Appl Physiol, April 1, 2005; 98(4): 1154 - 1162. [Abstract] [Full Text] [PDF]

				E. W. Petersen, A. L. Carey, M. Sacchetti, G. R. Steinberg, S. L. Macaulay, M. A. Febbraio, and B. K. Pedersen Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E155 - E162. [Abstract] [Full Text] [PDF]

				S. Zvonic, J. C. Hogan, P. Arbour-Reily, R. L. Mynatt, and J. M. Stephens Effects of Cardiotrophin on Adipocytes J. Biol. Chem., November 12, 2004; 279(46): 47572 - 47579. [Abstract] [Full Text] [PDF]

				T. You, A. S. Ryan, and B. J. Nicklas The Metabolic Syndrome in Obese Postmenopausal Women: Relationship to Body Composition, Visceral Fat, and Inflammation J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5517 - 5522. [Abstract] [Full Text] [PDF]

				M. E. Trujillo, S. Sullivan, I. Harten, S. H. Schneider, A. S. Greenberg, and S. K. Fried Interleukin-6 Regulates Human Adipose Tissue Lipid Metabolism and Leptin Production in Vitro J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5577 - 5582. [Abstract] [Full Text] [PDF]

				C. R. Bruce and D. J. Dyck Cytokine regulation of skeletal muscle fatty acid metabolism: effect of interleukin-6 and tumor necrosis factor-{alpha} Am J Physiol Endocrinol Metab, October 1, 2004; 287(4): E616 - E621. [Abstract] [Full Text] [PDF]

				A. N. Vgontzas, E. Zoumakis, H.-M. Lin, E. O. Bixler, G. Trakada, and G. P. Chrousos Marked Decrease in Sleepiness in Patients with Sleep Apnea by Etanercept, a Tumor Necrosis Factor-{alpha} Antagonist J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4409 - 4413. [Abstract] [Full Text] [PDF]

				J. Rieusset, K. Bouzakri, E. Chevillotte, N. Ricard, D. Jacquet, J.-P. Bastard, M. Laville, and H. Vidal Suppressor of Cytokine Signaling 3 Expression and Insulin Resistance in Skeletal Muscle of Obese and Type 2 Diabetic Patients Diabetes, September 1, 2004; 53(9): 2232 - 2241. [Abstract] [Full Text] [PDF]

				A. S. Ryan and B. J. Nicklas Reductions in Plasma Cytokine Levels With Weight Loss Improve Insulin Sensitivity in Overweight and Obese Postmenopausal Women Diabetes Care, July 1, 2004; 27(7): 1699 - 1705. [Abstract] [Full Text] [PDF]

				J. N. Fain, A. K. Madan, M. L. Hiler, P. Cheema, and S. W. Bahouth Comparison of the Release of Adipokines by Adipose Tissue, Adipose Tissue Matrix, and Adipocytes from Visceral and Subcutaneous Abdominal Adipose Tissues of Obese Humans Endocrinology, May 1, 2004; 145(5): 2273 - 2282. [Abstract] [Full Text] [PDF]

				K. E. Wellen, K. T. Uysal, S. Wiesbrock, Q. Yang, H. Chen, and G. S. Hotamisligil Interaction of Tumor Necrosis Factor-{alpha}- and Thiazolidinedione-Regulated Pathways in Obesity Endocrinology, May 1, 2004; 145(5): 2214 - 2220. [Abstract] [Full Text] [PDF]

				M. Mohlig, H. Boeing, J. Spranger, M. Osterhoff, A. Kroke, E. Fisher, M. M. Bergmann, M. Ristow, K. Hoffmann, and A. F. H. Pfeiffer Body Mass Index and C-174G Interleukin-6 Promoter Polymorphism Interact in Predicting Type 2 Diabetes J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1885 - 1890. [Abstract] [Full Text] [PDF]

				P. J. Klover, T. A. Zimmers, L. G. Koniaris, and R. A. Mooney Chronic Exposure to Interleukin-6 Causes Hepatic Insulin Resistance in Mice Diabetes, November 1, 2003; 52(11): 2784 - 2789. [Abstract] [Full Text] [PDF]

				L. B Tanko, Y. Z Bagger, P. Alexandersen, P. J Larsen, C. Christiansen, and for the PERF study group Central and peripheral fat mass have contrasting effect on the progression of aortic calcification in postmenopausal women Eur. Heart J., August 2, 2003; 24(16): 1531 - 1537. [Abstract] [Full Text] [PDF]

				J. M. Fernandez-Real and W. Ricart Insulin Resistance and Chronic Cardiovascular Inflammatory Syndrome Endocr. Rev., June 1, 2003; 24(3): 278 - 301. [Abstract] [Full Text] [PDF]

				J. J. Senn, P. J. Klover, I. A. Nowak, T. A. Zimmers, L. G. Koniaris, R. W. Furlanetto, and R. A. Mooney Suppressor of Cytokine Signaling-3 (SOCS-3), a Potential Mediator of Interleukin-6-dependent Insulin Resistance in Hepatocytes J. Biol. Chem., April 11, 2003; 278(16): 13740 - 13746. [Abstract] [Full Text] [PDF]

				S. Zvonic, P. Cornelius, W. C. Stewart, R. L. Mynatt, and J. M. Stephens The Regulation and Activation of Ciliary Neurotrophic Factor Signaling Proteins in Adipocytes J. Biol. Chem., January 17, 2003; 278(4): 2228 - 2235. [Abstract] [Full Text] [PDF]

				M. Freemark Pharmacologic Approaches to the Prevention of Type 2 Diabetes in High Risk Pediatric Patients J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 3 - 13. [Full Text] [PDF]

				M. Fukui, Y. Kitagawa, N. Nakamura, and T. Yoshikawa Response to Oncul: Insulin sensitivity in patients with chronic hepatitis C virus infection Diabetes Care, October 1, 2002; 25(10): 1900 - 1901. [Full Text]

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