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Division of Endocrinology, Department of Medicine, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Adipose tissue expresses
tumor necrosis factor (TNF) and interleukin (IL)-6, which may cause
obesity-related insulin resistance. We measured TNF and IL-6 expression
in the adipose tissue of 50 lean and obese subjects without diabetes.
Insulin sensitivity (SI) was determined by an intravenous
glucose tolerance test with minimal-model analysis. When lean [body
mass index (BMI) <25 kg/m2] and obese (BMI 30-40
kg/m2) subjects were compared, there was a 7.5-fold
increase in TNF secretion (P < 0.05) from adipose tissue,
and the TNF secretion was inversely related to SI
(r = 
0.42, P < 0.02). IL-6 was
abundantly expressed by adipose tissue. In contrast to TNF, plasma
(rather than adipose) IL-6 demonstrated the strongest relationship with obesity and insulin resistance. Plasma IL-6 was significantly higher in
obese subjects and demonstrated a highly significant inverse
relationship with SI (r = 0.71,
P < 0.001). To separate the effects of BMI from
SI, subjects who were discordant for SI were
matched for BMI, age, and gender. By use of this approach, subjects
with low SI demonstrated a 3.0-fold increased level of TNF
secretion from adipose tissue and a 2.3-fold higher plasma IL-6 level
(P < 0.05) compared with matched subjects with a high SI. Plasma IL-6 was significantly associated with plasma
nonesterified fatty acid levels (r = 0.49, P < 0.002). Thus the local expression of TNF and
plasma IL-6 are higher in subjects with obesity-related insulin resistance.
type 2 diabetes
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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OBESITY HAS BECOME a national epidemic with enormous public health implications (25), and recent studies have demonstrated a further 6% increase in the incidence of obesity [body mass index (BMI) >30 kg/m2] over a 7-yr period (30). There is a strong correlation between obesity and insulin resistance in both diabetic and nondiabetic subjects (27), and the risk of diabetes increases 11-fold as the BMI increases from 20 to 30 (8). Although insulin resistance accompanies all patients who become obese, the degree of insulin resistance varies considerably, and the relationships between obesity, insulin resistance, and type 2 diabetes are not well understood.
Obesity represents an expansion of adipose tissue mass, and one
explanation for obesity-related insulin resistance is the production of
factors by adipose tissue that render some subjects more insulin
resistant than others. Numerous adipocyte secretory products have
recently been described that play a role in carbohydrate and lipid
metabolism (14, 21, 23). One such adipocyte secretory product is tumor necrosis factor (TNF)-
. A new role for TNF was proposed in 1993 with the description of TNF expression by adipose tissue and the elevated expression of TNF in obese, insulin-resistant rodents and humans (17, 20, 24). Although it is unclear how adipose TNF expression may cause insulin resistance
(36), TNF is known to impair insulin receptor signaling
(18). TNF also inhibits lipoprotein lipase (LPL) and
stimulates lipolysis in adipocytes (34), and the resulting
increase in circulating nonesterified fatty acids (NEFA) would be
expected to contribute to insulin resistance (7).
Another adipocyte secretory product that may be involved in insulin resistance is interleukin (IL)-6, which is a cytokine secreted by many cells, including adipocytes and adipose stromal cells (11, 15). Like TNF, IL-6 inhibits the expression of LPL, but, unlike TNF, IL-6 does not stimulate lipolysis (13, 16). IL-6 secretion is increased in the adipocytes of obese subjects (29) and may be important either as a circulating hormone or as a local regulator of insulin action.
Although many studies have examined the role of TNF in insulin resistance, relatively few of these have been in humans, and none has examined cytokine expression in detail along with the measurement of insulin resistance. In this study, we examined the expression of TNF and IL-6 in human adipose tissue from nondiabetic subjects with varying degrees of obesity and insulin resistance. We found that TNF secretion from human adipose tissue and circulating plasma IL-6 were both highly associated with obesity-associated insulin resistance.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. Fifty subjects were recruited for these studies. This research was approved by the Institutional Review Board, and all subjects gave informed consent. All subjects were weight stable at the time of the study. Subjects initially underwent an oral glucose tolerance test using 75 g of glucose, and blood glucose was measured fasting and at 2 h. Subjects with diabetes (fasting blood sugar >126 mg/dl, 2-h glucose >200 mg/dl) were excluded. Of the 50 subjects, 15 had impaired glucose tolerance based on a 2-h glucose of 140-200 mg/dl, and three of these subjects had impaired fasting glucose based on a fasting glucose of 110-126 mg/dl. Subjects then underwent a frequently sampled intravenous glucose tolerance test (FSIVGTT) and an adipose tissue biopsy. The FSIVGTT and the biopsy were performed at least 3 days apart.
Characteristics of the subjects that comprised this study are shown in Table 1. Blood lipids were measured using standard clinical assays, and plasma NEFA were measured using a colorimetric assay (Waco Chemical, Richmond, VA). Of the 50 subjects studied, 39 were women and 8 were African-American. The subjects ranged from lean to very obese, and insulin sensitivity (SI; using the SI index from the FSIVGTT] varied considerably. Some subjects demonstrated moderate dyslipidemia, but no subject demonstrated fasting triglycerides >400 mg/dl. Body composition was determined using bioelectric impedance (38).
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SI measurements. The measurement of in vivo SI was performed in the fasting state with the minimal-model analysis of the FSIVGTT (4, 5). We used the classic tolbutamide-modified test, which has been validated against the euglycemic clamp in humans (6, 41). In brief, catheters were placed for glucose injection and blood sampling. Four basal blood samples were obtained, and the patient was given an intravenous glucose bolus (11.4 g/m2) at time 0. At 20 min after the glucose injection, patients were given an injection of tolbutamide (125 mg/m2), again followed by frequent blood sampling, according to the standard protocol. Together, 4 basal and 27 postglucose blood samples were taken, the last one at 240 min. Glucose was measured in a glucose analyzer by use of the glucose oxidase method, and insulin was measured using radioimmunoassay. These measurements were performed in the Endocrinology Laboratory of the Indiana University School of Medicine (Indianapolis, IN). The SI was calculated using the MINMOD program (4) and was expressed in microunits per milliliter per minute.
Adipose tissue biopsy. Abdominal subcutaneous adipose tissue (~10 g) was removed from each patient by incision, which avoids trauma to fat cells and minimizes the amount of blood in contact with the fat cells. Some of the tissue was immediately frozen in liquid N2 for later RNA extraction, whereas the rest of the tissue was placed into cold DMEM for other assays.
Adipose tissue cytokine secretion.
TNF and IL-6 may function in an autocrine or paracrine manner; hence,
we wished to measure the local secretion of these cytokines into the
medium. Immediately after the biopsy, adipose tissue pieces of ~500
mg were minced and placed into serum-free DMEM (pH 7.4, 10 mM HEPES) at
37°C for varying times. Figure 1
illustrates the secretion of TNF and IL-6 into the medium of three
subjects. There was little secretion of either cytokine into the medium for the first 60 min, followed by an increase in secretion over the
next 60 min. Medium cytokine levels continued to increase for up to
24 h. To compare TNF and IL-6 secretion among different subjects,
we measured cytokine levels in the medium after 2 h at 37°C. All
data were normalized to adipose DNA content to control for differences
in fat cell size. In general, IL-6 secretion from adipose tissue was
much higher than TNF. In all subjects studied, the TNF level in the
medium at 2 h was 0.78 ± 0.14 pg/µg DNA, and the IL-6
level in the medium was 9.8 ± 1.8 pg/µg DNA.
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Measurement of TNF and IL-6. Adipose tissue TNF protein was measured using an ELISA (R&D Systems, Minneapolis, MN). This assay demonstrates an 8% intra-assay and a 15% interassay variation. This ELISA method was used to measure TNF in fasting plasma as well as TNF secretion by adipose tissue (see Relationship between TNF and obesity). TNF mRNA levels were measured by competitive RT-PCR, as described by us previously (24). IL-6 was measured in fasting plasma and secreted from adipose tissue using an ELISA assay (R&D Systems). This assay demonstrates intra- and interassay variations of <5%.
Statistics.
All data are expressed as means ± SE. To analyze data between
groups, a one-way ANOVA was performed, and secondary analysis was
performed with the Student's t-test with Bonferroni
correction. Analysis of trends was performed using linear regression
after log transformation. The Wilcoxon matched-pair sign-rank test was used for the paired data in Table 2.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Relationship between TNF and obesity.
To better define the effects of obesity on TNF expression, we measured
TNF mRNA in the adipose tissue from each subject, along with plasma TNF
and TNF secretion from the adipose tissue. Subjects were divided into
four BMI groups representing lean (BMI <25, n = 9),
overweight (BMI 25-30, n = 9), moderately obese
(BMI 30-40, n = 17), and very obese subjects (BMI
>40, n = 15). Figure
2B shows TNF mRNA levels from
subjects with increasing BMI. There was considerable variability among
the obese subject groups with respect to TNF mRNA levels, such that the
differences between normal lean subjects (BMI <25 kg/m2)
and obese subjects were not statistically significant (NS; Fig. 2B). TNF protein was also measured in these subjects;
however, as shown in Fig. 2A, there was no relationship
between plasma TNF and BMI. However, TNF secretion from the adipose
tissue was higher in obese subjects. Mean TNF secretion was 0.16 ± 0.06 pg/µg DNA in lean subjects (BMI <25 kg/m2), and
1.21 ± 0.36 pg/µg DNA in subjects with a BMI between 30 and 40 kg/m2 (P < 0.05). Subjects with a BMI >45
kg/m2 demonstrated slightly lower TNF secretion (0.90 ± 0.21 pg/µg DNA), but this was not significantly decreased compared
with subjects with a BMI of 30-40 kg/m2. This effect
of BMI on TNF secretion was still present when women and Caucasians
were each considered separately and when subjects with impaired glucose
tolerance were eliminated. TNF secretion from adipose tissue was also
low in subjects with low body fat. TNF secretion in subjects with
<30%, 30-45%, and >45% body fat was 0.16 ± 0.07 (n = 10), 0.76 ± 0.16 (n = 14),
and 1.1 ± 0.28 pg/µg DNA (n = 18, P < 0.05 vs. <30% group).
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TNF expression and insulin sensitivity.
As expected, there was a significant relationship between obesity and
insulin sensitivity. As described previously by others (22), the relationship between BMI and SI is
curvilinear and best represented by a log/log transformation, and in
our subjects, BMI and SI were significantly related
(r = 0.65, P < 0.001). Because
SI varies considerably among nonobese subjects with normal glucose tolerance, we did not divide SI into subgroups but
instead examined TNF expression over the spectrum of SI.
There was no significant relationship between either plasma TNF or TNF
mRNA levels and SI (data not shown). However, there was a
significant decrease in TNF secretion with increasing SI
(Fig. 3), such that most of the
insulin-sensitive subjects (SI >5) had lower levels of TNF
secretion, and most of the insulin-resistant subjects (SI <2) had the highest levels of TNF secretion.
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IL-6 expression with obesity and insulin resistance.
The adipose tissue fragments secreted relatively high levels of IL-6.
When IL-6 expression was examined in the same BMI groups, as described
in the preceding section for TNF, there was a tendency for an increase
in IL-6 secretion from adipose tissue with increasing BMI and
increasing body fat (Fig. 4B);
however, these changes were not statistically significant. Plasma IL-6,
however, was strongly associated with increasing obesity (Fig.
4A). In lean subjects (BMI <25), plasma IL-6 was 0.73 ± 0.23 pg/ml and increased about fourfold to 2.86 ± 0.61 pg/ml
in the most obese subjects (BMI >40, P < 0.05). In a
similar manner, plasma IL-6 was lower in subjects with low percent body
fat. Plasma IL-6 was 0.84 ± 0.19 pg/ml (n = 10)
in subjects with <30% body fat and was 2.05 ± 0.38 (n = 14) and 2.58 ± 0.44 (n = 18)
pg/ml in subjects with 30-45 and >45% fat, respectively
(P < 0.05). The relationship between SI
and plasma IL-6 was examined in the same manner as described for TNF.
In contrast to TNF, adipose-secreted IL-6 demonstrated no significant
relationship with SI (r = 0.04,
P = NS). However, there was a highly significant
relationship (r = 0.71, n = 38, P < 0.001) between plasma IL-6 and SI, as
shown in Fig. 5. Plasma IL-6 was 3.0 ± 0.53 pg/ml in the most insulin-resistant subjects (SI
<2) and was 0.82 ± 0.19 pg/ml in the most insulin-sensitive subjects (SI >5, P < 0.05).
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Cytokines and insulin resistance independent of obesity. Insulin resistance is exacerbated by obesity, leading to a significant relationship between SI and BMI. Therefore, we examined the relationship between adipose cytokine expression and SI without the confounding effects of BMI. To factor out obesity, we identified subjects who were of the same BMI but who were discordant for SI. We compared the cytokine expression of subjects with insulin resistance (SI <2.0) with that of subjects with less insulin resistance (SI >3.0) who were matched for BMI (±5 kg/m2), age (±10 yr), and gender. Using these criteria, we were able to match nine subjects with SI <2.0 with nine subjects with SI >3.0. As shown in Table 2, these subjects were well matched for age and BMI, and there were significant differences in SI by virtue of subject selection. No differences were noted between plasma TNF or adipose IL-6 expression. However, the insulin-resistant subjects had significantly higher levels of plasma IL-6 as well as significantly higher levels of adipose TNF secretion (P < 0.05). In these matched subjects, TNF secretion and plasma IL-6 were two- to threefold higher in the insulin-resistant subjects.
Previous studies have demonstrated that IL-6 and TNF interact with each other in both 3T3-L1 adipocytes and mice (3, 16). We examined TNF and IL-6 expression from each subject's adipose tissue to determine whether there was any relationship between IL-6 and TNF expression. As shown in Fig. 7, there was a strong linear relationship between the secretions of IL-6 and TNF from the adipose tissue (r = 0.81, P < 0.0001). On the other hand, there was no significant relationship between plasma IL-6 and plasma TNF (data not shown).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Since the initial description of TNF expression by adipose tissue, several lines of evidence have suggested that TNF overproduction by adipose tissue may be involved in the pathogenesis of the insulin resistance of obesity. TNF mRNA levels were high in obese, insulin-resistant rodents, and the infusion of a soluble TNF binding protein into insulin-resistant fa/fa rats improved insulin sensitivity and improved the defect in insulin receptor and insulin receptor substrate-1 autophosphorylation in fat and muscle (18, 20). Recent studies using genetic manipulations resulting in knockout or depletion of TNF or TNF receptor have confirmed the importance of TNF in rodent insulin resistance (9, 19, 40), although one such study (37) found no role for TNF or the TNF receptor in insulin resistance.
Relatively few studies have examined the relationship between TNF and insulin resistance in humans. Studies by us (24) and others (1, 17) demonstrated elevated levels of adipose TNF mRNA and protein in obese subjects and a decrease in TNF with weight loss. No study has examined the relationship between SI and TNF, although one study noted a significant correlation between TNF mRNA levels and fasting insulin (17), and several studies observed a decrease in TNF after weight loss (12, 17, 24). High TNF secretion from human adipose tissue was associated with decreased [3H]glucose incorporation into lipids (26).
It is not clear whether TNF functions locally or circulates in a sufficiently high concentration to influence distant targets. Plasma TNF has been measured, and several studies have observed increased plasma TNF levels in obese subjects and in subjects with hyperinsulinemia or insulin resistance (10, 42, 43). Plasma TNF was elevated in male diabetic subjects compared with male controls, but no such relationship was observed in women (35). In an attempt to bind plasma TNF and reverse insulin resistance in humans, diabetic or insulin-resistant subjects have been given an injection of anti-TNF binding protein. In both studies, there was no improvement in insulin resistance (31, 33).
The role of IL-6 in insulin resistance has been much less studied. IL-6 is secreted by many cells, including adipocytes and adipose stromal cells (11, 15) and is increased after a meal (32). Like TNF, IL-6 inhibits the expression of LPL, but unlike TNF, IL-6 does not stimulate lipolysis (13, 16). Linking IL-6 to insulin resistance are studies demonstrating increased IL-6 secretion in the adipocytes of subjects with obesity (29) and diabetes (2).
In the studies described herein, we measured TNF and IL-6 gene expression at several levels from the adipose tissue of lean and obese subjects and related this expression to SI, a reliable measure of insulin sensitivity. Both IL-6 and TNF were expressed and secreted by human adipose tissue, although IL-6 levels were much higher in both adipose tissue and plasma. The most consistent relationship between cytokine expression and obesity-related insulin resistance involved increased TNF secretion from adipose tissue and increased plasma IL-6 levels. Elevated TNF and IL-6 expression was found in subjects who were only moderately obese (BMI >30) and increased progressively with decreasing SI. The relationship between plasma IL-6 and SI was very strong, with a highly significant inverse correlation and a fivefold difference between the most insulin-resistant and most insulin-sensitive subjects. Thus both TNF and IL-6 were associated with both obesity and insulin resistance; however, it was the adipose-secreted form of TNF and the plasma level of IL-6 that displayed the strongest relationships.
The subjects in this study were heterogeneous with regard to degree of obesity, gender, and race, and it is possible that a study using a more focused group of subjects would yield different results. However, we observed no consistent effect of gender or race on cytokine expression in these subjects. This study also relied on plasma cytokine levels and cytokine secretion from adipose tissue, and these measurements may not be reflective of cytokine biological effects at the tissue level.
Because obesity and insulin resistance are related to each other, we wished to determine whether TNF and IL-6 expression were related to insulin resistance independently of obesity. As described in Table 2, we paired insulin-resistant subjects with more-insulin-sensitive subjects and matched them for BMI and age. By use of this analysis, high levels of TNF secretion and plasma IL-6 were both significantly associated with insulin resistance. Thus the expression of these cytokines was associated with insulin resistance independently of obesity.
There are differences in the expression of TNF and IL-6 that may be important in understanding their functions. IL-6 was secreted at high levels from adipose tissue, and there was a significant arteriovenous difference in IL-6 across the adipose tissue bed, whereas there was no arteriovenous difference with TNF (29). We found no relationship between plasma TNF and obesity or insulin resistance, although other studies have noted increased plasma TNF with obesity (2, 10, 42, 43). IL-6 and TNF may interact with each other, as suggested by the strong correlation between TNF secretion and IL-6 secretion in this study and by previous studies that demonstrated increased IL-6 expression in response to TNF (3, 16). Together, these data suggest that TNF functions locally at the level of the adipocyte in a paracrine fashion, perhaps stimulating the secretion of NEFA, IL-6, or other circulating substances. On the other hand, plasma IL-6 circulates at high levels and may be more important systemically and perhaps represents a hormonal factor that induces muscle insulin resistance.
It is noteworthy that two studies have tried, and failed, to reverse insulin resistance with an injection of anti-TNF binding proteins (31, 33). On the basis of the studies described herein, we can speculate on several possible reasons for the failure of anti-TNF therapy in humans. If TNF functions in a paracrine or autocrine fashion in adipose tissue, then the anti-TNF binding proteins may not reach the microcirculation in sufficient concentration to prevent TNF-mediated effects. In addition, our data raise the possibility that IL-6 is the major circulating component of obesity-related insulin resistance.
The development of insulin resistance with increasing adiposity suggests that an adipocyte product may be important in insulin resistance. Both TNF and IL-6 are adipocyte products that are overexpressed in obese insulin-resistant subjects, and we have shown that the secretion of these cytokines is interrelated. Some of these cytokines may function systemically, others may function locally, and still others may function to increase the secretion or synthesis of other adipocyte factors or to act as an adjuvant to the actions of other insulin resistance factors. One such insulin resistance factor is NEFA, which are closely associated with insulin resistance (28, 39). TNF stimulates lipolysis in adipocytes (34); hence, it is possible that TNF functions at the level of the adipocyte to stimulate lipolysis. Although IL-6 is not known to stimulate lipolysis (13, 16), we found a significant relationship between plasma IL-6 and plasma NEFA levels, whereas the relationship between TNF expression and plasma NEFA was much less robust.
These studies provide the first comprehensive analysis of IL-6 expression in obese, insulin-resistant humans and add to the data on TNF expression. Together, these studies suggest that obesity-related insulin resistance represents a complex syndrome, mediated by a number of adipocyte secretory products, which ultimately lead to defects in insulin action in other target organs.
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ACKNOWLEDGEMENTS |
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We thank Dr. Richard Evans for statistical assistance, Denise Hargrove for assistance with subject recruitment, and the nurses of the General Clinical Research Center at the University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System. We also thank Dr. Richard Bergman for supplying the MINMOD program, and Sarah Dunn for excellent secretarial assistance.
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FOOTNOTES |
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This study was supported by a Veterans Affairs Department Merit Review Grant M01-RR-14288 of the General Clinical Research Center, a Career Development Award from the American Diabetes Association, and DK-39176 from the National Institutes of Health.
Address for reprint requests and other correspondence: P. A. Kern, Central Arkansas Veterans Healthcare System, 598/151 LR 4300 West 7th St., Little Rock, AR 72205 (E-mail: KernPhilipA{at}uams.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 1 August 2000; accepted in final form 23 January 2001.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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 W. Lim, S. Hong, R. Nelesen, and J. E. Dimsdale The Association of Obesity, Cytokine Levels, and Depressive Symptoms With Diverse Measures of Fatigue in Healthy Subjects Arch Intern Med, April 25, 2005; 165(8): 910 - 915. [Abstract] [Full Text] [PDF]
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B. Wang, J. R. Jenkins, and P. Trayhurn Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: integrated response to TNF-{alpha} Am J Physiol Endocrinol Metab, April 1, 2005; 288(4): E731 - E740. [Abstract] [Full Text] [PDF]
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 F. Haugen, N. Zahid, K. T. Dalen, K. Hollung, H. I. Nebb, and C. A. Drevon Resistin expression in 3T3-L1 adipocytes is reduced by arachidonic acid J. Lipid Res., January 1, 2005; 46(1): 143 - 153. [Abstract] [Full Text] [PDF]
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 J. Okapcova and D. Gabor The Levels of Soluble Adhesion Molecules in Diabetic and Nondiabetic Patients with Combined Hyperlipoproteinemia and the Effect of Ciprofibrate Therapy Angiology, November 1, 2004; 55(6): 629 - 639. [Abstract] [PDF]
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J. Okapcova and D. Gabor The Levels of Soluble Adhesion Molecules in Diabetic and Nondiabetic Patients with Combined Hyperlipoproteinemia and the Effect of Ciprofibrate Therapy Angiology, November 1, 2004; 55(6): 629 - 639. [Abstract] [PDF]
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 L. Khaodhiar, P.-R. Ling, G. L. Blackburn, and B. R. Bistrian Serum Levels of Interleukin-6 and C-Reactive Protein Correlate With Body Mass Index Across the Broad Range of Obesity JPEN J Parenter Enteral Nutr, November 1, 2004; 28(6): 410 - 415. [Abstract] [Full Text] [PDF]
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P. Keller, C. Keller, L. E. Robinson, and B. K. Pedersen Epinephrine infusion increases adipose interleukin-6 gene expression and systemic levels in humans J Appl Physiol, October 1, 2004; 97(4): 1309 - 1312. [Abstract] [Full Text] [PDF]
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J. A. McKenzie, E. P. Weiss, I. A. Ghiu, O. Kulaputana, D. A. Phares, R. E. Ferrell, and J. M. Hagberg Influence of the interleukin-6 -174 G/C gene polymorphism on exercise training-induced changes in glucose tolerance indexes J Appl Physiol, October 1, 2004; 97(4): 1338 - 1342. [Abstract] [Full Text] [PDF]
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G. B. Di Gregorio, R. Westergren, S. Enerback, T. Lu, and P. A. Kern Expression of FOXC2 in adipose and muscle and its association with whole body insulin sensitivity Am J Physiol Endocrinol Metab, October 1, 2004; 287(4): E799 - E803. [Abstract] [Full Text] [PDF]
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G. B. Di Gregorio, L. Hensley, T. Lu, G. Ranganathan, and P. A. Kern Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene: absence of development of age-related obesity Am J Physiol Endocrinol Metab, July 1, 2004; 287(1): E182 - E187. [Abstract] [Full Text] [PDF]
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T. Skurk, V. van Harmelen, and H. Hauner Angiotensin II Stimulates the Release of Interleukin-6 and Interleukin-8 From Cultured Human Adipocytes by Activation of NF-{kappa}B Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1199 - 1203. [Abstract] [Full Text] [PDF]
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 S. Klein, L. Fontana, V. L. Young, A. R. Coggan, C. Kilo, B. W. Patterson, and B. S. Mohammed Absence of an Effect of Liposuction on Insulin Action and Risk Factors for Coronary Heart Disease N. Engl. J. Med., June 17, 2004; 350(25): 2549 - 2557. [Abstract] [Full Text] [PDF]
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C. Weigert, K. Brodbeck, H. Staiger, C. Kausch, F. Machicao, H. U. Haring, and E. D. Schleicher Palmitate, but Not Unsaturated Fatty Acids, Induces the Expression of Interleukin-6 in Human Myotubes through Proteasome-dependent Activation of Nuclear Factor-{kappa}B J. Biol. Chem., June 4, 2004; 279(23): 23942 - 23952. [Abstract] [Full Text] [PDF]
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 J. T. Lane Microalbuminuria as a marker of cardiovascular and renal risk in type 2 diabetes mellitus: a temporal perspective Am J Physiol Renal Physiol, March 1, 2004; 286(3): F442 - F450. [Abstract] [Full Text] [PDF]
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 K. M. Ajuwon, S. K. Jacobi, J. L. Kuske, and M. E. Spurlock Interleukin-6 and interleukin-15 are selectively regulated by lipopolysaccharide and interferon-{gamma} in primary pig adipocytes Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2004; 286(3): R547 - R553. [Abstract] [Full Text] [PDF]
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K. F. Petersen, S. Dufour, D. Befroy, R. Garcia, and G. I. Shulman Impaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes N. Engl. J. Med., February 12, 2004; 350(7): 664 - 671. [Abstract] [Full Text] [PDF]
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R. Krogh-Madsen, P. Plomgaard, P. Keller, C. Keller, and B. K. Pedersen Insulin stimulates interleukin-6 and tumor necrosis factor-{alpha} gene expression in human subcutaneous adipose tissue Am J Physiol Endocrinol Metab, February 1, 2004; 286(2): E234 - E238. [Abstract] [Full Text] [PDF]
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J. A. Johnson, J. B. Albu, E. S. Engelson, S. K. Fried, Y. Inada, G. Ionescu, and D. P. Kotler Increased systemic and adipose tissue cytokines in patients with HIV-associated lipodystrophy Am J Physiol Endocrinol Metab, February 1, 2004; 286(2): E261 - E271. [Abstract] [Full Text] [PDF]
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H. Wang, W. S. Chu, T. Lu, S. J. Hasstedt, P. A. Kern, and S. C. Elbein Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion Am J Physiol Endocrinol Metab, January 1, 2004; 286(1): E1 - E7. [Abstract] [Full Text]
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T. Mazurek, L. Zhang, A. Zalewski, J. D. Mannion, J. T. Diehl, H. Arafat, L. Sarov-Blat, S. O'Brien, E. A. Keiper, A. G. Johnson, et al. Human Epicardial Adipose Tissue Is a Source of Inflammatory Mediators Circulation, November 18, 2003; 108(20): 2460 - 2466. [Abstract] [Full Text] [PDF]
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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]
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C. Rask-Madsen, H. Dominguez, N. Ihlemann, T. Hermann, L. Kober, and C. Torp-Pedersen Tumor Necrosis Factor-{alpha} Inhibits Insulin's Stimulating Effect on Glucose Uptake and Endothelium-Dependent Vasodilation in Humans Circulation, October 14, 2003; 108(15): 1815 - 1821. [Abstract] [Full Text] [PDF]
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S. P. Kim, M. Ellmerer, G. W. Van Citters, and R. N. Bergman Primacy of Hepatic Insulin Resistance in the Development of the Metabolic Syndrome Induced by an Isocaloric Moderate-Fat Diet in the Dog Diabetes, October 1, 2003; 52(10): 2453 - 2460. [Abstract] [Full Text] [PDF]
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 J. A. Daniel, T. H. Elsasser, C. D. Morrison, D. H. Keisler, B. K. Whitlock, B. Steele, D. Pugh, and J. L. Sartin Leptin, tumor necrosis factor-{alpha} (TNF), and CD14 in ovine adipose tissue and changes in circulating TNF in lean and fat sheep J Anim Sci, October 1, 2003; 81(10): 2590 - 2599. [Abstract] [Full Text] [PDF]
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J. M. Bruun, A. S. Lihn, C. Verdich, S. B. Pedersen, S. Toubro, A. Astrup, and B. Richelsen Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans Am J Physiol Endocrinol Metab, September 1, 2003; 285(3): E527 - E533. [Abstract] [Full Text] [PDF]
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N. Varo, D. Vicent, P. Libby, R. Nuzzo, A. L. Calle-Pascual, M. R. Bernal, A. Fernandez-Cruz, A. Veves, P. Jarolim, J. J. Varo, et al. Elevated Plasma Levels of the Atherogenic Mediator Soluble CD40 Ligand in Diabetic Patients: A Novel Target of Thiazolidinediones Circulation, June 3, 2003; 107(21): 2664 - 2669. [Abstract] [Full Text] [PDF]
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H.P. Kopp, C.W. Kopp, A. Festa, K. Krzyzanowska, S. Kriwanek, E. Minar, R. Roka, and G. Schernthaner Impact of Weight Loss on Inflammatory Proteins and Their Association With the Insulin Resistance Syndrome in Morbidly Obese Patients Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 1042 - 1047. [Abstract] [Full Text] [PDF]
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T.-B. Nguyen-Duy, M. Z. Nichaman, T. S. Church, S. N. Blair, and R. Ross Visceral fat and liver fat are independent predictors of metabolic risk factors in men Am J Physiol Endocrinol Metab, June 1, 2003; 284(6): E1065 - E1071. [Abstract] [Full Text] [PDF]
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A. Abderrahim-Ferkoune, O. Bezy, C. Chiellini, M. Maffei, P. Grimaldi, F. Bonino, N. Moustaid-Moussa, F. Pasqualini, A. Mantovani, G. Ailhaud, et al. Characterization of the long pentraxin PTX3 as a TNF{alpha}-induced secreted protein of adipose cells J. Lipid Res., May 1, 2003; 44(5): 994 - 1000. [Abstract] [Full Text] [PDF]
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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]
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S. Engeli, M. Feldpausch, K. Gorzelniak, F. Hartwig, U. Heintze, J. Janke, M. Mohlig, A. F.H. Pfeiffer, F. C. Luft, and A. M. Sharma Association Between Adiponectin and Mediators of Inflammation in Obese Women Diabetes, April 1, 2003; 52(4): 942 - 947. [Abstract] [Full Text] [PDF]
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M. Wolf, L. Sandler, K. Hsu, K. Vossen-Smirnakis, J. L. Ecker, and R. Thadhani First-Trimester C-Reactive Protein and Subsequent Gestational Diabetes Diabetes Care, March 1, 2003; 26(3): 819 - 824. [Abstract] [Full Text] [PDF]
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H. Lan, M. E. Rabaglia, J. P. Stoehr, S. T. Nadler, K. L. Schueler, F. Zou, B. S. Yandell, and A. D. Attie Gene Expression Profiles of Nondiabetic and Diabetic Obese Mice Suggest a Role of Hepatic Lipogenic Capacity in Diabetes Susceptibility Diabetes, March 1, 2003; 52(3): 688 - 700. [Abstract] [Full Text] [PDF]
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J. J. Senn, P. J. Klover, I. A. Nowak, and R. A. Mooney Interleukin-6 Induces Cellular Insulin Resistance in Hepatocytes Diabetes, December 1, 2002; 51(12): 3391 - 3399. [Abstract] [Full Text] [PDF]
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A. Steensberg, C. Keller, R. L. Starkie, T. Osada, M. A. Febbraio, and B. K. Pedersen IL-6 and TNF-alpha expression in, and release from, contracting human skeletal muscle Am J Physiol Endocrinol Metab, December 1, 2002; 283(6): E1272 - E1278. [Abstract] [Full Text] [PDF]
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