Division of Endocrinology, Department of Medicine, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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).
|
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.
|
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.
|
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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).
|
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.
|
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).
|
|
|
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).
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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.
![]() |
ACKNOWLEDGEMENTS |
---|
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.
![]() |
FOOTNOTES |
---|
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.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Arner, P.
Obesity and insulin resistance in Swedish subjects.
Diabet Med
13, Suppl6:
S85-S86,
1996[ISI][Medline].
2.
Bastard, JP,
Jardel C,
Bruckert E,
Blondy P,
Capeau J,
Laville M,
Vidal H,
and
Hainque B.
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,
2000
3.
Berg, M,
Fraker DL,
and
Alexander HR.
Characterization of differentiation factor/leukaemia inhibitory factor effect on lipoprotein lipase activity and mRNA in 3T3-L1 adipocytes.
Cytokine
6:
425-432,
1994[ISI][Medline].
4.
Bergman, RN,
Finegood DT,
and
Ader M.
Assessment of insulin sensitivity in vivo.
Endocr Rev
6:
45-86,
1985[ISI][Medline].
5.
Bergman, RN,
Phillips LS,
and
Cobelli C.
Physiologic evaluation of factors controlling glucose tolerance in man. Measurement of insulin sensitivity and beta-cell sensitivity from the response to intravenous glucose.
J Clin Invest
68:
1456-1467,
1981[ISI][Medline].
6.
Bergman, RN,
Prager R,
Volund A,
and
Olefsky JM.
Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp.
J Clin Invest
79:
790-800,
1987[ISI][Medline].
7.
Boden, G.
Role of fatty acids in the pathogenesis of insulin resistance and NIDDM.
Diabetes
46:
3-10,
1997[Abstract].
8.
Carey, VJ,
Walters EE,
Colditz GA,
Solomon CG,
Willett WC,
Rosner BA,
Speizer FE,
and
Manson JE.
Body fat distribution and risk of noninsulin-dependent diabetes mellitus in women. The Nurses' Health Study.
Am J Epidemiol
145:
614-619,
1997[Abstract].
9.
Cheung, AT,
Ree D,
Kolls JK,
Fuselier J,
Coy DH,
and
Bryer-Ash M.
An in vivo model for elucidation of the mechanism of tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance: evidence for differential regulation of insulin signaling by TNF-alpha.
Endocrinology
139:
4928-4935,
1998
10.
Corica, F,
Allegra A,
Corsonello A,
Buemi M,
Calapai G,
Ruello A,
Nicita Mauro V,
and
Ceruso D.
Relationship between plasma leptin levels and the tumor necrosis factor-alpha system in obese subjects.
Int J Obes
23:
355-360,
1999[ISI].
11.
Crichton, MB,
Nichols JE,
Zhao Y,
Bulun SE,
and
Simpson ER.
Expression of transcripts of interleukin-6 and related cytokines by human breast tumors, breast cancer cells, and adipose stromal cells.
Mol Cell Endocrinol
118:
215-220,
1996[ISI][Medline].
12.
Dandona, P,
Weinstock R,
Thusu K,
Abdel-Rahman E,
Aljada A,
and
Wadden T.
Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss.
J Clin Endocrinol Metab
83:
2907-2910,
1998
13.
Feingold, KR,
Doerrler W,
Dinarello CA,
Fiers W,
and
Grunfeld C.
Stimulation of lipolysis in cultured fat cells by tumor necrosis factor, interleukin-1, and the interferons is blocked by inhibition of prostaglandin synthesis.
Endocrinology
130:
10-16,
1992[Abstract].
14.
Flier, JS.
The adipocyte: storage depot or node on the energy information superhighway?
Cell
80:
15-18,
1995[ISI][Medline].
15.
Fried, SK,
Bunkin DA,
and
Greenberg AS.
Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.
J Clin Endocrinol Metab
83:
847-850,
1998
16.
Greenberg, AS,
Nordan RP,
McIntosh J,
Calvo JC,
Scow RO,
and
Jablons D.
Interleukin 6 reduces lipoprotein lipase activity in adipose tissue of mice in vivo and in 3T3-L1 adipocytes: a possible role for interleukin 6 in cancer cachexia.
Cancer Res
52:
4113-4116,
1992[Abstract].
17.
Hotamisligil, GS,
Arner P,
Caro JF,
Atkinson RL,
and
Spiegelman BM.
Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.
J Clin Invest
95:
2409-2415,
1995[ISI][Medline].
18.
Hotamisligil, GS,
Budavari A,
Murray D,
and
Spiegelman BM.
Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-.
J Clin Invest
94:
1543-1549,
1994[ISI][Medline].
19.
Hotamisligil, GS,
Johnson RS,
Distel RJ,
Ellis R,
Papaioannou VE,
and
Spiegelman BM.
Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein.
Science
274:
1377-1379,
1996
20.
Hotamisligil, GS,
Shargill NS,
and
Spiegelman BM.
Adipose expression of tumor necrosis factor-: direct role in obesity-linked insulin resistance.
Science
259:
87-91,
1993[ISI][Medline].
21.
Hotamisligil, GS,
and
Spiegelman BM.
Tumor necrosis factor : a key component of the obesity-diabetes link.
Diabetes
43:
1271-1278,
1994[Abstract].
22.
Kahn, SE,
Prigeon RL,
McCulloch DK,
Boyko EJ,
Bergman RN,
Schwartz MW,
Neifing JL,
Ward WK,
Beard JC,
and
Palmer JP.
Quantification of the relationship between insulin sensitivity and -cell function in human subjects. Evidence for a hyperbolic function.
Diabetes
42:
1663-1672,
1993[Abstract].
23.
Kern, PA.
Potential role of TNF and lipoprotein lipase as candidate genes for obesity.
J Nutr
127:
1917S-1922S,
1997[Medline].
24.
Kern, PA,
Saghizadeh M,
Ong JM,
Bosch RJ,
Deem R,
and
Simsolo RB.
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,
1995[ISI][Medline].
25.
Kuczmarski, RJ,
Flegal KM,
Campbell SM,
and
Johnson CL.
Increasing prevalence of overweight among US adults: the National Health and Nutrition Examination Surveys, 1960 to 1991.
JAMA
272:
205-211,
1994[Abstract].
26.
Lofgren, P,
Van H,
Reynisdottir VS,
Naslund E,
Ryden M,
Rossner S,
and
Arner P.
Secretion of tumor necrosis factor- shows a strong relationship to insulin-stimulated glucose transport in human adipose tissue.
Diabetes
49:
688-692,
2000[Abstract].
27.
Ludvik, B,
Nolan JJ,
Baloga J,
Sacks D,
and
Olefsky J.
Effect of obesity on insulin resistance in normal subjects and patients with NIDDM.
Diabetes
44:
1121-1125,
1995[Abstract].
28.
McGarry, JD.
What if Minkowski had been ageusic? An alternative angle on diabetes.
Science
258:
766-770,
1992[ISI][Medline].
29.
Mohamed-Ali, V,
Goodrick S,
Rawesh A,
Katz DR,
Miles JM,
Yudkin JS,
Klein S,
and
Coppack SW.
Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo.
J Clin Endocrinol Metab
82:
4196-4200,
1997
30.
Mokdad, A,
Serdula MK,
Dietz WH,
Bowman B,
Marks J,
and
Koplan J.
The spread of the obesity epidemic in the United States, 1991-1998.
JAMA
282:
1519-1522,
1999
31.
Ofei, F,
Hurel S,
Newkirk J,
Sopwith M,
and
Taylor R.
Effects of an engineered human anti-TNF- antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM.
Diabetes
45:
881-885,
1996[Abstract].
32.
Orban, Z,
Remaley AT,
Sampson M,
Trajanoski Z,
and
Chrousos GP.
The differential effect of food intake and beta-adrenergic stimulation on adipose-derived hormones and cytokines in man.
J Clin Endocrinol Metab
84:
2126-2133,
1999
33.
Paquot, N,
Castillo MJ,
Lefebvre PJ,
and
Scheen AJ.
No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients.
J Clin Endocrinol Metab
85:
1316-1319,
2000
34.
Patton, JS,
Shepard HM,
Wilking H,
Lewis G,
Aggarwal BB,
Eessalu TE,
Gavin LA,
and
Grunfeld C.
Interferons and tumor necrosis factors have similar catabolic effects on 3T3-L1 cells.
Proc Natl Acad Sci USA
83:
8313-8317,
1986[Abstract].
35.
Pfeiffer, A,
Janott J,
Mohlig M,
Ristow M,
Rochlitz H,
Busch K,
Schatz H,
and
Schifferdecker E.
Circulating tumor necrosis factor alpha is elevated in male but not female patients with type II diabetes mellitus.
Horm Metab Res
29:
111-114,
1997[ISI][Medline].
36.
Qi, C,
and
Pekala PH.
Tumor necrosis factor-alpha-induced insulin resistance in adipocytes.
Proc Soc Exp Biol Med
223:
128-135,
2000
37.
Schreyer, SC,
Chua SA, Jr,
and
LeBoeuf RC.
Obesity and diabetes in TNF- receptor-deficient mice.
J Clin Invest
102:
402-411,
1998
38.
Segal, KR,
Gutin B,
Presta E,
Wang J,
and
Van Itallie TB.
Estimation of human body composition by electrical impedance methods: a comparative study.
J Appl Physiol
58:
1565-1571,
1985
39.
Unger, RH.
Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications.
Diabetes
44:
863-870,
1995[Abstract].
40.
Uysal, KT,
Wiesbrock SM,
Marino MW,
and
Hotamisligil GS.
Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function.
Nature
389:
610-614,
1997[ISI][Medline].
41.
Welch, S,
Gebhart SSP,
Bergman RN,
and
Phillips LS.
Minimal model analysis of intravenous glucose tolerance test-derived insulin sensitivity in diabetic subjects.
J Clin Endocrinol Metab
71:
1508-1518,
1990[Abstract].
42.
Winkler, G,
Lakatos P,
Salamon F,
Nagy Z,
Speer G,
Kovacs M,
Harmos G,
Dworak O,
and
Cseh K.
Elevated serum TNF-alpha level as a link between endothelial dysfunction and insulin resistance in normotensive obese patients.
Diabetic Med
16:
207-211,
1999[ISI][Medline].
43.
Zinman, B,
Hanley AJ,
Harris SB,
Kwan J,
and
Fantus IG.
Circulating tumor necrosis factor-alpha concentrations in a native Canadian population with high rates of type 2 diabetes mellitus.
J Clin Endocrinol Metab
84:
272-278,
1999