© 1999 American Heart Association, Inc.
Thrombosis |
PAI-1 Produced Ex Vivo by Human Adipose Tissue Is Relevant to PAI-1 Blood Level
From the Laboratory of Hematology, CHU Timone (P.E.M., M.C.A., M.V., I.J.-V.), and the Department of Plastic Surgery, CHU Conception (D.C., G.M.), Marseille, France.
Correspondence to Pr I. Juhan-Vague, Laboratory of Hematology, CHU Timone, 13385 Marseille Cedex 5, France.
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Abstract |
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Abstract—Human adipose tissue has been shown to produce plasminogen activator inhibitor type 1 (PAI-1). However, the importance of adipose tissue in the regulation of the PAI-1 plasma level is not known. The aim of this study was to investigate the relation between the production of PAI-1 by adipose tissue, plasma PAI-1 level, and variables related to the insulin resistance state. The link between the production of PAI-1 inducers such as tumor necrosis factor-
and transforming growth factor-ß and the
production of PAI-1 by adipose tissue was also evaluated. Blood
samples were obtained as soon as possible to the induction of
anesthesia from 30 patients undergoing elective
abdominoplasty. PAI-1 antigen levels measured in conditioned media
after a 19-hour incubation period of adipose tissue explants were
significantly correlated with plasma PAI-1 antigen levels
(r=0.54, P=0.004) and with systemic lipid
parameters such as triglycerides and high
density lipoprotein cholesterol (r=0.46,
P=0.014; r=-0.50, P=0.01,
respectively) but not with insulinemia and body mass index. PAI-1
production by adipose tissue was correlated with those of
TNF- (r=0.5, P=0.01) and TGF-ß
(r=0.53, P=0.007). These results
emphasize the role of adipose tissue in determining plasma levels of
PAI-1, with a local contribution of TNF- and TGF-ß in PAI-1
production by adipose tissue.
Key Words: PAI-1 • humans • adipose tissue • TNF- • TGF-ß
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Introduction |
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Insulin resistance is a common metabolic disorder that includes a cluster of abnormalities such as hyperinsulinemia, hypertriglyceridemia, a decrease in HDL cholesterol, and obesity with a predominant fat distribution in the upper part of the body. The insulin resistance syndrome is associated with an increased risk of ischemic heart disease.1 Among the mechanisms explaining this relation, an increase in type 1 plasminogen activator inhibitor (PAI-1) concentration in plasma has been invoked.2 PAI-1 is a specific inhibitor of plasminogen activators. Its modulation in vivo affects fibrin deposition and smooth muscle cell migration, 2 mechanisms involved in atherosclerosis development. Clinical and epidemiological studies conducted in healthy populations or in patients with coronary heart disease suggest that an increased plasma PAI-1 level is a biological risk factor for the development of atherosclerosis complications, mainly in patients with insulin resistance.3 Indeed, the ability of PAI-1 to predict such sequelae disappears after adjustment for parameters belonging to the insulin resistance syndrome.3 The mechanisms responsible for this original association between a metabolic situation and a fibrinolytic inhibitor remain unclear. Several studies conducted in humans and animals have underlined the importance of fat mass in explaining such a relation.4 5 6 7 8 9 10 11 12 13 14 We have recently contributed to this discussion by demonstrating the synthesis of PAI-1 by human adipose tissue, this production being higher in omental than in subcutaneous tissue.15 Furthermore, Eriksson et al16 have shown that this production is higher in the fat of obese individuals and is related to the size of the adipocytes. To evaluate the relevance of this phenomenon in patients, we have investigated the relation between the production of PAI-1 by adipose tissue, the plasma PAI-1 level, and variables related to the insulin resistance state. To observe this relation, blood and adipose tissue samples were taken nearly simultaneously. Tumor necrosis factor-
(TNF-)
and transforming growth factor-ß (TGF-ß) are potent inducers of
PAI-1 synthesis.17 18 19 Moreover, TNF- expressed in
adipose tissue is an important component of the link between obesity
and insulin resistance.20 We thus evaluated in vitro the
relationship between PAI-1, TNF-, and TGF-ß produced by adipose
tissue. |
Methods |
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Correlation analysis between plasma and adipose tissue parameters was performed on subcutaneous tissue obtained during elective abdominoplasty from 30 patients (group 1), 3 men and 27 women, whose age ranged from 16 to 70 years (mean, 47) and with a body mass index (BMI: weight in kilograms divided by the square of height in meters) ranging from 21 to 42 kg/m2 (mean, 27).
Comparison between omental and subcutaneous adipose tissue was made in a group of 16 patients (group 2), 7 men and 9 women, whose age ranged from 35 to 79 years and whose BMI ranged from 18 to 39 kg/m2 (mean, 27). Tissues were obtained during elective abdominal surgery. Informed consent was obtained from each patient, and the study protocol was approved by the ethics committee of Marseille. The investigation was conducted according to the principles expressed in the Declaration of Helsinki.
Tissue explant incubations for measurements of PAI-1 protein secretion by adipose tissue were made as previously described. In brief, freshly obtained fat specimens were cut into small pieces (1 mm3) under sterile conditions, rinsed once in PBS, weighed, and incubated (1 mL medium per 300 mg tissue) in a medium consisting of minimal essential medium/HAMF12, 100 U/mL penicillin, 100 µg/mL streptomycin, 2 mmol/l L glutamine, 1% FCS, and 1% BSA at 37°C under a 5% CO2, 95% O2 atmosphere. Media were collected after a 19-hour incubation, centrifuged, and frozen at -80°C. We have previously shown that the secretion of PAI-1 is linear during an incubation time of at least 19 hours.15
Venous blood samples were obtained just before anesthesia in the 30 patients from group 1. For PAI-1 antigen, samples were drawn into chilled trisodium citrate tubes and were centrifuged as previously described to obtain platelet-free plasma. Parameters reflecting the insulin resistance state, such as fasting insulin triglycerides (TGs) and HDL cholesterol, were evaluated from serum samples by using routine clinical assays. PAI-1 antigen from conditioned media (expressed as ng per mL or ng per g of adipose tissue) and plasma (ng per mL) was assayed using a specific ELISA as previously described.21 PAI-1 activity was quantified using a commercially available kit (Chromolize, Biopool).
Total TGF-ß1 protein and TNF- from conditioned media (expressed as
pg per mL) were assayed using ELISA assays from R&D Systems in 27
patients from group 1. All measurements were performed in triplicate.
All supplies and reagents were obtained as described in detail
previously.15
Results were expressed as mean±SD. The value n represents the
number of independent tissue preparations. In the study aimed to
compare visceral and subcutaneous production of PAI-1, the
between-group comparison was tested by 2-tailed, paired Student's
t test. Significance was defined at P
0.05. The
nonparametric correlation coefficient (Spearman's) was
utilized to examine the relations among study variables.
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Results |
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Relation Between PAI-1 Production by Adipose Tissue and Plasma PAI-1 Level
A significant correlation was observed between plasma PAI-1 antigen or activity and the PAI-1 antigen level measured in conditioned media from subcutaneous adipose tissue explants (r=0.54, P=0.004; r=0.52, P=0.005, respectively; Figure 1
).
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Relation Between PAI-1 Production by Adipose Tissue, Plasma
PAI-1 Level, BMI, and Insulin Resistance Parameters
Plasma PAI-1 level and PAI-1 antigen measured in conditioned media
were significantly correlated with plasma variables belonging to
the insulin resistance syndrome, such as TGs (r=0.51,
P=0.006; r=0.46, P=0.01, respectively)
and HDL cholesterol (r=-0.59,
P=0.003; r=-0.50, P=0.01,
respectively), whereas no relation was observed between PAI-1 levels
and insulinemia, PAI-1, or BMI.
Within the cluster of variables related to insulin resistance, associations were found between TGs and HDL cholesterol (r=-0.65, P=0.001), insulin, and TGs (r=0.41, P=0.038).
Relation Between PAI-1, TNF-, and TGF-ß Productions by
Adipose Tissue
TNF- production by adipose tissue correlated well with
that of PAI-1 (r=0.50, P=0.01; Figure 2). TNF- production by adipose
tissue was correlated with fasting insulinemia (r=0.49,
P=0.03). A significant correlation was observed between the
production of PAI-1 and TGF-ß by adipose tissue
(r=0.53, P=0.007; Figure 2).
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Relation Between Visceral and Subcutaneous Adipose Tissue
Productions of PAI-1
We compared the production of PAI-1 antigen by
subcutaneous and visceral fat in patients from group 1. The relation
between these productions after a 19-hour incubation period is
represented in Figure 3. A
high correlation was observed between the production of PAI-1
by visceral and subcutaneous adipose tissue (r=0.91,
P<0.001). As we have previously shown, PAI-1 antigen level
(expressed in ng per g of tissue) produced in the conditioned medium
from omental tissue was higher than that secreted from subcutaneous
tissue. The mean±SD and (range) values for omental and subcutaneous
tissues were 712.2±464.8 (92 to 1442) and 335.8±183 (46 to 620) ng/g,
respectively (P<0.001).
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Discussion |
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An increased plasma PAI-1 level belongs to the insulin resistance syndrome. Among the variables grouped with insulin resistance, obesity appears to be particularly relevant for explaining the relationships observed between plasma PAI-1 levels and insulin resistance. Indeed, PAI-1 may be an adipose tissue–derived circulating peptide. Sawdey and Loskutoff9 showed that murine adipose tissue expressed PAI-1 mRNA. Mice with genetically induced obesity have an increased PAI-1 expression in adipose tissue, this local increase in PAI-1 concentration being parallel to that in plasma.22 The contribution of this adipose production on plasma PAI-1 level has not yet been investigated in humans. Recently, we have demonstrated production of PAI-1 by human adipose tissue.15 In the present work, we describe a positive association between the PAI-1 production rate by human subcutaneous adipose tissue and plasma PAI-1 levels. This observation is in favor of a role for adipose tissue in the increased plasma PAI-1 levels found in obesity.
Elevated plasma PAI-1 levels are associated with excessive visceral rather than subcutaneous adiposity.12 13 14 The relation between PAI-1 produced by visceral territories and PAI-1 plasma levels was not analyzed in this study, as blood samples could not be obtained for all of the patients from group 2. However, the strong correlation observed between the PAI-1 quantities produced by the 2 fat territories suggests a similar regulatory pathway of PAI-1 in these 2 tissues despite their different anatomic and metabolic characteristics and validates the use of subcutaneous tissue as a suitable model for studying the production of PAI-1 by adipose tissue. The confirmation in a larger population15 that omental tissue explants produced more PAI-1 than did explants from subcutaneous tissue during an incubation that lasted 4 times longer underlines the role of omental tissue as a major source of PAI-1.
On examining the relation between the insulin resistance parameters and PAI-1, we found that plasma PAI-1 concentration as well as PAI-1 antigen level measured in conditioned medium was correlated with TGs and HDL cholesterol, whereas no relation was observed with insulinemia and BMI. The lack of correlation between PAI-1 and each of these last 2 parameters could in part be due to the time of blood sampling. Indeed, in most studies showing a correlation between plasma PAI-1 concentration, BMI, and insulinemia, blood samples were obtained early in the morning to avoid the influence of circadian variations in plasma PAI-1 levels. As our main interest was to compare PAI-1 in plasma and PAI-1 production by adipose tissue, plasma samples were not always obtained in the early morning (at the peak of PAI-1) but as soon as possible to the time of induction of anesthesia (which ranged from 8 AM to 4 PM). Moreover, because our study population was mostly female, we could evoke the inclusion of patients presenting a gynoid fat distribution that is known to be not associated with insulin resistance and increased PAI-1 levels.23 24 Then, the fact that circadian variations in plasma PAI-1 were not considered for blood sampling and the particular composition of the population studied could both contribute to the lack of correlation observed between PAI-1, insulinemia, and BMI. Furthermore, despite demonstration of an in vitro effect of insulin on PAI-1 production by some cultured cells,25 26 27 28 29 our results do not favor the hypothesis of a direct contribution of insulin to PAI-1 level regulation. They also underline the link between PAI-1 expression and a qualitative rather than a quantitative aspect of adipose tissue.
Several studies inferred a role for TNF- in the relation
between obesity and insulin resistance.30 Recent
experiments conducted in TNF-–deficient obese mice have shown that
the absence of TNF- resulted in a significantly improved insulin
sensitivity in obesity.31 32 Moreover, an infusion of
TNF- into humans has been reported to result in reduced insulin
sensitivity.20 TNF- is a potent inducer of PAI-1
synthesis; when administered to mice, it increased PAI-1 mRNA
expression in adipose tissue.10 The correlation between
the secretion rate of PAI-1 and TNF- secreted by human adipose
tissue suggests that TNF- is involved in the regulation of PAI-1
production in insulin-resistant patients with obesity.
It has been proposed that TNF- could function in an autocrine
fashion to regulate insulin sensitivity in adipocytes.33
We confirmed the link between insulinemia and TNF-
production by adipose tissue: a strong correlation between
insulinemia and TNF- antigen measured in conditioned media was
found, as was previously reported in mice.34 Since
Hotamisligil et al34 have demonstrated a strong, positive
correlation between TNF- mRNA expression levels in fat tissue and
the level of insulinemia, our results emphasize the fact that the
measurement of TNF- protein in conditioned media after a 19-hour
incubation could be a surrogate for the quantification of TNF-
mRNA.
TGF-ß is a multifunctional agent present in many cells such
as platelets, monocytes, and tissue macrophages. It has
been implicated in a number of biological processes, including cell
adhesion and migration, extracellular matrix production, tissue
remodeling, and wound repair.35 TGF-ß stimulates PAI-1
synthesis in human endothelial cells,17
vascular smooth muscle cells,18 and HepG2
cells.19 Injected in vivo into mice, TGF-ß is 1 of the
major inducers of PAI-1 expression in adipose
tissue.9 11 36 37 Moreover, Samad et al36
have shown that TGF-ß mRNA and protein levels were increased in the
adipose tissues of obese mice compared with their lean counterparts.
The correlation that we have observed between the production of
PAI-1 and of TGF-ß by human fat tissue suggests, as for TNF-, an
involvement of TGF-ß in the regulation of PAI-1 production by
human adipose tissue. However, further larger studies are needed to
evaluate the respective contribution of each effector. By increasing
the production of PAI-1 by adipose tissue, TNF- and TGF-ß
could be important determinants in the link between circulating PAI-1
concentrations and the insulin resistance syndrome. Evaluation of the
importance of TGF-ß and TNF- in adipose tissue
metabolism and insulin resistance is a question that should
be addressed.
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Acknowledgments |
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This work was supported by INSERM and Ministère de l'Education Nationale, de la Recherche Médicale et de la Technologie (Contrat Quadriennal) and by Fondation de France. The authors wish to thank Pr H.R. Lijnen (Center for Molecular and Vascular Biology, Leuven, Belgium) for the gift of PAI-1 antibodies; Drs Farnarier and Marin (Laboratory of Immunology, CHU Sainte-Marguerite, Marseilles, France) for the TNF-
and TGF-ß1 assays; and D.
Nivière, O. Geel, B. Bonardo, and A. Olivi for their skillful
assistance. Received June 19, 1998; accepted October 13, 1998.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Desprès JP, Lamarche B, Mauriège P, Cantin B, Dagenais GR, Moorjani S, Lupien PJ. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med. 1996;334:952–957.
2. Juhan-Vague I, Alessi MC, Vague P. Increased plasma plasminogen activator inhibitor 1 levels: a possible link between insulin resistance and atherothrombosis. Diabetologia. 1991;34:457–462.[Medline] [Order article via Infotrieve]
3.
Juhan-Vague I, Pyke S, Alessi MC, Jespersen J,
Haverkate F, Thompson SG. Fibrinolytic factor and the risk of
myocardial infarction or sudden death in patients with angina pectoris.
Circulation. 1996;94:2057–2063.
4. Sylvan A, Rutergard JN, Janunger KG, Sjölund B, Nilsson TK. Normal plasminogen activator inhibitor levels at long-term follow-up after jejuno-ileal bypass in morbidly obese individuals. Metabolism. 1992;41:1370–1372.[Medline] [Order article via Infotrieve]
5.
Folsom AR, Qamhieh HT, Wing RR, Jeffrey RW, Stinson
VL, Kuller LH, Wu KK. Impact of weight loss on plasminogen
activator inhibitor (PAI-1), factor VII, and
other hemostatic factors in moderately overweight adults.
Arterioscler Thromb. 1993;13:162–169.
6. Primrose JN, Davies JA, Prentice CRM, Hughes R, Johnston D. Reduction in factor VII, fibrinogen and plasminogen activator inhibitor 1 activity after surgical treatment of morbid obesity. Thromb Haemost. 1992;68:396–399.[Medline] [Order article via Infotrieve]
7. McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes. 1994;43:104–109.[Abstract]
8. Alessi MC, Parrot G, Guenoun E, Scelles V, Vague P, Juhan-Vague I. Relation between plasma PAI activity and adipsin levels. Thromb Haemost. 1995;74:1200–1202.[Medline] [Order article via Infotrieve]
9.
Sawdey S, Loskutoff DJ. Regulation of murine type 1
plasminogen activator inhibitor
(PAI-1) gene expression in vivo: tissue specificity and induction by
lipopolysaccharide, tumor necrosis factor and
transforming growth factor ß. J Clin Invest. 1991;88:1346–1353.
10. Samad F, Yamamoto K, Loskutoff DJ. Distribution and regulation of plasminogen activator inhibitor 1 in murine adipose tissue in vivo. J Clin Invest. 1996;97l:37–46.
11.
Lundgren CH, Brown SL, Nordt TD, Sobel BE, Fujii S.
Elaboration of type 1 plasminogen activator
inhibitor from adipocytes: a potential pathogenic link
between obesity and cardiovascular disease.
Circulation. 1996;93:106–110.
12.
Cigolini M, Targher G, Bergamo Andreis IA, Tonoli M,
Agostino G, De Sandre G. Visceral fat accumulation and its relation to
plasma hemostatic factors in healthy men. Arterioscler Thromb
Vasc Biol. 1996;16:368–374.
13. Shimomura I, Funahashi T, Takahashi M, Maeda k, Kotani K, Nakamura T, Yamashita S, Miura M, Fukuda Y, Takemura K, Tokunaga K, Matsuzawa Y. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med. 1996;2:800–803.[Medline] [Order article via Infotrieve]
14. Janand-Delenne B, Chagnaud C, Raccah D, Alessi MC, Juhan-Vague I, Vague P. Visceral fat as a main determinant of plasminogen activator inhibitor 1 level in women. Int J Obes Relat Metab Disord. 1998;22:312–317.[Medline] [Order article via Infotrieve]
15. Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I. Production of plasminogen activator inhibitor 1 by human adipose tissue. Diabetes. 1997;46:860–867.[Abstract]
16. Eriksson P, Reynisdottir S, Lönnqvist F, Stemme V, Hamsten A, Arner P. Adipose tissue secretion of plasminogen activator inhibitor-1 in non-obese and obese individuals. Diabetologia. 1998;41:65–71.[Medline] [Order article via Infotrieve]
17.
Fujii S, Hopkins WE, Sobel BE. Mechanisms contributing
to increased synthesis of plasminogen activator
inhibitor type 1 in endothelial cells by
constituents of platelets and their implications for
thrombolysis. Circulation. 1991;83:645–651.
18.
Reilly CF, McFall RC. Platelet derived growth
factor and transforming growth factor-ß regulate
plasminogen activator inhibitor-1
in vascular smooth muscle cells. J Biol Chem. 1991;266:9419–9427.
19. Fujii S, Lucore CL, Hopkins WE, Billadello JJ, Sobel BE. Potential attenuation of fibrinolysis by growth factors released from platelets and their pharmacologic implications. Am J Cardiol. 1989;63:1505–1511.[Medline] [Order article via Infotrieve]
20. Hotamisligil GS, Spiegelman BM. Tumor necrosis factor: a key component of the obesity-diabetes link. Diabetes. 1994;43:1271–1278.[Abstract]
21.
Declerck PJ, Alessi MC, Verstreken M, Kruithof EKO,
Juhan-Vague I, Collen D. Measurement of plasminogen
activator inhibitor 1 (PAI-1) in biological
fluids with a murine monoclonal antibody, based on enzyme-linked
immunoadsorbent assay. Blood. 1988;71:220–225.
22. Samad F, Loskutoff DJ. Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice. Mol Med. 1996;2:568–582.[Medline] [Order article via Infotrieve]
23. Vague P, Juhan-Vague I, Chabert V, Alessi MC, Atlan C. Fat distribution and plasminogen activator inhibitor activity in nondiabetic obese women. Metabolism. 1989;38:913–915.[Medline] [Order article via Infotrieve]
24. Landin K, Stigendal L, Eriksson E, Krotiewski M, Risberg B, Tengborn L, Smith U. Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1. Metabolism. 1990;39:1044–1048.[Medline] [Order article via Infotrieve]
25. Alessi MC, Juhan-Vague I, Kooistra T, Declerck PJ, Collen D. Insulin stimulates the synthesis of plasminogen activator 1 by the human hepatocellular cell line Hep G2. Thromb Haemost. 1988;60:491–494.[Medline] [Order article via Infotrieve]
26. Kooistra T, Bosma PJ, Tons HAM, Van Den Berg AP, Meyer P, Princen HMG. Plasminogen activator inhibitor 1: biosynthesis and mRNA level are increased by insulin in cultured hepatocytes. Thromb Haemost. 1989;62:723–728.[Medline] [Order article via Infotrieve]
27.
Schneider DJ, Sobel BE. Augmentation of synthesis of
plasminogen activator type 1 by insulin and
insulin-like growth factor type 1: implications for vascular disease by
hyperinsulinemic states. Proc Natl Acad Sci
U S A. 1991;88:9959–9963.
28. Anfosso F, Chomiki N, Alessi MC, Vague P, Juhan-Vague I. Plasminogen activator inhibitor 1 synthesis in the human hepatoma cell line Hep G2: metformin inhibits the stimulating effect of insulin. J Clin Invest. 1993;91:2185–2193.
29. Alessi MC, Anfosso F, Henry M, Peiretti F, Nalbone G, Juhan-Vague I. Up-regulation of PAI-1 synthesis by insulin and proinsulin in Hep G2 cells but not in endothelial cells. Fibrinolysis. 1995;9:237–242.
30.
Hotamisligil GS, Shargill NS, Spiegelman BS. Adipose
expression of tumor necrosis factor-: direct role in
obesity-linked insulin resistance. Science. 1993;259:87–91.
31.
Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS.
Protection from obesity-induced insulin resistance in mice lacking
TNF- function. Nature. 1997;389:610–614.[Medline]
[Order article via Infotrieve]
32.
Ventre J, Doebber T, Wu M, MacNaul K, Stevens K,
Pasparakis M, Kollias G, Moller DE. Targeted disruption of the tumor
necrosis factor- gene: metabolic consequences in
obese and non obese mice. Diabetes. 1997;46:1526–1531.[Abstract]
33.
Saghizadeh M, Ong JM, Garvey WT, Henry RR,
Kern PA. The expression of TNF- by human muscle: relationship
to insulin resistance. J Clin Invest. 1996;97:1111–1116.[Medline]
[Order article via Infotrieve]
34.
Hotamisligil GS, Arner P, Caro JF, Atkinson
RL, Spiegelman BM. Increased adipose tissue expression of tumor
necrosis factor- in human obesity and insulin resistance.
J Clin Invest. 1995;95:2409–2415.
35.
Sporn MB, Roberts AB, Wakefield LM, de
Crombrugghe B. Some recent advances in the chemistry and biology of
transforming growth factor-ß. J Cell Biol. 1987;105:1039–1045.
36. Samad F, Yamamoto K, Pandey M, Loskutoff DJ. Elevated expression of transforming growth factor-ß in adipose tissue from obese mice. Mol Med. 1997;3:37–48.[Medline] [Order article via Infotrieve]
37.
Loskutoff DJ, Samad F. The adipocyte and
hemostatic balance in obesity studies of PAI-1. Arterioscler
Thromb Vasc Biol. 1998;18:1–6.
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