ABSTRACT
An increased amount of deep abdominal visceral fat has generally been accepted as an important cardiovascular risk factor, and disturbances in hemostasis and fibrinolysis have been suggested to play a role. Fibrinogen and von Willebrand factor, representatives of the hemostatic system, and plasminogen activator inhibitor 1 (PAI-1), as the most important inhibitor of the fibrinolytic system, have been associated with visceral obesity, with the most convincing evidence found for the involvement of PAI-1. The association with fibrinogen and von Willebrand factor has been suggested to be merely a reflection of the association with inflammation and endothelial dysfunction. The fact that PAI-1 is secreted by adipose tissue has attracted much attention. The increase of PAI-1 in visceral obesity could be because visceral adipose tissue produces more PAI-1 compared with subcutaneous abdominal adipose tissue. The contribution of other cell types such as hepatocytes or endothelial cells is probably more important, with stimulation of PAI-1 production by different components of the metabolic syndrome. PAI-1 secretion by adipose tissue has been suggested to have a more local effect, playing a role in tissue remodeling during the development of obesity.
KEYWORDS
Visceral obesity - fibrinogen - vWF - PAI-1
REFERENCES
1
Sharma A M.
Adipose tissue: a mediator of cardiovascular risk.
Int J Obes Relat Metab Disord.
2002;
26 Suppl 4
S5-S7
2
Alberti K G, Zimmet P Z.
Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation.
Diabet Med.
1998;
15
539-553
3
Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Pressure in Adults (Adult Treatment Panel III).
JAMA.
2001;
285
2486-2497
4
Festa A, D'Agostino R, Howard G, Mykkänen L, Tracy R P, Haffner S M.
Chronic subclinical inflammation as part of the insulin resistance syndrome: The Insulin Resistance Atherosclerosis Study (IRAS).
Circulation.
2000;
102
42-47
5
Yudkin J S.
Abnormalities of coagulation and fibrinolysis in insulin resistance. Evidence for a common antecedent?.
Diabetes Care.
1999;
22(suppl. 3)
C25-C30
6
Mertens I, Van Gaal L F.
Obesity, haemostasis and the fibrinolytic system.
Obes Rev.
2002;
3
85-101
7
Pouliot M C, Després J P, Lemieux S et al..
Waist circumference and abdominal sagittal diameter: best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women.
Am J Cardiol.
1994;
73
460-468
8
Rillaerts E, Van Gaal L, Xiang D Z, Vansant G, De Leeuw I.
Blood viscosity in human obesity: relation to glucose tolerance and insulin status.
Int J Obes.
1989;
13
739-745
9
Avellone G, Di Garbo V, Cordova R et al..
Evaluation of cardiovascular risk factors in overweight and obese subjects.
Int Angiol.
1994;
13
25-29
10
Haffner S M, D'Agostino Jr R, Mykkänen L et al..
Insulin sensitivity in subjects with type 2 diabetes.
Diabetes Care.
1999;
22
562-568
11
Festa A, D'Agostino Jr R, Tracy R P, Haffner S M.
Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes. Relationship to cardiovascular risk factors: The Insulin Resistance Atherosclerosis Study.
Diabetes.
2002;
51
1131-1137
12
Kain K, Catto A J, Grant P J.
Associations between insulin resistance and thrombotic risk factors in high-risk South Asian subjects.
Diabet Med.
2003;
20
651-655
13
Sakkinen P A, Wahl P, Cushman M, Lewis M R, Tracy R P.
Clustering of procoagulation, inflammation and fibrinolysis variables with metabolic factors in insulin resistance syndrome.
Am J Epidemiol.
2000;
152
897-907
14
Cigolini M, Targher G, Bergamo Andreis I A, 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
15
Asakawa H, Tokunaga K, Kawakami F.
Relationship of abdominal fat with metabolic disorders in diabetes mellitus patients.
Diabetes Res Clin Pract.
2002;
55
139-149
16
Rattarasarn C, Leelawattana R, Soonthornpun S et al..
Regional abdominal fat distribution in lean and obese Thai type 2 diabetic women: relationships with insulin sensitivity and cardiovascular risk factors.
Metabolism.
2003;
52
1444-1447
17
Barbeau P, Litaker M S, Woods K F et al..
Hemostatic and inflammatory markers in obese youths: effects of exercise and adiposity.
J Pediatr.
2002;
141
415-420
18
Anand S S, Yi Q, Gerstein H et al..
Relationship of metabolic syndrome and fibrinolytic dysfunction to cardiovascular disease.
Circulation.
2003;
108
420-425
19
Agewall S, Bokemark L, Wikstrand J, Lindahl A, Fagerberg B.
Insulin sensitivity and hemostatic factors in clinically healthy 58-year-old men.
Thromb Haemost.
2000;
84
571-575
20
Marques-Vidal P, Mazoyer E, Bongard V et al..
Prevalence of insulin resistance syndrome in southwestern France and its relationship with inflammatory and hemostatic markers.
Diabetes Care.
2002;
25
1371-1377
21
Pickart L R, Thaler M M.
Fatty acids, fibrinogen and blood flow: a general mechanism for hyperfibrinogenemia and its pathological consequences.
Med Hypotheses.
1980;
6
545-557
22
Tracy R P.
Epidemiological evidence for inflammation in cardiovascular disease.
Thromb Haemost.
1999;
82
826-831
23
Lemieux I, Pascot A, Prud'homme D et al..
Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity.
Arterioscler Thromb Vasc Biol.
2001;
21
961-967
24
Arcaro G, Zamboni M, Rossi L et al..
Body fat distribution predicts the degree of endothelial dysfunction in uncomplicated obesity.
Int J Obes Relat Metab Disord.
1999;
23
936-942
25
Perticone F, Ceravolo R, Candigliota M et al..
Obesity and body fat distribution induce endothelial dysfunction by oxidative stress: protective effect of vitamin C.
Diabetes.
2001;
50
159-165
26
De Pergola G, De Mitrio V, Giorgino F et al..
Increase in both pro-thrombotic and anti-thrombotic factors in obese premenopausal women: relationship with body fat distribution.
Int J Obes Relat Metab Disord.
1997;
21
527-535
27
Blann A D, Bushell D, Davies A, Faragher E B, Miller J P, McCollum C N.
von Willebrand factor, the endothelium and obesity.
Int J Obes Relat Metab Disord.
1993;
17
723-725
28
De Pergola G, De Mitrio V, Sciaraffia M et al..
Lower androgenicity is associated with higher plasma levels of prothrombotic factors irrespective of age, obesity, body fat distribution, and related metabolic parameters in men.
Metabolism.
1997;
46
1287-1293
29
Ferri C, Desideri G, Valenti M et al..
Early upregulation of endothelial adhesion molecules in obese hypertensive men.
Hypertension.
1999;
34
568-573
30
van der Poll T, van Deventer S J, Pasterkamp G, van Mourik J A, Buller H R, ten Cate J W.
Tumor necrosis factor induces von Willebrand factor release in healthy humans.
Thromb Haemost.
1992;
67
623-626
31
Nilsson T K, Boman K, Bjerle P, Hallmans G, Hellsten G.
von Willebrand factor and fibrinolytic variables are differently affected in the insulin resistance syndrome.
J Intern Med.
1994;
235
419-423
32
Lyon C J, Hsueh W A.
Effect of plasminogen activator inhibitor-1 in diabetes mellitus and cardiovascular disease.
Am J Med.
2003;
115 Suppo 8A
62S-68S
33
Juhan Vague I, Thompson S G, Jespersen J. on behalf of the ECAT Angina Pectoris Study Group .
Involvement of the hemostatic system in the insulin resistance syndrome. A study of 1500 patients with angina pectoris.
Arterioscler Thromb.
1993;
13
1865-1873
34
Mertens I, Van der Planken M, Corthouts B et al..
Visceral fat is a determinant of PAI-1 activity in diabetic and non-diabetic overweight and obese women.
Horm Metab Res.
2001;
33
602-607
35
Pannacciulli N, De Mitrio V, Marino R, Giorgino R, De Pergola G.
Effect of glucose tolerance status on PAI-1 plasma levels in overweight and obese subjects.
Obes Res.
2002;
10
717-725
36
Kockx M, Leenen R, Seidell J, Princen H M, Kooistra T.
Relationship between visceral fat and PAI-1 in overweight men and women before and after weight loss.
Thromb Haemost.
1999;
82
1490-1496
37
Janand-Delenne B, Chagnaud C, Raccah D, Alessi M C, 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
38
Giltay E J, Elbers J M, Gooren L J et al..
Visceral fat accumulation is an important determinant of PAI-1 levels in young, nonobese men and women. Modulation by cross-sex hormone administration.
Arterioscler Thromb Vasc Biol.
1998;
18
1716-1722
39
Bastard J P, Vidal H, Jardel C et al..
Subcutaneous adipose tissue expression of plasminogen activator inhibitor-1 gene during very low calorie diet in obese subjects.
Int J Obes Relat Metab Disord.
2000;
24
70-74
40
Mavri A, Alessi M C, Bastelica D et al..
Subcutaneous abdominal, but not femoral fat expression of plasminogen activator inhibitor-1 (PAI-1) is related to plasma PAI-1 levels and insulin resistance and decreases after weight loss.
Diabetologia.
2001;
44
2025-2031
41
Alessi M C, Juhan-Vague I, Kooistra T, Declerck P J, Collen D.
Insulin stimulates the synthesis of plasminogen activator inhibitor 1 by the human hepatocellular cell line Hep G2.
Thromb Haemost.
1988;
60
491-494
42
Nordt T K, Klassen K J, Schneider D J, Sobel B E.
Augmentation of synthesis of plasminogen activator inhibitor type-1 in arterial endothelial cells by glucose and its implications for local fibrinolysis.
Arterioscler Thromb.
1993;
13
1822-1828
43
Li X N, Grenett H E, Benza R L et al..
Genotype-specific transcriptional regulation of PAI-1 expression by hypertriglyceridemic VLDL and Lp(a) in cultured human endothelial cells.
Arterioscler Thromb Vasc Biol.
1997;
17
3215-3223
44
Sawdey M, Podor T J, Loskutoff D J.
Regulation of type 1 plasminogen activator inhibitor gene expression in cultured bovine aortic endothelial cells. Induction by transforming growth factor-beta, lipopolysaccharide, and tumor necrosis factor-alpha.
J Biol Chem.
1989;
264
10396-10401
45
Devaraj S, Xu D Y, Jialal I.
C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells. Implications for the metabolic syndrome and atherothrombosis.
Circulation.
2003;
107
398-404
46
Feener E P, Northrup J M, Aiello L P, King G L.
Angiotensin II induces plasminogen activator inhibitor-1 and -2 expression in vascular endothelial and smooth muscle cells.
1995;
95
1353-1362
47
Samad F, Yamamoto K, Loskutoff D J.
Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo. Induction by tumor necrosis factor-alpha and lipopolysaccharide.
J Clin Invest.
1996;
97
37-46
48
Alessi M C, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I.
Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease.
Diabetes.
1997;
46
860-867
49
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
50
Cigolini M, Tonoli M, Borgato L et al..
Expression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNF-α?.
Atherosclerosis.
1999;
143
81-90
51
Morange P E, Alessi M C, Verdier M, Casanova D, Magalon G, Juhan-Vague I.
PAI-1 produced ex vivo by human adipose tissue is relevant to PAI-1 blood level.
Arterioscler Thromb Vasc Biol.
1999;
19
1361-1365
52
He G, Bruun J M, Lihn A S, Pedersen S B, Richelsen B.
Stimulation of PAI-1 and adipokines by glucose in human adipose tissue in vitro.
Biochem Biophys Res Commun.
2003;
310
878-883
53
Gottschling-Zeller H, Birgel M, Röhrig K, Hauner H.
Effect of tumor necrosis factor alpha and transforming growth factor beta 1 on plasminogen activator inhibitor-1 secretion from subcutaneous and omental human fat cells in suspension culture.
Metabolism.
2000;
49
666-671
54
Alessi M C, Bastelica D, Morange P et al..
Plasminogen activator inhibitor 1, transforming growth factor-β1 , and BMI are closely associated in human adipose tissue during morbid obesity.
Diabetes.
2000;
49
1374-1380
55
Halleux C M, Declerck P J, Tran S L, Detry R, Brichard S M.
Hormonal control of plasminogen activator inhibitor-1 gene expression and production in human adipose tissue: stimulation by glucocorticoids and inhibition by catecholamines.
J Clin Endocrinol Metab.
1999;
84
4097-4105
56
Skurk T, Lee Y M, Hauner H.
Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture.
Hypertension.
2001;
37
1336-1340
57
Morange P E, Aubert J, Peiretti F et al..
Glucocorticoids and insulin promote plasminogen activator inhibitor 1 production by human adipose tissue.
Diabetes.
1999;
48
890-895
58
Samad F, Pandey M, Bell P A, Loskutoff D J.
Insulin continues to induce plasminogen activator inhibitor 1 gene expression in insulin resistant mice and adipocytes.
Mol Med.
2000;
6
680-692
59
Crandall D L, Groeling T M, Busler D E, Antrilli T M.
Release of PAI-1 by human preadipocytes and adipocytes independent of insulin and IGF-1.
Biochem Biophys Res Commun.
2000;
279
984-988
60
Hotamisligil G S, Shargill N S, Spiegelman B M.
Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.
Science.
1993;
259
87-91
61
Lundgren C H, Brown S L, Nordt T K, Sobel B E, Fujii S.
Elaboration of type-1 plasminogen activator inhibitor from adipocytes. A potential pathogenetic link between obesity and cardiovascular disease.
Circulation.
1996;
93
106-110
62
Crandall D L, Quinet E M, Morgan G A, Busler D E, McHendry-Rinde B, Kral J G.
Synthesis and secretion of plasminogen activator inhibitor-1 by human preadipocytes.
J Clin Endocrinol Metab.
1999;
84
3222-3227
63
Polac I, Cierniewska-Cieslak A, Stachowiak G, Pertynski T, Cierniewski C S.
Similar PAI-1 expression in visceral and subcutaneous fat of postmenopausal women.
Thromb Res.
2001;
102
397-405
64
Eriksson P, Van Harmelen V, Hoffstedt J et al..
Regional variation in plasminogen activator inhibitor-1 expression in adipose tissue from obese individuals.
Thromb Haemost.
2000;
83
545-548
65
Arner P.
Regional differences in protein production by human adipose tissue.
Biochem Soc Trans.
2001;
29
72-75
66
He G, Pedersen S B, Bruun J M, Lihn A S, Jensen P F, Richelsen B.
Differences in plasminogen activator inhibitor 1 in subcutaneous versus omental adipose tissue in non-obese and obese subjects.
Horm Metab Res.
2003;
35
178-182
67
Bastelica D, Morange P, Berthet B et al..
Stromal cells are the main plasminogen activator inhibitor-1-producing cells in human fat. Evidence of differences between visceral and subcutaneous deposits.
Arterioscler Thromb Vasc Biol.
2002;
22
173-178
68
Fain J N, Cheema P J, Basbouth S W, Lloyed Hiler M.
Resistin release by human adipose tissue explants in primary culture.
Biochem Biophys Res Commun.
2003;
300
674-678
69
Nilsson L, Banfi C, Diczfalusy U, Tremoli E, Hamsten A, Eriksson P.
Unsaturated fatty acids increase plasminogen activator inhibitor-1 expression in endothelial cells.
Arterioscler Thromb Vasc Biol.
1998;
18
1679-1685
70
Morange P E, Lijnen H R, Alessi M C, Kopp F, Collen D, Juhan-Vague I.
Influence of PAI-1 on adipose tissue growth and metabolic parameters in a murine model of diet-induced obesity.
Arterioscler Thromb Vasc Biol.
2000;
20
1150-1154
71
Lijnen H R, Maquoi E, Morange P et al..
Nutritionally induced obesity is attenuated in transgenic mice overexpressing plasminogen activator inhibitor-1.
Arterioscler Thromb Vasc Biol.
2003;
23
78-84
72
Hoover-Plow J, Ellis J, Yuen L.
In vivo plasminogen deficiency reduces fat accumulation.
Thromb Haemost.
2002;
87
1011-1019
73
Schäfer K, Fujisawa K, Konstantinides S, Loskutoff D J.
Disruption of the plasminogen activator inhibitor 1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice.
FASEB J.
2001;
15
1840-1842
74
Alessi M C, Bastelica D, Mavri A et al..
Plasma PAI-1 levels are more strongly related to liver steatosis than to adipose tissue accumulation.
Arterioscler Thromb Vasc Biol.
2003;
23
1262-1268
Prof. Dr. L. F Van Gaal
Department of Diabetology, Metabolism, and Clinical Nutrition
Antwerp University Hospital
Wilrijkstraat 10, B-2650 Edegem, Antwerp, Belgium