Food deprivation induces adipose plasminogen activator inhibitor-1 (PAI-1) expression without accumulation of plasma PAI-1 in genetically obese and diabetic db/db mice

Katsutaka Oishi; Naoki Ohkura; Juzo Matsuda; Norio Ishida

doi:10.1160/TH07-04-0268

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 98(04): 864-870
DOI: 10.1160/TH07-04-0268

Animal Models

Schattauer GmbH

Food deprivation induces adipose plasminogen activator inhibitor-1 (PAI-1) expression without accumulation of plasma PAI-1 in genetically obese and diabetic db/db mice

Katsutaka Oishi

¹Clock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology (AIST), Higashi, Tsukuba, Ibaraki, Japan

,

Naoki Ohkura

²Department of Clinical Molecular Biology, Faculty of Pharmaceutical Sciences, Teikyo University, Suarashi, Sagamiko, Sagamihara, Kanagawa, Japan

,

Juzo Matsuda

²Department of Clinical Molecular Biology, Faculty of Pharmaceutical Sciences, Teikyo University, Suarashi, Sagamiko, Sagamihara, Kanagawa, Japan

,

Norio Ishida

¹Clock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology (AIST), Higashi, Tsukuba, Ibaraki, Japan

³Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan

› Author Affiliations

Abstract

Summary

Relationships between energy intake and fibrinolytic functions have been documented in detail. We evaluated food deprivation (FD) as a means of modulating fibrinolytic activity in genetically obese and diabetic db/db mice and in their lean counterparts. Twelve hours of FD induced considerable gene expression of plasminogen activator inhibitor-1 (PAI-1) in both epididymal (3.8-fold, p<0.05) and intestinal (2.4-fold, p<0.05) adipose tissues without affecting plasma PAI-1 levels in db/db mice, whereas the FD did not affect these parameters in wild-type mice. Importantly, 24 hours of FD increased the plasma PAI-1 content in wild-type (1.9-fold, p<0.01) but not in db/db mice, although adipose PAI-1 mRNA levels were significantly increased in db/db mice. The plasma PAI-1 content significantly correlated with hepatic PAI-1 mRNA levels in wild-type (r=0.84, p<0.01) and in db/db (r=0.63, p<0.01) mice. However, plasma PAI-1 did not correlate with adipose PAI-1 expression in db/db mice, although adipose tissue in general is thought to be the principal site of PAI-1 production in obesity. Hepatic PAI-1 expression was closely correlated with serum levels of free fatty acids in wild-type (r=0.72, p<0.01), but not in db/db mice. Adipose PAI-1 expression significantly correlated with serum corticosterone levels in both genotypes (wild-type, r=0.52, p<0.05; db/db, r=0.51, p<0.01), suggesting that adipose PAI-1 expression is up-regulated by fastinginduced glucocorticoids. The present findings suggested that fasting differentially affects fibrinolytic activity in obese and lean subjects and that PAI-1 expression in the liver as well as in adipose tissues comprises an important determinant of increased risk for cardiovascular disease in obesity.

Keywords

Plasminogen activator inhibitor-1 - adipose tissue - liver - obesity - food deprivation - db/db mouse

Full Text

References

References
1 Van Gaal LF. et al. Mechanisms linking obesity with cardiovascular disease.. Nature 2006; 444: 875-880.
2 Anand SS. et al. Relationship of metabolic syndrome and fibrinolytic dysfunction to cardiovascular disease.. Circulation 2003; 108: 420-425.
3 Mertens I, Van Gaal LF. Visceral fat as a determinant of fibrinolysis and hemostasis.. Semin Vasc Med 2005; 5: 48-55.
4 Trost S. et al. Impaired fibrinolysis and risk for cardiovascular disease in the metabolic syndrome and type 2 diabetes.. Curr Diab Rep 2006; 6: 47-54.
5 Alessi MC, Juhan-Vague I. PAI-1 and the metabolic syndrome: links, causes, and consequences.. Arterioscler Thromb Vasc Biol 2006; 26: 2200-2207.
6 Mutch NJ. et al. Plasminogen activator inhibitor-1 and haemostasis in obesity.. Proc Nutr Soc 2001; 60: 341-347.
7 Vaughan DE. et al. Studies of recombinant plasminogen activator inhibitor-1 in rabbits. Pharmacokinetics and evidence for reactivation of latent plasminogen activator inhibitor-1 in vivo.. Circ Res 1990; 67: 1281-1286.
8 Eren M. et al. Tissue- and agonist-specific regulation of human and murine plasminogen activator inhibitor- 1 promoters in transgenic mice.. J Thromb Haemost 2003; 1: 2389-2396.
9 Skurk T, Hauner H. Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1.. Int J Obes Relat Metab Disord 2004; 28: 1357-1364.
10 Vaughan DE. PAI-1 and atherothrombosis.. J Thromb Haemost 2005; 3: 1879-1883.
11 Samad F, Loskutoff DJ. The fat mouse: a powerful genetic model to study elevated plasminogen activator inhibitor 1 in obesity/NIDDM.. Thromb Haemost 1997; 78: 652-655.
12 Shimomura I. et al. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity.. Nat Med 1996; 2: 800-803.
13 Samad F, Loskutoff DJ. Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice.. Mol Med 1996; 2: 568-582.
14 Lijnen HR. et al. On the role of plasminogen activator inhibitor-1 in adipose tissue development and insulin resistance in mice.. JThromb Haemost 2005; 3: 1174-1179.
15 Coleman DL. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice.. Diabetologia 1978; 14: 141-148.
16 Oishi K. et al. Gene- and tissue-specific alterations of circadian clock gene expression in streptozotocininduced diabetic mice under restricted feeding.. Biochem Biophys Res Commun 2004; 317: 330-334.
17 Oishi K. et al. CLOCK is involved in obesity-induced disordered fibrinolysis in ob/ob mice by regulating PAI-1 gene expression.. J Thromb Haemost 2006; 4: 1774-1780.
18 Oishi K. et al. Tissue-specific augmentation of circadian PAI-1 expression in mice with streptozotocininduced diabetes.. Thromb Res 2004; 114: 129-135.
19 Ohkura N. et al. Circadian clock molecules CLOCK and CRYs modulate fibrinolytic activity by regulating the PAI-1 gene expression.. J Thromb Haemost 2006; 4: 2478-2485.
20 Oishi K. et al. Identification of the circadian clockregulated E-box element in the mouse plasminogen activator inhibitor-1 gene.. J Thromb Haemost 2007; 5: 428-431.
21 Maemura K. et al. CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene expression.. J Biol Chem 2000; 275: 36847-36851.
22 Alessi MC. 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.
23 van Hinsbergh VW. et al. Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo.. Blood 1988; 72: 1467-1473.
24 Hopkins WE. et al. Synergistic induction of plasminogen activator inhibitor type-1 in HEP G2 cells by thrombin and transforming growth factor-beta.. Blood 1992; 79: 75-81.
25 Healy AM, Gelehrter TD. Induction of plasminogen activator inhibitor-1 in HepG2 human hepatoma cells by mediators of the acute phase response.. J Biol Chem 1994; 269: 19095-100.
26 Yamashita M. Tumor necrosis factor alpha is involved in the induction of plasminogen activator inhibitor- 1 by endotoxin.. Thromb Res 1997; 87: 165-170.
27 Dong J. et al. IL-1 and IL-6 induce hepatocyte plasminogen activator inhibitor-1 expression through independent signaling pathways converging on C/EBPdelta.. Am J Physiol Cell Physiol 2007; 292: C209-215.
28 Alessi MC. et al. Insulin stimulates the synthesis of plasminogen activator inhibitor 1 by the human hepatocellular cell line Hep G2.. Thromb Haemost 1988; 60: 491-494.
29 Kooistra T. et al. Plasminogen activator inhibitor 1: biosynthesis and mRNA level are increased by insulin in cultured human hepatocytes.. Thromb Haemost 1989; 62: 723-728.
30 Konkle BA. et al. Plasminogen activator inhibitor-1 messenger RNA expression is induced in rat hepatocytes in vivo by dexamethasone.. Blood 1992; 79: 2636-2642.
31 Anfosso F. et al. Up-regulated expression of plasminogen activator inhibitor-1 in Hep G2 cells: interrelationship between insulin and insulin-like growth factor 1.. Thromb Haemost 1995; 73: 268-274.
32 Sironi L. et al. Plasminogen activator inhibitor type-1 synthesis and mRNA expression in HepG2 cells are regulated by VLDL.. Arterioscler Thromb Vasc Biol 1996; 16: 89-96.
33 Banfi C. et al. Very low density lipoprotein-mediated signal transduction and plasminogen activator inhibitor type 1 in cultured HepG2 cells.. Circ Res 1999; 85: 208-217.
34 Chen Y. et al. Effect of fatty acid chain length and thioesterification on the augmentation of expression of plasminogen activator inhibitor-1.. Nutr Metab Cardiovasc Dis 2002; 12: 325-330.
35 Sawdey MS, Loskutoff DJ. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta.. J Clin Invest 1991; 88: 1346-1353.
36 Kudo T. et al. Night-time restricted feeding normalises clock genes and Pai-1 gene expression in the db/db mouse liver.. Diabetologia 2004; 47: 1425-1436.
37 Alessi MC. et al. Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease.. Diabetes 1997; 46: 860-867.
38 Gottschling-Zeller H. et al. 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.
39 Bastard JP. 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 Correia ML, Haynes WG. A role for plasminogen activator inhibitor-1 in obesity: from pie to PAI?. Arterioscler Thromb Vasc Biol 2006; 26: 2183-2185.
41 Yamamoto K. et al. Obesity enhances the induction of plasminogen activator inhibitor-1 by restraint stress: a possible mechanism of stress-induced renal fibrin deposition in obese mice.. J Thromb Haemost 2005; 3: 1495-1502.