[en] OBJECTIVE: The objective of this study was to investigate the role of plasminogen activator inhibitor-1 (PAI-1) in adipose tissue development in vivo. METHODS AND RESULTS: Transgenic (Tg) mice overexpressing murine PAI-1 under control of the adipocyte promoter aP2 and wild-type (WT) controls were kept on standard food (SFD) or on high-fat diet (HFD) for 15 weeks. The body weight and the weight of the isolated subcutaneous and gonadal fat deposits of the Tg mice kept on the HFD were significantly lower than those of the WT mice. The number of adipocytes in the adipose tissue was similar for Tg and WT mice on the HFD, but adipocyte hypotrophy and a significantly lower ratio of stroma cells/adipocytes were observed in the Tg mice. A significant negative correlation (P<0.01) was observed between expression of preadipocyte factor-1, which blocks adipocyte differentiation, and adipose tissue weight. Fasting insulin and total cholesterol levels on the HFD were lower in Tg than in WT mice. CONCLUSIONS: High circulating PAI-1 levels attenuate nutritionally induced obesity. This may be related to modifications in adipose tissue cellularity affecting weight and plasma metabolic parameters.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Lijnen, Roger
Maquoi, Erik ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Morange, Pierre
Vörös, Gabor
Van Hoef, Berthe
Kopp, F.
Collen, Désiré
Juhan-Vague, I.
Alessi, Marie-Christine
Language :
English
Title :
Nutritionally induced obesity is attenuated in transgenic mice overexpressing plasminogen activator inhibitor-1
Publication date :
01 January 2003
Journal title :
Arteriosclerosis, Thrombosis and Vascular Biology
ISSN :
1079-5642
eISSN :
1524-4636
Publisher :
Lippincott Williams & Wilkins, Baltimore, United States - Maryland
Crandall DL, Hausman GJ, Kral JG. A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives. Microcirculation. 1997;4:211-232.
Carmeliet P, Collen D. Development and disease in proteinase-deficient mice: role of the plasminogen, matrix metalloproteinase and coagulation system. Thromb Res. 1998;91:255-285.
Lijnen HR. Plasmin and matrix metalloproteinases in vascular remodeling. Thromb Haemost. 2001;86:324-333.
Juhan-Vague I, Alessi MC. Regulation of fibrinolysis in the development of atherothrombosis: role of adipose tissue. Thromb Haemost. 1999;82:832-836.
Samad F, Loskutoff DJ. Hemostatic gene expression and vascular disease in obesity: insights from studies of genetically obese mice. Thromb Haemost. 1999;82:742-747.
Samad F, Loskutoff DJ. Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice. Mol Med. 1996;2:568-582.
Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K, Nakamura T, Yamashita S, Miura M, Fukada Y, Takemura K, Man Z, Toide K, Nakayama N, Fukuda Y, Lin M-C, Wetterau J-R, Matsuzawa Y. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med. 1996;2:800-803.
Vague P, Juhan-Vague I, Aillaud MF, Badier C, Viard R, Alessi MC, Collen D. Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level, and relative body weight in normal and obese subjects. Metabolism. 1986;35:250-253.
Mavri A, Stegnar M, Krebs M, Sentocnik JT, Geiger M, Binder BR. Impact of adipose tissue on plasma plasminogen activator inhibitor-1 in dieting obese women. Arterioscler Thromb Vasc Biol. 1999;19:1582-1587.
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.
Giltay EJ, Elbers JM, Gooren LJ, Emeis JJ, Kooistra T, Asscheman H, Stehouwer CD. 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.
Mykkanen L, Ronnemaa T, Marniemi J, Haffner SM, Bergman R, Laakso M. Insulin sensitivity is not an independent determinant of plasma plasminogen activator inhibitor-1 activity. Arterioscler Thromb. 1994;14:1264-1271.
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.
Alessi MC, 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.
Eriksson P, Reynisdottir S, Lönngvist F, Stemme V, Arner P. Adipose tissue secretion of plasminogen activator inhibitor-1 in non obese individuals. Diabetologia. 1998;41:65-71.
Samad F, Yamamoto K, Loskutoff DJ. Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo: induction by tumor necrosis factor-α and lipopolysaccharide. J Clin Invest. 1996;97:37-46.
Morange PE, Aubert J, Peiretti F, Lijnen HR, Vague P, Verdier M, Negrel R, Juhan-Vague I, Alessi MC. Glucocorticoids and insulin promote plasminogen activator inhibitor 1 production by human adipose tissue. Diabetes. 1999;48:890-895.
Sakamoto T, Woodcock-Mitchell J, Marutsuka K, Mitchell JJ, Sobel BE, Fujii S. TNF-alpha and insulin, alone and synergistically, induce plasminogen activator inhibitor-1 expression in adipocytes. Am J Physiol. 1999;276:C1391-C1397.
Samad F, Schneiderman J, Loskutoff D. Expression of fibrinolytic genes in tissues from human atherosclerotic aneurysms and from obese mice. Ann N Y Acad Sci. 1997;811:350-358.
Lundgren CH, Brown SL, Nordt TK, 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.
Morange PE, Alessi MC, 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.
Cigolini M, Tonoli M, Borgato L, Frigotto L, Manzato F, Zeminian S, Cardinale C, Camin M, Chiaramonte E, De Sandre G, Lunardi C. Expression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNF-alpha? Atherosclerosis. 1999;143:81-90.
Crandall DL, Groeling TM, Busler DE, Antrilli TM. Release of PAI-1 by human preadipocytes and adipocytes independent of insulin and IGF-1. Biochem Biophys Res Commun. 2000;279:984-988.
Gottschling-Zeller H, Rohrig K, Hauner H. Troglitazone reduces plasminogen activator inhibitor-1 expression and secretion in cultured human adipocytes. Diabetologia. 2000;43:377-383.
Bastelica D, Morange P, Berthet B, Borghi H, Lacdroi O, Grino M, Juhan-Vague I, Alessi M-C. 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.
Mavri A, Alessi M-C, Bastelica D, Geel-Georgelin O, Fina F, Sentocnik JT, Stegnar M, Juhan-Vague I. 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.
Morange PE, Lijnen HR, Alessi MC, Kopp F, Collen D, Juhan-Vague I. Influence of PAI-1 on adipose tissue growth and on metabolic parameters in a murine model of diet-induced obesity. Arterioscler Thromb Vasc Biol. 2000;20:1150-1154.
Èren M, Su M, Atkinson J, King L, Declerck P, Vaughan DE. Phenotypic derangements associated with overexpression of plasminogen activator inhibitor-1 (PAI-1) in transgenic mice. Arterioscler Thromb Vasc Biol. 2001;21:695. Abstract 230.
Schafer K, Fujisawa K, Konstantinides S, Loskutoff 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.
Giles AR. Guidelines for the use of animals in biomedical research. Thromb Haemost. 1987;58:1078-1084.
Declerck PJ, Verstreken M, Collen D. Immunoassay of murine t-PA, u-PA and PAI-1 using monoclonal antibodies raised in gene-inactivated mice. Thromb Haemost. 1995;74:1305-1309.
Lijnen HR, Okada K, Matsuo O, Collen D, Dewerchin M. α2-Antiplasmin gene-deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding. Blood. 1999;93:2274-2281.
Lijnen HR, Van Hoef B, Lupu F, Moons L, Carmeliet P, Collen D. Function of plasminogen/plasmin and matrix metalloproteinase systems after vascular injury in mice with targeted inactivation of fibrinolytic system genes. Arterioscler Thromb Vasc Biol. 1998;18:1035-1045.
Laifinen L. Griffonia Simplicifolia lectins bind specifically to endothelial cells and some epithelial cells in mouse tissues. Histochem J. 1987;19:225-234.
Qiu J, Ogus S, Lu R, Chehab FF. Transgenic mice overexpressing leptin accumulate adipose mass at an older, but not younger, age. Endocrinology. 2001;142:348-358.
Massiéra F, Bloch-Faure M, Ceiler D, Murakami K, Fukamizu A, Gasc J-M, Quignard-Boulangé A, Negrel R, Ailhaud G, Seydoux J, Meneton P, Teboul M. Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation. FASEB J. 2001;15:2727-2729.
Moitra J, Mason MM, Olive M, Krylov D, Gavrilova O, Marcus-Samuels B, Feigenbaum L, Lee E, Aoyama T, Eckhaus M, Reitman ML, Vinson C. Life without white fat: a transgenic mouse. Genes Dev. 1998;12:3168-3181.
Tazawa Y, Noguchi H, Nishinomiya F, Takada G. Serum alanine aminotransferase activity in obese children. Acta Paediatr. 1997;86:238-241.
Wolf G. The molecular mechanism of the stimulation of adipocyte differentiation by a glucocorticoid. Nutr Rev. 1999;57:324-326.
Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL, Brown MS. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev. 1998;12:3182-3194.
Zhou Y-T, Wang Z-W, Higa M, Newgard CB, Unger RH. Reversing adipocyte differentiation: implications for treatment of obesity. Proc Natl Acad Sci U S A. 1999;96:2391-2395.
Hoover-Plow J, Ellis J, Yuen L. In vivo plasminogen deficiency reduces fat accumulation. Thromb Haemost. 2002;87:1011-1019.
