[en] A nutritionally induced obesity model was used to investigate the modulation of fibrinolytic and gelatinolytic activity during the development of adipose tissue. Five week old male mice were fed a standard fat diet (SFD, 13% kcal as fat) or a high fat diet (HFD, 42% kcal as fat) for up to 15 weeks. The HFD resulted in body weights of 31 +/- 0.9 g, 38 +/- 2.0 g and 47 +/- 1.9 g at 5, 10 and 15 weeks, respectively; corresponding values for mice on the SFD were 26 +/- 0.6 g, 31 +/- 0.9 g and 31 +/- 1.2 g (all p < 0.001). The weight of the isolated subcutaneous (s.c.) or gonadal (GON) fat after 15 weeks of HFD was 1,870 +/- 180 mg or 1,470 +/- 160 mg, as compared to 250 +/- 58 mg or 350 +/- 71 mg for the SFD (p < 0.001). The HFD induced marked time-dependent hyperglycemia and elevated levels of triglycerides and total cholesterol. The HFD diet also induced a marked hypertrophy of the adipocytes as compared to the SFD, e.g. diameter of 83 +/- 3.0 microns versus 52 +/- 4.2 microns for GON adipocytes at 15 weeks (p < 0.005). Plasma plasminogen activator inhibitor-1 (PAI-1) levels were higher in mice on the HFD as compared to the SFD; they were comparable in extracts of s.c. or GON adipose tissue, whereas at different time points tissue-type (t-PA) and urokinase-type (u-PA) plasminogen activator activity was somewhat lower in the adipose tissues of mice on HFD. Gelatinolytic activity (mainly MMP-2) was detected in s.c. but not in GON adipose tissue of mice on SFD, and decreased on the HFD. In situ zymography on cryosections did not reveal different fibrinolytic activities in s.c. or GON adipose tissues of the HFD as compared to the SFD groups, whereas significantly lower gelatinolytic and higher caseinolytic activities were detected in s.c. and GON tissues of mice on the HFD (p < or = 0.05). The fibrillar collagen content was lower in adipose tissue of mice on HFD. Thus, in this model time-dependent development of adipose tissue appears to be associated with modulation of proteolytic activity.
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
Demeulemeester, Désiré
Van Hoef, Berthe
Collen, Désiré
Language :
English
Title :
Modulation of fibrinolytic and gelatinolytic activity during adipose tissue development in a mouse model of nutritionally induced obesity
Crandall D.L., Hausman G.J., Kral J.G. (1997) A review of the microcirculation of adipose tissue: Anatomic, metabolic, and angiogenic perspectives. Microcirculation 4:211-232.
Dollery C.M., McEwan J.R., Henney A.M. (1995) Matrix metalloproteinases and cardiovascular disease. Circ Res 77:863-868.
Carmeliet P., Collen D. (1998) Development and disease in proteinase-deficient mice: Role of the plasminogen, matrix metalloproteinase and coagulation system. Thromb Res 91:255-285.
Lijnen H.R. (2001) Plasmin and matrix metalloproteinases in vascular remodeling. Thromb Haemost 86:324-333.
Samad F., Yamamoto K., Loskutoff D.J. (1996) 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 97:37-46.
Alessi M.C., Peiretti F., Morange P., Henry M., Nalbone G., Juhan-Vague I. (1997) Production of plasminogen activator inhibitor 1 by human adipose tissue. Possible link between visceral fat accumulation and vascular disease. Diabetes 46:860-867.
Juhan-Vague I., Alessi M.C. (1999) Regulation of fibrinolysis in the development of atherothrombosis: Role of adipose tissue. Thromb Haemost 82:832-836.
Samad F., Loskutoff D.J. (1999) Hemostatic gene expression and vascular disease in obesity: Insights from studies of genetically obese mice. Thromb Haemost 82(742-747).
Morange P.E., Lijnen H.R., Alessi M.C., Kopp F., Collen D., Juhan-Vague I. (2000) Influence of PAI-1 on adipose tissue growth and on metabolic parameters in a murine model of diet-induced obesity. Arterioscler Thromb Vasc Biol 20:1150-1154.
Èren M., Su M., Atkinson J., King L., Declerck P., Vaughan D.E. (2001) Phenotypic derangements associated with overexpression of plasminogen activator inhibitor-1 (PAI-1) in transgenic mice. Arterioscler Thromb Vasc Biol , (Abstract 230); 21:695.
Brown L.M., Fox H.L., Hazen S.A., LaNoue K.F., Rannels S.R., Lynch C.J. (1997) Role of the matrixin MMP-2 in multicellular organization of adipocytes cultured in basement membrane components. Am J Physiol 272.
Lijnen H.R., Maquoi E., Holvoet P., Mertens A., Lupu F., Morange P., Alessi M.C., Juhan-Vague I. (2001) Adipose tissue expression of gelatinases in mouse models of obesity. Thromb Haemost 85:1111-1116.
Bouloumié A., Sengenès C., Portolan G., Galitzky J., Lafontan M. (2001) Adipocyte produces matrix metalloproteinases 2 and 9. Involvement in adipocyte differentiation. Diabetes 50:2080-2086.
Maquoi E., Munaut C., Colige A., Collen D., Lijnen H.R. (2002) Modulation of adipose tissue expression of murine matrix metalloproteinases and their tissue inhibitors with obesity. Diabetes 51(4):1093-1101.
Giles A.R. (1987) Guidelines for the use of animals in biomedical research. Thromb Haemost 58:1078-1084.
Declerck P.J., Verstreken M., Collen D. (1995) Immunoassay of murine t-PA, u-PA and PAI-1 using monoclonal antibodies raised in gene-inactivated mice. Thromb Haemost 74:1305-1309.
Lijnen H.R., Van Hoef B., Lupu F., Moons L., Carmeliet P., Collen D. (1998) Function of plasminogen/plasmin and matrix metalloproteinase systems after vascular injury in mice with targeted inactivation of fibrinolytic system genes. Arterioscler Thromb Vasc Biol 18:1035-1045.
Kleiner D.E., Stetler Stevenson W.G. (1994) Quantitative zymography: Detection of picogram quantities of gelatinases. Anal Biochem 218:325-329.
Galis Z.S., Sukhova G.K., Libby P. (1995) Microscopic localization of active proteases by in situ zymography: Detection of matrix metalloproteinase activity in vascular tissue. FASEB J 9:974-980.
Rodbell M. (1964) Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis. J Biol Chem 239:375-380.
Kubo Y., Kaidzu S., Nakajima I., Takenouchi K., Nakamura F. (2000) Organization of extracellular matrix components during differentiation of adipocytes in long-term culture. In Vitro Cell Dev Biol Anim 36:38-44.
Nakajima I., Yamaguchi T., Ozutsumi K., Aso H. (1998) Adipose tissue extracellular matrix: Newly organized by adipocytes during differentiation. Differentiation 63:193-200.
Kuri-Harcuch W., Arguello C., Marsch-Moreno M. (1984) Extracellular matrix production by mouse 3T3-F442A cells during adipose differentiation in culture. Differentiation 28:173-178.
Zangani D., Darcy K.M., Masso-Welch P.A., Bellamy E.S., Desole M.S., Ip M.M. (1999) Multiple differentiation pathways of rat mammary stromal cells in vitro: Acquisition of a fibroblast, adipocyte or endothelial phenotype is dependent on hormonal and extracellular matrix stimulation. Differentiation 64:91-101.
McCawley L.J., Matrisian L.M. (2000) Matrix metalloproteinases: Multi-functional contributors to tumor progression. Mol Med Today 6:149-156.
Pierleoni C., Verdenelli F., Castellucci M., Cinti S. (1998) Fibronectins and basal lamina molecules expression in human subcutaneous white adipose tissue. Eur J Histochem 42:183-188.
Stetler-Stevenson W.G. (1999) Matrix metalloproteinases in angiogenesis: A moving target for therapeutic intervention. J Clin Invest 103:1237-1241.
Bastelica D., Morange P., Berthet B., Borghi H., Lacroix O., Grino M., Juhan-Vague I., Alessi M.-C. (2002) Stromal cells are the main plasminogen activator inhibitor-1 producing cells in human fat. Evidence of differences between visceral and subcutaneous deposits. Arterioscl Thromb Vasc Biol 22:173-178.
Morange P.E., Bastelica D., Bonzi M.F., Van Hoef B., Collen D., Juhan-Vague I., Lijnen H.R. (2002) Influence of t-PA and u-PA on adipose tissue development in a murine model of diet-induced obesity. Thromb Haemost 87(2):306-310.
Lijnen H.R., Maquoi E., Hansen L.B., Van Hoef B., Frederix L., Collen D. (2002) Matrix metalloproteinase inhibition impairs adipose tissue development in mice. Arterioscler Thromb Vasc Biol 22(3):374-379.
