Thromb Haemost 2002; 87(06): 1011-1019
DOI: 10.1055/s-0037-1613126
Review Article
Schattauer GmbH

In Vivo Plasminogen Deficiency Reduces Fat Accumulation

Jane Hoover-Plow
1   Department of Molecular Cardiology, J. J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
,
Jill Ellis
1   Department of Molecular Cardiology, J. J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
,
Lawrence Yuen
1   Department of Molecular Cardiology, J. J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
› Author Affiliations
Further Information

Publication History

Received 27 July 2001

Accepted after resubmission 17 February 2002

Publication Date:
08 December 2017 (online)

Summary

Obesity and non-insulin dependent diabetes are associated with a decrease in fibrinolysis, which is mediated by the plasminogen system. The purpose of the current study was to investigate the role of the plasminogen system in the reduced body weight of the plasminogen deficient (Plg−/−) mice. In this study we have found that the reduced body weight in Plg−/− mice is due to a reduced rate of the adipose tissue (25% less) and whole body fat (30% less) accumulation during growth in Plg−/− compared to wild-type (WT) littermates. When the mice are fed a high fat-lipogenic diet, adipose tissue accumulation increases in the Plg−/− mice indicating that the capacity for lipid filling of cells was not blocked. In addition, glycerol phosphate dehydrogenase, a marker of late differentiation, was not different in the depots from WT and Plg−/− mice. The number of stromal cells (number × 105/g adipose tissue), isolated from inguinal (Plg−/− 3.4 ± 1.2, n = 6; WT 0.17 ± 0.07, n = 7, p < 0.02) and gonadal (Plg−/− 11.0 ± 0.4, n = 6; WT 3.1 ± 0.7, n = 7, p < 0.05) fat depots, was markedly higher in the depots from the Plg−/− mice than WT mice. Differentiation of stromal cells in culture from the Plg−/− mice was reduced compared to cells from WT mice. These results suggest that differences in the stromal cell population are responsible for the reduced adipose tissue accumulation in the Plg−/− mice, and that the plasminogen system plays an important role in adipose tissue accumulation.

 
  • References

  • 1 DeFronzo RA. Insulin resistance, hyperinsulinemia, and coronary artery disease: A complex metabolic web. J Cardiovasc Pharmacol 1992; 20 Suppl. (Suppl. 11) S1-S16.
  • 2 Perriello G, Misericordia P, Volpi E, Pampanelli S, Santeusanio F, Brunetti P, Bolli GB. Contribution of obesity to insulin resistance in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1995; 80: 2464-9.
  • 3 McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes 1994; 43 (01) 104-9.
  • 4 Juhan-Vague I, Alessi MC. Fibrinolysis and risk of coronary artery disease. Fibrinolysis 1996; 10: 127-36.
  • 5 Collen D, Lijnen HR. Basic and clinical aspects of fibrinolysis and thrombolysis. Blood 1991; 78: 3114-24.
  • 6 Carmeliet P, Collen D. Evaluation of the plasminogen/plasmin system in transgenic mice. Fibrinolysis 1994; 08 supp. (Suppl. 01) 269-76.
  • 7 Ploplis VA, French EL, Carmeliet P, Collen D, Plow EF. Plasminogen deficiency differentially affects recruitment of inflammatory cell populations in mice. Blood 1998; 91: 2005-9.
  • 8 Romer J, Bugge TH, Pyke C, Lund LR, Flick MJ, Degen JL, Dano K. Impaired wound healing in mice with a disrupted plasminogen gene. Nature Med 1996; 02: 287-92.
  • 9 Carmeliet P, Moons L, Ploplis V, Plow E, Collen D. Impaired arterial neointima formation in mice with disruption of the plasminogen gene. J Clin Invest 1997; 99: 200-8.
  • 10 Leonardsson G, Peng XR, Liu D, Nordstrom L, Carmeliet P, Mulligan R, Collen D, Ny T. Ovulation efficiency is reduced in mice that lack plasminogen activator gene function: Functional redundancy among physiological plasminogen activators. Proc Natl Acad Sci USA 1995; 92: 12446-50.
  • 11 Ailhaud G, Grimaldi P, Negrel R. Cellular and molecular aspects of adipose tissue development. Annu Rev Nutr 1992; 12: 207-33.
  • 12 Ploplis VA, Carmeliet P, Vazirzadeh S, Van Vlaenderen I, Moons L, Plow EF, Collen D. Effects of disruption of the plasminogen gene in mice on thrombosis, growth and health. Circulation 1995; 92: 2585-93.
  • 13 Hoover-Plow J, Wang N, Ploplis V. Growth and behavioral development in plasminogen gene-targeted mice. Growth Dev Aging 1999; 63: 13-32.
  • 14 Clark RG, Tarttelin MR. An accurate method for preparation and analysis of the composition of animal tissue. Physiol Behav 1976; 17: 351-2.
  • 15 Rice SA, Fish KJ, Hoover-Plow J, Jawaharlal K. In vitro hepatic anesthetic and drug metabolism of Fischer 344 rats with dietary-induced obesity. Arch Int Pharmacodyn Ther 1990; 299: 286-93.
  • 16 Folch J, Lees M, Sloane SG. A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 1957; 226: 497-509.
  • 17 Hoover-Plow JL, Nelson B. Oxygen consumption in mice (I strain) after feeding. J Nutr 1985; 115: 303-10.
  • 18 McGowan MW, Artiss JD, Strandbergh DR, Zak B. A peroxidase-coupled method for the colorimetric determination of serum triglycerides. Clin Chem 1978; 29: 538-42.
  • 19 Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem 1974; 20: 470-5.
  • 20 Wise LS, Green H. Participation of one isozyme of cytosolic glycerophosphate dehydrogenase in the adipose conversion of 3T3 cells. J Biol Chem 1979; 254: 273-5.
  • 21 Hoover-Plow JL, Guerre-Millo M, Lavau M. Increased insulin effect on glucose metabolism in fat cells from I versus C57BL mice. Proc Soc Exper Biol Med 1987; 184: 410-5.
  • 22 Hirsch J, Gallian E. Methods for the determination of adipose cell size in man and animals. J Lipid Res 1968; 09: 110-9.
  • 23 Hoover-Plow JL. Adipose tissue development and metabolism in two strains of mice. Nutr Rep Inter 1984; 29: 1171-9.
  • 24 Swaisgood CM, French EL, Noga C, Simon RH, Ploplis VA. The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system. Am J Pathol 2000; 157: 177-87.
  • 25 Hoover-Plow J, Skomorovska-Prokvolit O, Welsh S. Selective behaviors altered in plasminogen-deficient mice are reconstituted with intracerebroventricular injection of plasminogen. Brain Res 2001; 898: 256-64.
  • 26 Ellis JR, McDonald RB, Stern JS. A diet high in fat stimulates adipocyte proliferation in older (22 month) rats. Exp Gerontol 1990; 25 (02) 141-8.
  • 27 Bugge TH, Flick MJ, Daugherty CC, Degen JL. Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction. Genes Dev 1995; 09: 794-807.
  • 28 Schafer K, Fujisawa K, Konstantinides S, Loskutoff DJ. 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 (10) 1840-2.
  • 29 Ignotz RA, Massagué J. Type b transforming growth factor controls the adipogenic differentiation of 3T3 fibroblasts. Proc Natl Acad Sci USA 1985; 82: 8530-4.
  • 30 Sparks RL, Scott RE. Transforming growth factor type b is a specific inhibitor of 3T3 mesenchymal stem cell differentiation. Exp Cell Res 1986; 165: 345-52.
  • 31 Roberts AB, McCune BK, Sporn MB. TGF-b: Regulation of extracellular matrix. Kidney Int 1992; 41: 557-9.
  • 32 Miller DA, Pelton RW, Derynck R, Moses HL. Transforming growth factor-beta. A family of growth regulatory peptides. Ann N Y Acad Sci 1990; 593: 208-17.
  • 33 Sato Y, Rifkin DB. Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor beta1 like molecule by plasmin during co-culture. J Cell Biol 1989; 109: 309-15.
  • 34 Samad F, Uysal KT, Wiesbrock SM, Pandey M, Hotamisligil GS, Loskutoff DJ. Tumor necrosis factor a is a key component in the obesitylinked elevation of plasminogen activator inhibitor 1. Proc Natl Acad Sci USA 1999; 96: 6902-7.
  • 35 Murphy G, Atkinson S, Ward R, Gavrilovic J, Reynolds JJ. The role of plasminogen activators in the regulation of connective tissue metalloproteinases. Ann NY Acad Sci 1992; 667: 1-12.
  • 36 Lijnen HR, Van Hoef B, Lupu F, Moons L, Carmeliet P, Collen D. Function of the plasminogen/plasmin and matrix metalloproteinase systems after vascular injury in mice with targeted inactivation of fibrinolytic system genes. Arterioscler Thromb Vasc Biol 1998; 18: 1035-45.
  • 37 Lijnen HR, Van Hoef B, Soloway P, Collen D. Plasminogen/plasmin system function in mice deficient in stromelysis-1 (MMP-3) or in tissue inhibitor of metalloproteinases type-1 (TIMP-1). Fibrinolysis Proteolysis 1998; 12: 1-8.
  • 38 Brown LM, Fox HL, Hazen SA, Lanoue KF, Rannels SR, Lynch CJ. Role of the matrix in MMP-2 in multicellular organization of adipocytes cultured in basement membrane components. Am J Physiol Cell Physiol 1997; 272: C937-C949.
  • 39 Lijnen HR, Maquoi E, Holvoet P, Mertens A, Lupu F, Morange P, Alessi MC, Juhan-Vague I. Adipose tisue expression of gelatinases in mouse models of obesity. Thromb Haemost 2001; 85: 1111-6.
  • 40 Salvarajan S, Lund LR, Takeuchi T, Craik CS, Werb Z. A plasma kallikrein-dependent plasminogen cascade required for adipcocyte differentiation. Nat Cell Biol 2001; 03: 267-75.
  • 41 Hoover-Plow J, Yuen L. Plasminogen binding is increased with adipocyte differentiation. Biochem and Biophys Res Commun 2001; 284: 389-94.
  • 42 Stack MS, Rinehart AR, Pizzo SV. Comparison of plasminogen binding and activation on extracellular matrices produced by vascular smooth muscle and endothelial cells. Eur J Biochem 1994; 226: 937-43.
  • 43 Kubo Y, Kaidzu S, Nakajima I, Takenouchi K, Nakamura F. Organization of extracellular matrix components during differentiation of adipocytes in long-term culture. In Vitro Cell Dev Biol Anim 2000; 36: 38-44.
  • 44 Dong ZM, Gutierrez-Ramos JC, Coxon A, Mayadas TN, Wagner DD. A new class of obesity genes encodes leukocyte adhesion receptors. Proc Natl Acad Sci USA 1997; 94: 7526-30.
  • 45 Ploplis V, Bussutil S, French E, Tang L, Carmeliet P, Collen D, Plow E. The inflammatory response to biopolymer implants in plasminogen deficient mice. Thromb Haemost 1997; 2234.