Download PDF
Thromb Haemost 2002; 87(03): 530-535
DOI: 10.1055/s-0037-1613035
Review Article
Schattauer GmbH

Adipocyte Hypertrophy in Stromelysin-3 Deficient Mice with Nutritionally Induced Obesity

H. R. Lijnen
1   Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
,
B. Van Hoef
1   Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
,
L. Frederix
1   Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
,
M.-C. Rio
2   CNRS-INSERM-ULP, Illkirch, France
,
D. Collen
1   Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
› Author Affiliations
Further Information

Publication History

Received 15 October 2001

Accepted after revision 17 December 2001

Publication Date:
14 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Several matrix metalloproteinases (MMPs), including the stromelysins MMP-3 and MMP-11, are expressed in adipose tissue. To investigate a potential role of MMP-11 (stromelysin-3) in adipose tissue development, five-week-old male wild-type mice (MMP-11+/+) or mice with deficiency of MMP-11 (MMP-11−/−) were fed a high fat diet (HFD, 42% fat) for 15 weeks. Haematologic parameters, including white and red blood cells, platelets, haemoglobin and haematocrit, and metabolic parameters including glucose, triglycerides and total cholesterol were not different for both genotypes. At the time of sacrifice, the body weight of the MMP-11-/mice was higher than that of the MMP-11+/+ mice (36 ± 1.4 g versus 29 ± 0.9 g, p = 0.0002). The weight of the isolated subcutaneous (SC) and gonadal (GON) fat deposits was also higher in MMP-11−/−mice (620 ± 150 mg versus 280 ± 28 mg for SC fat, and 970 ± 180 mg versus 430 ± 62 mg, p < 0.05, for GON fat). Adipocytes in MMP-11−/−adipose tissue were hypertrophic as compared to MMP-11+/+ adipocytes (volume of 57 ± 12 × 103 µm3 versus 31 ± 2.4 × 103 µm3 for SC fat, and 100 ± 18 × 103 µm3 versus 57 ± 7.6 × 103 µm3 for GON fat; both p < 0.06). In nutritionally induced obesity models in mice a potential role of the fibrinolytic system was suggested in adipocyte hypertrophy. The hypertrophy observed in this model is, however, not related to changes in fibrinolytic parameters, as suggested by our finding that levels of t-PA, u-PA and PAI-1 antigen as well as t-PA and u-PA activity were not different in SC or GON adipose tissue extracts of both genotypes. As the main biological function of MMP-11 remains unknown, it is not clear whether the adipocyte hypertrophy in MMP-11−/−adipose tissue is directly related to the deficiency or to other pathways affected by MMP-11.

Keywords

Obesity - stromelysin - adipocyte
 

  • References

  • 1 Crandall DL, Hausman GJ, Kral JG. A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives. Microcirculation 1997; 04: 211-32.
    CrossrefPubMedSearch in Google Scholar
  • 2 Dollery CM, McEwan JR, Henney AM. Matrix metalloproteinases and cardiovascular disease. Circ Res 1995; 77: 863-8.
    CrossrefPubMedSearch in Google Scholar
  • 3 Carmeliet P, Collen D. Development and disease in proteinase-deficient mice: role of the plasminogen, matrix metalloproteinase and coagulation system. Thromb Res 1998; 91: 255-85.
    CrossrefPubMedSearch in Google Scholar
  • 4 Lijnen HR. Plasmin and matrix metalloproteinases in vascular remodeling. Thromb Haemost 2001; 86: 324-33.
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 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.
    CrossrefPubMedSearch in Google Scholar
  • 6 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: 860-7.
    CrossrefPubMedSearch in Google Scholar
  • 7 Juhan-Vague I, Alessi MC. Regulation of fibrinolysis in the development of atherothrombosis: role of adipose tissue. Thromb Haemost 1999; 82: 832-6.
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Samad F, Loskutoff DJ. Hemostatic gene expression and vascular disease in obesity: insights from studies of genetically obese mice. Thromb Haemost 1999; 82: 742-7.
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 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: 1150-4.
    CrossrefPubMedSearch in Google Scholar
  • 10 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 1997; 272: C937-49.
    CrossrefPubMedSearch in Google Scholar
  • 11 Lijnen HR, Maquoi E, Holvoet P, Mertens A, Lupu F, Morange P, Alessi MC, Juhan-Vague I. Adipose tissue expression of gelatinases in mouse models of obesity. Thromb Haemost 2001; 85: 1111-6.
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Bouloumié A, Sengenès C, Portolan G, Galitzky J, Lafontan M. Adipocyte produces matrix metalloproteinases 2 and 9. Involvement in adipocyte differentiation. Diabetes 2001; 50: 2080-6.
    CrossrefPubMedSearch in Google Scholar
  • 13 Maquoi E, Alessi MC, Collen D, Lijnen HR. Modulation of the expression of matrix metalloproteinases and their tissue inhibitors in adipose tissue. Thromb Haemost. Suppl July 2001 0C2503.
    PubMedSearch in Google Scholar
  • 14 Pei D, Weiss SJ. Furin-dependent intracellular activation of the human stromelysin-3 zymogen. Nature 1995; 375: 244-7.
    CrossrefPubMedSearch in Google Scholar
  • 15 Pei D, Majmudar G, Weiss SJ. Hydrolytic activation of a breast carcinoma cell-derived serpin by human stromelysin-3. J Biol Chem 1994; 269: 25849-55.
    PubMedSearch in Google Scholar
  • 16 Mañez S, Mira E, del Mar Barbacid M, Ciprés A, Fernández-Resa P, Buesa JM, Mérida I, Aracil M, Márquez G, Martínez-A C. Identification of insulin-like growth factor-binding protein-1 as a potential physiological substrate for human stromelysin-3. J Biol Chem 1997; 272: 25706-12.
    CrossrefPubMedSearch in Google Scholar
  • 17 Murphy G, Segain J-P, O’Shea M, Cockett M, Iannou C, Lefebvre O, Chambon P, Basset P. The 28-kDa N-terminal domain of mouse stromelysin-3 has the general properties of a weak metalloproteinase. J Biol Chem 1993; 269: 15435-41.
    PubMedSearch in Google Scholar
  • 18 Noël A, Santavicca M, Stoll I, L’Hoir C, Staub A, Murphy G, Rio M-C, Basset P. Identification of structural determinants controlling human and mouse stromelysin-3 proteolytic activities. J Biol Chem 1995; 270: 22866-72.
    CrossrefPubMedSearch in Google Scholar
  • 19 Basset P, Wolf C, Chambon P. Expression of the stromelysin-3 gene in fibroblastic cells of invasive carcinomas of the breast and other human tissues: a review. Breast Cancer Res Treat 1993; 24: 185-93.
    CrossrefPubMedSearch in Google Scholar
  • 20 Basset P, Bellocq J-P, Lefebvre O, Noël A, Chenard M-P, Wolf C, Anglard P, Rio M-C. Stromelysin-3: a paradigm for stroma-derived factors implicated in carcinoma progression. Crit Rev Oncol/Hematol 1997; 26: 43-53.
    CrossrefPubMedSearch in Google Scholar
  • 21 Duffy MJ, Maquire TM, Hill A, McDermott E, O’Higgins N. Metalloproteinases: role in breast carcinogenesis, invasion and metastasis. Breast Cancer Res 2000; 02: 252-7.
    CrossrefPubMedSearch in Google Scholar
  • 22 Lefebvre O, Wolf C, Limacher J-M, Hutin P, Wendling C, LeMeur M, Basset P, Rio M-C. The breast cancer-associated stromelysin-3 gene is expressed during mouse mammary gland apoptosis. J Cell Biol 1992; 119: 997-1002.
    CrossrefPubMedSearch in Google Scholar
  • 23 Lijnen HR, Van Hoef B, Vanlinthout I, Verstreken M, Rio M-C, Collen D. Accelerated neointima information after vascular injury in mice with stromelysin-3 (MMP-11) gene inactivation. Arterioscler Thromb Vasc Biol 1999; 19: 2863-70.
    CrossrefPubMedSearch in Google Scholar
  • 24 Masson R, Lefebvre O, Noël A, El Fahime M, Chenard MP, Wendling C, Kebers F, LeMeur M, Dierich A, Foidart JM, Basset P, Rio M-C. In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy. J Cell Biol 1998; 140: 1535-41.
    CrossrefPubMedSearch in Google Scholar
  • 25 Alexander CM, Selvarajan S, Mudgett J, Werb Z. Stromelysin-1 regulates adipogenesis during mammary gland involution. J Cell Biol 2001; 152: 693-703.
    CrossrefPubMedSearch in Google Scholar
  • 26 Giles AR. Guidelines for the use of animals in biomedical research. Thromb Haemost 1987; 58: 1078-84.
    Thieme ConnectPubMedSearch in Google Scholar
  • 27 Lemonnier D. Effect of age, sex, and site on the cellularity of adipose tissue in mice and rats rendered obese by a high fat diet. J Clin Invest 1972; 51: 2907-15.
    CrossrefPubMedSearch in Google Scholar
  • 28 Kleiner DE, Stetler WGStevenson. Quantitative zymography: detection of picogram quantities of gelatinases. Anal Biochem 1994; 218: 325-9.
    CrossrefPubMedSearch in Google Scholar
  • 29 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: 1035-45.
    CrossrefPubMedSearch in Google Scholar
  • 30 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: 1305-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 31 Lowell BB, S-Susulic V, Hamann A, Lawitts JA, Himms-Hagen J, Boyer BB, Kozak LP, Flier JS. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 1993; 366: 740-2.
    CrossrefPubMedSearch in Google Scholar
  • 32 Morange PE, Bastelica D, Bonzi MF, Van Hoef B, Collen D, Juhan-Vague I, Lijnen HR. Influence of t-PA and u-PA on adipose tissue development in a murine model of diet-induced obesity. Thromb Haemost. in press.
    PubMed
  • 33 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).
    PubMedSearch in Google Scholar
  • 34 Lijnen HR, Ugwu F, Rio MC, Collen D. Plasminogen/plasmin and matrix metalloproteinase system function in mice with targeted inactivation of stromelysin-3 (MMP-11). Fibrinolysis & Proteolysis 1998; 12: 155-64.
    CrossrefPubMedSearch in Google Scholar
  • 35 Guller S, Corin RE, Mynarcik DC, London BM, Sonenberg M. Role of insulin in growth hormone-stimulated 3T3 cell adipogenesis. Endocrinology 1988; 122: 2084-2089.
    CrossrefPubMedSearch in Google Scholar
  • 36 Adashi EY, Resnick CE, Ricciarelli E, Hurwitz A, Kokia E, Tedeschi C, Botero L, Hernández ER, Rosenfeld RG, Carlsson-Skwirut C, Francis GL. Granulosa cell-derived insulin-like growth factor (IGF) binding proteins are inhibitory to IGF-I hormonal action. Evidence derived from the use of a truncated IGF-I analogue. J Clin Invest 1992; 90: 1593-9.
    PubMedSearch in Google Scholar
  • 37 Elgin RG, Busby WH, Clemmons DR. An insulin-like growth factor (IGF) binding protein enhances the biologic response to IGF-I. Proc Natl Acad Sci USA 1987; 84: 3254-8.
    CrossrefPubMedSearch in Google Scholar
  • 38 Cohen P, Lamson G, Okajima T, Rosenfeld RG. Transfection of the human insulin-like growth factor binding protein-3 gene into Balb/c fibroblasts inhibits cellular growth. Mol Endocrinol 1993; 07: 380-6.
    PubMedSearch in Google Scholar
  • 39 Camacho-Hubner C, McCusker RH, Clemmons DR. Secretion and biological actions of insulin-like growth factor binding proteins in two human tumor-derived cell lines in vitro. J Cell Physiol 1991; 148: 281-9.
    CrossrefPubMedSearch in Google Scholar