Overexpression of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in mice does not affect adipogenesis or adipose tissue developmentFinancial support: This study was supported financially by grants from the Flemish Fund for Scientific Research (FWO, G.0112.02), the Institute for the promotion of Innovation through Science and Technology in Flanders (IWT Vlaanderen) and the “Bijzonder Onderzoeksfonds K. U. Leuven” (OT/03/48).
16. November 2005
Accepted after resubmission 06. April 2006
30. November 2017 (online)
In order to evaluate a potential functional role of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in development of obesity, we studied the effect of overexpression of human TIMP-1 (hTIMP-1) in C57Bl/6J mice in vivo and in 3T3-F442A preadipocytes in vitro. Stable long-term overexpression of hTIMP-1 in mice was achieved by adenoviral gene transfer, yielding plasma levels exceeding 250 ng/ml at eight weeks after injection. Mice overexpressing hTIMP-1 and kept on a high fat diet for 14 weeks had body weights, adipose tissue weights, and adipocyte diameters that were somewhat, but not significantly, lower than those of control mice. Similar observations were made after overexpression of hTIMP-1 in mice with lipectomy of the subcutaneous adipose tissue, kept on a high fat diet for 20 weeks. In both in vivo models, blood vessels in the adipose tissues were significantly smaller after hTIMP-1 gene transfer than in control mice. Overexpression of hTIMP-1 in 3T3-F442A preadipocytes had no effect on their subsequent differentiation into mature adipocytes. Thus, overexpression of hTIMP-1 in mice had no significant effect on ongoing adipogenesis or adipose tissue development, although the blood vessel size in adipose tissues was reduced.
- 1 Crandall DL, Hausman GJ, Kral JG. A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives. Microcirculation 1997; 04: 211-2.
- 2 Dollery CM, McEwan JR, Henney AM. Matrix metalloproteinases and cardiovascular disease. Circ Res 1995; 77: 863-8.
- 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.
- 4 Lijnen HR. Molecular interactions between the plasminogen/plasmin and matrix metalloproteinase systems. Fibrinolysis Proteolysis 2000; 14: 175-81.
- 5 Lijnen HR, Maquoi E, Holvoet P. et al. Adipose tissue expression of gelatinases in mouse models of obesity. Thromb Haemost 2001; 85: 1111-6.
- 6 Boulomié A, Sengenès C, Portolan G. et al. Adipocyte produces matrix metalloproteinase 2 and 9. Involvement in adipocyte differentiation. Diabetes 2001; 50: 2080-6.
- 7 Maquoi E, Demeulemeester D, Voros G. et al. Enhanced nutritionally induced adipose tissue development in mice with stromelysin-1 gene inactivation. Thromb Haemost 2003; 89: 696-704.
- 8 Maquoi E, Munaut C, Colige A. et al. Modulation of the expression of murine matrix metalloproteinases and their tissue inhibitors with obesity. Diabetes 2002; 51: 1093-101.
- 9 Lijnen HR, Maquoi E, Hansen LB. et al. Matrix metalloproteinase inhibition impairs adipose tissue development in mice. Arterioscler Thromb Vasc Biol 2002; 22: 374-9.
- 10 Demeulemeester D, Collen D, Lijnen HR. Effect of matrix metalloproteinase inhibition on adipose tissue development. Biochem Biophys Res Commun 2005; 329: 105-10.
- 11 Willenbrock F, Murphy G. Structure-function relationships in the tissue inhibitors of metalloproteinases. Am J Respir Crit Care Med 1994; 150: S165-70.
- 12 Lijnen HR, Demeulemeester D, Van Hoef B. et al. Deficiency of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) impairs nutritionally induced obesity in mice. Thromb Haemost 2003; 89: 249-55.
- 13 Lijnen HR, Maquoi E, Demeulemeester D. et al. Modulation of fibrinolytic and gelatinolytic activity during adipose tissue development in a mouse model of nutritionally induced obesity. Thromb Haemost 2002; 88: 345-53.
- 14 Mauer MM, Harris RB, Bartness TJ. The regulation of total body fat: lessons learned from lipectomy studies. Neurosci Biobehav Rev 2001; 25: 15-28.
- 15 Mauer MM, Bartness TJ. Fat pad-specific compensatory mass increases after varying degrees of lipectomy in Siberian hamsters. Am J Physiol 1997; 273: R2117-23.
- 16 Giles AR. Guidelines for the use of animals in biomedical research. Thromb Haemost 1987; 58: 1078-84.
- 17 De Geest B, Van Linthout S, Collen D. Sustained expression of human apo A-I following adenoviral gene transfer in mice. Gene Ther 2001; 08: 121-7.
- 18 Van Linthout S, Collen D, De Geest B. Effect of promoters and enhancers on expression, transgene DNA persistence, and hepatotoxicity after adenoviral gene transfer of human apolipoprotein A-I. Hum Gene Ther 2002; 13: 829-40.
- 19 Negrel R, Dani C. Cultures of adipose precursor cells and cells of clonal lines from animal white adipose tissue. Methods Mol Biol 2001; 155: 225-7.
- 20 Ramirez-Zacarias JL, Castro-Munozledo F, Kuri-Harcuch W. Quantitation of adipose conversion and triglycerides by staining intracytoplasmic lipids with Oil red O. Histochemistry 1992; 97: 493-7.
- 21 Laitinen L. Griffonia simplicifolia lectins bind specifically to endothelial cells and some epithelial cells in mouse tissues. Histochem J 1987; 19: 225-4.
- 22 D’Angelo M, Billings PC, Pacifici M, Leboy PS, Kirsch T. Authentic matrix vesicles contain active metalloproteases (MMP): a role for matrix vesicle-associated MMP-13 in activation of transforming growth factor-beta. J Biol Chem 2001; 276: 11347-53.
- 23 Bordier C. Phase separation of integral membrane proteins in Triton X-114 solution. J Biol Chem 1981; 256: 1604-7.
- 24 Chavey C, Mari B, Monthouel MN. et al. Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation. J Biol Chem 2003; 278: 11888-96.
- 25 Bourlier V, Zakaroff-Girard A, De Barros S. et al. Protease inhibitor treatments reveal specific involvement of matrix metalloproteinase-9 in human adipocyte differentiation. J Pharmacol Exp Ther 2005; 312: 1272-9.
- 26 Andarawewa KL, Motrescu ER, Chenard MP. et al. Stromelysin-3 is a potent negative regulator of adipogenesis participating to cancer cell-adipocyte interaction/crosstalk at the tumor invasive front. Cancer Res 2005; 65: 10862-71.
- 27 Rupnick MA, Panigrahy D, Zhang CY. et al. Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci USA 2002; 99: 10730-5.
- 28 Devy L, Blacher S, Grignet-Debrus C. et al. The proor antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB J 2002; 16: 147-54.
- 29 Harris RB, Hausman DB, Bartness TJ. Compensation for parial lipectomy in mice with genetic alterations of leptin and its receptor subtypes. Am J Physiol Regul Integr Comp Physiol 2002; 283: R1094-103.
- 30 Voros G, Maquoi E, Demeulemeester D. et al. Modulation of angiogenesis during adipose tissue development in murine models. Endocrinology 2005; 146: 4545-54.
- 31 Ikenaka Y, Yoshiji H, Kuriyama S. et al. Tissue inhibitor of metalloproteinases-1 (TIMP-1) inhibits tumor growth and angiogenesis in the TIMP-1 transgenic mouse model. Int J Cancer 2003; 105: 340-6.
- 32 Bloomston M, Shafii A, Zervos EE. et al. TIMP-1 overexpression in pancreatic cancer attenuates tumor growth, decreases implantation and metastasis, and inhibits angiogenesis. J Surg Res 2002; 102: 39-44.
- 33 Zacchigna S, Zentilin L, Morini M. et al. AAVmediated gene transfer of tissue inhibitor of metalloproteinase-1 inhibits vascular tumor growth and angiogenesis in vivo . Cancer Gene Ther 2004; 11: 73-80.
- 34 Arlt M, Kopitz C, Pennington C. et al. Increase in gelatinase-specificity of matrix metalloproteinase inhibitors correlates with antimetastatic efficacy in T-cell lymphoma model. Cancer Res 2002; 62: 5543-50.
- 35 Lein M, Jung K, Ortel B. et al. The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival ina prostate cancer standard rat model. Oncogene 2002; 21: 2089-96.
- 36 Alexander CM, Selvarajan S, Mudgett J. et al. Stromelysin-1 regulates adipogenesis during mammary gland involution. J Cell Biol 2001; 152: 693-703.