Tiplaxtinin impairs nutritionally induced obesity in mice

H. Roger Lijnen; Marie-Christine Alessi; Liesbeth Frederix; Désiré Collen; Irène Juhan-Vague

doi:10.1160/TH06-08-0422

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 96(06): 731-737
DOI: 10.1160/TH06-08-0422

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Tiplaxtinin impairs nutritionally induced obesity in mice

H. Roger Lijnen

¹Center for Molecular and Vascular Biology, KU Leuven, Belgium

,

Marie-Christine Alessi

²Haematology Laboratory, INSERM U626, Marseille, France; Faculty of Medicine, Marseille, France

,

Liesbeth Frederix

¹Center for Molecular and Vascular Biology, KU Leuven, Belgium

,

Désiré Collen

,

Irène Juhan-Vague

²Haematology Laboratory, INSERM U626, Marseille, France; Faculty of Medicine, Marseille, France

› Author Affiliations

Abstract

Summary

To investigate the effect of tiplaxtinin, designed as a synthetic inhibitor of plasminogen activator inhibitor-1 (PAI-1), on obesity, male C57Bl/6 mice (13–14 weeks old) were kept on a high-fat diet (20.1 kJ/g) for four weeks without or with addition of tiplaxtinin (PAI-039) at a dose of 2 mg/g food. At the time of sacrifice, body weights were significantly lower in the inhibitor-treated mice (p < 0.0005). The weights of the isolated subcutaneous and gonadal fat deposits were also significantly lower (both p < 0.0005), associated with adipocyte hypotrophy. Inhibitor-treated adipose tissues displayed similar blood vessel size, but a higher blood vessel density. Fasting glucose and insulin levels, as well as glucose-tolerance tests were not significantly affected by the inhibitor treatment, whereas plasma triglyceride levels were significantly reduced (p = 0.02) and LDL-cholesterol levels significantly enhanced (p = 0.0002). Insulin-tolerance tests revealed significantly lower glucose levels at the end of the test in the inhibitor treated mice (p = 0.03). Thus, in this model of diet-in-duced obesity in mice administration of tiplaxtinin resulted in impaired adipose tissue development.

Keywords

PAI-1 - obesity - adipose tissue - glucose tolerance - insulin sensitivity

Full Text

References

References
1 Lijnen HR. Pleioptropic functions of plasminogen activator inhibitor-1. Thromb Haemost 2005; 03: 35-45.
2 Gils A, Declerck PJ. The structural basis for the pathophysiological relevance of PAI-1 in cardiovascular diseases and the development of potential PAI-1 inhibitors. Thromb Haemost 2004; 91: 425-37.
3 Shimomura I, Funahashi T, Takahashi M. et al. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med 1996; 02: 800-3.
4 Samad F, Loskutoff DJ. Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice. Mol Med 1996; 02: 568-82.
5 Alessi MC, Peiretti F, Morange P. et al. Production of plasminogen activator inhibitor1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 1997; 46: 860-7.
6 Alessi MC, Bastelica D, Morange P. et al. Plasminogen activator inhibitor 1, transforming growth factor-beta 1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 2000; 49: 1374-80.
7 Van Dielen FMH, Buurman WA, Hadfoune M. et al. Macrophage inhibitory factor, plasminogen activator inhibitor-1, other acute phase proteins, and inflammatory mediators normalize as a result of weight loss in morbidly obese subjects treated with gastric restrictive surgery. J Clin Endocrinol Metab 2004; 89: 4062-8.
8 Morange PE, Lijnen HR, Alessi MC. et al. 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.
9 Lijnen HR, Maquoi E, Morange P. et al. Nutritionally induced obesity is attenuated in trangenic mice overexpressing plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol 2003; 23: 78-84.
10 Eren M, Su M, Atkinson J L. et al. Phenotypic derangements associated with overexpression of plasminogen activator inhibitor-1 (PAI-1) in transgenic mice. Arterioscler Thromb Vasc Biol 2001; 21: 695 (Abstract).
11 Schafer K, Fujisawa K, Konstantinides S. et al. 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: 1840-2.
12 Ma L-J, Mao S-L, Taylor KL. et al. Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes 2004; 53: 336-46.
13 Lijnen HR. Effect of plasminogen activator inhibitor-1 deficiency on nutritionally-induced obesity in mice. Thomb Haemost 2005; 93: 816-9.
14 Elokdah H, Abou-Gharbia M, Hennan JK. et al. Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: Design, synthesis, and preclinical characterization. J Med Chem 2004; 47: 3491-4.
15 Crandall DL, Elokdah H, Di L. et al. Characterization and comparative evaluation of a structurally unique PAI-1 inhibitor exhibiting oral in-vivo efficacy. J Thromb Haemost 2004; 02: 1422-8.
16 Matthews DR, Hosker JP, Rudenski AS. et al. Homeostatic model assessment: insulin resistance and β-cell function from fasting glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-9.
17 Giles AR. Guidelines for the use of animals in biomedical research. Thromb Haemost 1987; 58: 1078-84.
18 Laitinen L. Griffonia Simplicifolia lectins bind specifically to endothelial cells and some epithelial cells in mouse tissues. Histochem J 1987; 19: 225-34.
19 Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol 2000; 182: 311-22.
20 Smith MD, Healy E, Thompson V. et al. Use of in situ detection of histone mRNA in the assessment of epidermal proliferation: comparison with the Ki-67 antigen and BrdU incorporation. Br J Dermatol 1995; 132: 359-66.
21 Lijnen HR, Van Hoef B, Lupu F. et al. 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.
22 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.
23 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.
24 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.
25 Rogers P, Webb GP. Estimation of body fat in normal and obese mice. Br J Nutr 1980; 43: 83-6.
26 Isomaa B, Almgren P, Tuomi T. et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001; 24: 683-9.
27 Lakka HM, Laaksonen DE, Lakka TA. et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. J Am Med Assoc 2002; 288: 2709-16.
28 Bays HE. Current and investigational antiobesity agents and obesity therapeutic treatment targets. Obesity Res 2004; 12: 1197-211.
29 Lijnen HR. Plasmin and matrix metalloproteinases in vascular remodeling. Thromb Haemost 2001; 86: 324-33.
30 Skurk T, Hauner H. Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. Int J Obes Relat Metab Disord 2004; 28: 1357-64.
31 Mavri A, Alessi MC, Bastelica D. et al. 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: 2025-31.
32 Reaven CM. Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med 1993; 44: 121-31.
33 Juhan-Vague I, Alessi M-C, Mavri A. et al. Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk. J Thromb Haemost 2003; 01: 1575-9.
34 Eren M, Cleaves L, Walker E. et al. Inhibition of PAI-1 activity reduces angiotensin II induced aortic atherosclerosis and aneurysm in ApoE deficient mice. American Heart Association Meetings; 2003. Orlando, FL: (Abstract).
35 Liu J, Antrilli TM, Elokdah H. et al. Inhibition of plasminogen activator inhibitor-1 protects against atherosclerosis progression in apolipoprotein E-deficient mice. Blood. 2003. 102 (11) Presented at the ASH meeting; San Diego: (Abstract).
36 Weisberg AD, Albornoz F, Griffin JP. et al. Pharmacological inhibition and genetic deficiency of plasminogen activator inhibitor-1 attenuates angiotensin II/ salt-induced aortic remodeling. Arterioscler Thromb Vasc Biol 2005; 25: 365-71.
37 Smith LH, Dixon JD, Stringham JR, Eren M. et al. Pivotal role of PAI-1 in a murine model of hepatic vein thrombosis. Blood 2006; 107: 132-34.
38 Lijnen HR, Alessi M-C, Van Hoef B. et al. On the role of plasminogen activator inhibitor-1 in adipose tissue development and insulin resistance in mice. J Thromb Haemost 2005; 03: 1174-9.
39 Crandall DL, Quinet EM, El Ayachi S. et al. Modulation of adipose tissue development by pharmacologic inhibition of PAI-1. Arterioscler Thromb Vasc Biol 2006; 26: 2209-15.
40 Claret M, Corominola H, Canals I. et al. S23521 decreases food intake and body weight gain in diet-induced obese rats. Obes Res 2004; 12: 1596-603.
41 Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395: 763-70.
42 Devy L, Blacher S, Grignet-Debrus CK. et al. The pro-or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. Faseb J 2002; 16: 147-54.
43 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.
44 Crandall DL, Hausman GJ, Kral JG. A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives. Microcirculation 1997; 04: 211-232.
45 Voros G, Maquoi E, Demeulemeester D. et al. Modulation of angiogenesis during adipose tissue development in murine models of obesity. Endocrinology 2005; 146: 4545-54.