Rofecoxib impairs adipose tissue development in a murine model of nutritionally induced obesity

H. Roger Lijnen; Berthe Van Hoef; Hua Rong Lu; David J. Gallacher

doi:10.1160/TH08-02-0114

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 100(02): 338-342
DOI: 10.1160/TH08-02-0114

Animal Models

Schattauer GmbH

Rofecoxib impairs adipose tissue development in a murine model of nutritionally induced obesity

Authors

H. Roger Lijnen

¹Center for Molecular andVa scular Biology, KU Leuven, Leuven, Belgium
Berthe Van Hoef

¹Center for Molecular andVa scular Biology, KU Leuven, Leuven, Belgium
Hua Rong Lu

²Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium
David J. Gallacher

²Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium

Abstract

Summary

The effect of rofecoxib (Vioxx), a cyclooxygenase (COX)-2 inhibitor, on adipose tissue development was studied in a murine model of diet-induced obesity. Oral administration of Vioxx for six weeks (34 mg/kg/day) to C57Bl/6 mice kept on high-fat diet (n = 19) resulted in a significant reduction in total body weight (p < 0.01) and of subcutaneous (p < 0.05) and gonadal (p< 0.01) adipose tissue mass, as compared to placebo-treated animals (n = 21).There was no significant difference in food intake between both groups (2.8 ± 0.09 vs.3.0 ± 0.10 g/day;p = 0.20).Administration ofVioxx resulted in reduced total cholesterol and high-density lipoprotein (HDL) cholesterol levels (p < 0.0001) and in enhanced levels of liver enzymes, as compared to placebo. In the gonadal but not in the subcutaneous adipose tissue, adipocytes were smaller after Vioxx treatment (p < 0.05).The macrophage content was significantly lower in gonadal adipose tissues of Vioxx-treated mice (p < 0.05), but not in the subcutaneous adipose tissues. This was, however, not associated with differences in adipose tissue levels of the pro-inflammatory tumor necrosis factor (TNF)-α. Blood vessel size or density in either fat pad were not affected by Vioxx treatment. Thus, in a nutritionally induced murine obesity model, oral administration of Vioxx, as compared to placebo, resulted in reduced adipose tissue development, associated with lower feeding efficiency and smaller adipocytes.

Keywords

Obesity - adipose tissue - cyclooxygenase - rofecoxib

Full Text

References

References
1 Crandall DL, Hausman GJ, Kral JG. A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives. Microcirculation 1997; 04: 211-232.
2 Kopelman PG. Obesity as a medical problem. Nature 2000; 404: 635-643.
3 Weisberg SP, McCann D, Desai M. et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796-1808.
4 Xu H, Barnes GT, Yang Q. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112: 1821-1830.
5 Lumeng CN, Deyoung SM, Bodzin JL. et al. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 2007; 56: 16-23.
6 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-alpha and lipopolysaccharide. J Clin Invest 1996; 87: 37-46.
7 Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87-91.
8 Wu KK. Cyclooxygenase-2 induction in congestive heart failure: friend or foe?. Circulation 1998; 98: 95-96.
9 Linton MF, Fazio S. Cyclooxygenase-2 and atherosclerosis. Curr Opin Lipidol 2002; 13: 497-504.
10 Mitchell JA, Lucas R, Vojnovic I. et al. Stronger inhibition by nonsteroid anti-inflammatory drugs of cyclooxygenase-1 in endothelial cells than platelets offers an explanation for increased risk of thrombotic events. FASEB J 2006; 20: 2468-2475.
11 Fajas L, Miard S, Briggs MR. et al. Selective cyclooxygenase-2 inhibitors impair adipocyte differentiation through inhibition of the clonal expansion phase. J Lipid Res 2003; 44: 1652-1659.
12 Kellinsalmi M, Parikka V, Risteli J. et al. Inhibition of cyclooxygenase-2 down-regulates osteoclast differentiation and favours adipocyte formation in vitro. Eur J Pharmacol 2007; 572: 102-110.
13 Yan H, Kermouni A, Abdel-Hafez M. et al. Role of cyclooxygenases COX-1 and COX-2 in modulating adipogenesis in 3T3-L1 cells. J Lipid Res 2003; 44: 424-429.
14 Bresalier RS, Sandler RS, Quan H. et al. Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092-1102.
15 Solomon SD, McMurray JJ, Pfeffer MA. et al. Adenoma Prevention with Celecoxib (APC) Study Investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005; 352: 1071-1080.
16 Kerr DJ, Dunn JA, Langmann MJ. et al. VICTOR Trial Group. Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N Engl J Med 2007; 357: 360-369.
17 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: 345-353.
18 Giles AR. Guidelines for the use of animals in biomedical research. Thromb Haemost 1987; 58: 1078-1084.
19 Laitinen L. Griffonia simplificifolia lectins bind specifically to endothelial cells and some epithelial cells in mouse tissues. Histochem J 1987; 19: 225-234.
20 Fain JN, Ballou LR, Bahouth SW. Obesity is induced in mice heterozygous for cyclooxygenase-2. Prostaglandins Other Lipid Mediat 2001; 65: 199-209.
21 Efstathiou JA, Sampson DA, Levine Z. et al. Nonsteroidal anti-inflammatory drugs differentially suppress endometriosis in a murine model. Fertil Steril 2005; 83: 171-181.
22 Guo JS, Cho CH, Lam Lin ES. et al. Antiangiogenic effect of highly selective cyclooxygenase-2 inhibitor on gastric ulcer healing in rats. To xicolAppl Pharmacol 2002; 183: 41-45.
23 Ma L, del Soldato P, Wallace JL. Divergent effects of new cyclooxygenase inhibitors on gastric ulcer healing shifting the angiogenic balance. Proc Natl Acad Sci USA 2002; 99: 13243-13247.
24 Fosslien E. Biochemistry of cycloxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Crit Rev Clin Lab Sci 2000; 37: 431-502.
25 Fain JN, Kanu A, Bahouth SW. et al. Comparison of PGE2, prostacyclin and leptin release by human adipocytes versus explants of adipose tissue in primary culture. Prostaglandins Leukot Essent Fatty Acids 2002; 67: 467-473.
26 Walter MF, Jacob RF, Day CA. et al. Sulfone COX-2 inhibitors increase susceptibility of human LDL and plasma to oxidative modification: comparison to sulfonamide COX-2 inhibitors and NSAIDs. Atherosclerosis 2004; 177: 235-243.
27 Mason RP, Walter MF, McNulty HP. et al. Rofecoxib increases susceptibility of human LDL and membrane lipids to oxidative damage: a mechanism of cardiotoxicity. J Cardiovasc Pharmacol 2006; 47 (Suppl. 01) S7-14.
28 Voros G, Maquoi E, Demeulemeester D. et al. Modulation of angiogenesis during adipose tissue development in murine models of obesity. Endocrinology 2005; 146: 4545-4554.
29 Wu D, Ren Z, Pae M. et al. Aging up-regulates expression of inflammatory mediators in mouse adipose tissue. J Immunol 2007; 179: 4829-4839.
30 Xie Y, Kang X, Ackerman 4^th WE. et al. Differentiation-dependent regulation of the cyclooxygenase cascade during adipogenensis suggests a complex role for prostaglandins. Diabetes Obes Metab 2006; 08: 83-93.