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The anti-angiogenic herbal composition Ob-X inhibits adipose tissue growth in obese mice

International Journal of Obesity volume 34, pages 820–830 (2010)Cite this article

Subjects

A Corrigendum to this article was published on 09 August 2010

Abstract

Objective:

The growth and development of adipose tissue are thought to be associated with angiogenesis and extracellular matrix remodeling. As the composition of the herbal extract called Ob-X has been shown to have both anti-angiogenic and matrix metalloproteinase (MMP)-inhibiting activities, we hypothesized that growth of adipose tissue can be regulated by Ob-X.

Materials and methods:

The effects of Ob-X on angiogenesis and extracellular matrix remodeling were measured using in vitro and ex vivo assays. The effects of Ob-X on adipose tissue growth were investigated in nutritionally obese mice.

Results:

Ob-X inhibited angiogenesis in a dose-dependent manner in the human umbilical vein endothelial cell tube formation assay in vitro and the rat aortic ring assay ex vivo. Ob-X also suppressed MMP activity in vitro. Administration of Ob-X to high fat diet-induced obese mice produced significant reductions in body weight gain and adipose tissue mass compared with control. The mass of both visceral (VSC) and subcutaneous (SC) fat was reduced in Ob-X-treated mice. The size of adipocytes in VSC and SC adipose tissues was also significantly reduced in Ob-X-treated mice. Ob-X treatment decreased the blood vessel density and MMP activity in VSC adipose tissues of nutritionally obese mice. Ob-X reduced mRNA levels of angiogenic factors (VEGF-A and FGF-2) and MMPs (MMP-2 and MMP-9), whereas it increased mRNA levels of angiogenic inhibitors (TSP-1, TIMP-1 and TIMP-2) in SC and VSC adipose tissues of nutritionally obese mice.

Conclusion:

Ob-X, which has anti-angiogenic and MMP-inhibitory activities, reduces adipose tissue mass in nutritionally induced obese mice, providing evidence that adipose tissue growth and development may be prevented by inhibiting angiogenesis. In addition, these data suggest that regulation of adipose tissue growth by inhibiting angiogenesis may alter the expression of genes involved in angiogenesis and the MMP system.

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References

  1. Couillard C, Mauriège P, Imbeault P, Prud'homme D, Nadeau A, Tremblay A et al. Hyperleptinemia is more closely associated with adipose cell hypertrophy than with adipose tissue hyperplasia. Int J Obes Relat Metab Disord 2000; 24: 782–788.

    Article  CAS  Google Scholar 

  2. Crandall DL, Hausman GJ, Kral JG . A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives. Microcirculation 1997; 4: 211–232.

    Article  CAS  Google Scholar 

  3. Hobson B, Denekamp J . Endothelial proliferation in tumours and normal tissues: continuous labelling studies. Br J Cancer 1984; 49: 405–413.

    Article  CAS  Google Scholar 

  4. Bouloumié A, Lolmède K, Sengenès C, Galitzky J, Lafontan M . Angiogenesis in adipose tissue. Ann Endocrinol (Paris) 2002; 63: 91–95.

    Google Scholar 

  5. Silverman KJ, Lund DP, Zetter BR, Lainey LL, Shahood JA, Freiman DG et al. Angiogenic activity of adipose tissue. Biochem Biophys Res Commun 1988; 153: 347–352.

    Article  CAS  Google Scholar 

  6. Rupnick MA, Panigrahy D, Zhang C, Dallabrida SM, Lowell BB, Langer R et al. Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci USA 2002; 99: 10730–10735.

    Article  CAS  Google Scholar 

  7. Bråkenhielm E, Cao R, Gao B, Angelin B, Cannon B, Parini P et al. Angiogenesis inhibitor, TNP-470, prevents diet-induced and genetic obesity in mice. Circ Res 2004; 94: 1579–1588.

    Article  Google Scholar 

  8. Neels JG, Thinnes T, Loskutoff DJ . Angiogenesis in an in vivo model of adipose tissue development. FASEB J 2004; 18: 983–985.

    Article  CAS  Google Scholar 

  9. Visse R, Nagase H . Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003; 92: 827–839.

    Article  CAS  Google Scholar 

  10. Lijnen HR, Maquoi E, Hansen LB, Van Hoef B, Frederix L, Collen D . Matrix metalloproteinase inhibition impairs adipose tissue development in mice. Arterioscler Thromb Vasc Biol 2002; 22: 374–379.

    Article  CAS  Google Scholar 

  11. Galardy RE, Grobelny D, Foellmer HG, Fernandez LA . Inhibition of angiogenesis by the matrix metalloprotease inhibitor N-[2R-2-(hydroxamidocarbonymethyl)-4-methylpentanoyl)]-L-tryptophan methylamide. Cancer Res 1994; 54: 4715–4718.

    CAS  PubMed  Google Scholar 

  12. Bouloumié A, Sengenès C, Portolan G, Galitzky J, Lafontan M . Adipocyte produces matrix metalloproteinases 2 and 9: involvement in adipose differentiation. Diabetes 2001; 50: 2080–2086.

    Article  Google Scholar 

  13. Kawaguchi N, Toriyama K, Nicodemou-Lena E, Inou K, Torii S, Kitagawa Y . De novo adipogenesis in mice at the site of injection of basement membrane and basic fibroblast growth factor. Proc Natl Acad Sci USA 1998; 95: 1062–1066.

    Article  CAS  Google Scholar 

  14. Christiaens V, Lijnen HR . Role of the fibrinolytic and matrix metalloproteinase systems in development of adipose tissue. Arch Physiol Biochem 2006; 112: 254–259.

    Article  CAS  Google Scholar 

  15. Chavey C, Mari B, Monthouel MN, Bonnafous S, Anglard P, Van Obberghen E et al. Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation. J Biol Chem 2003; 278: 11888–11896.

    Article  CAS  Google Scholar 

  16. Maquoi E, Munaut C, Colige A, Collen D, Lijnen HR . Modulation of adipose tissue expression of murine matrix metalloproteinases and their tissue inhibitors with obesity. Diabetes 2002; 51: 1093–1101.

    Article  CAS  Google Scholar 

  17. Lijnen HR, Maquoi E, Holvoet P, Mertens A, Lupu F, Morange P et al. Adipose tissue expression of gelatinases in mouse models of obesity. Thromb Haemost 2001; 85: 1111–1116.

    Article  CAS  Google Scholar 

  18. Lijnen HR, Maquoi E, Hansen LB, Van Hoef B, Frederix L, Collen D . Matrix metalloproteinase inhibition impairs adipose tissue development in mice. Arterioscler Thromb Vasc Biol 2002; 22: 374–379.

    Article  CAS  Google Scholar 

  19. Voros G, Maquoi E, Demeulemeester D, Clerx N, Collen D, Lijnen HR . Modulation of angiogenesis during adipose tissue development in murine models of obesity. Endocrinology 2005; 146: 4545–4554.

    Article  CAS  Google Scholar 

  20. Cao Y . Angiogenesis modulates adipogenesis and obesity. J Clin Invest 2007; 117: 2362–2368.

    Article  CAS  Google Scholar 

  21. Claffey KP, Wilkison WO, Spiegelman BM . Vascular endothelial growth factor. Regulation by cell differentiation and activated second messenger pathways. J Biol Chem 1992; 267: 16317–16322.

    CAS  PubMed  Google Scholar 

  22. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996; 380: 435–439.

    Article  CAS  Google Scholar 

  23. Bikfalvi A, Klein S, Pintucci G, Rifkin DB . Biological roles of fibroblast growth factor-2. Endocr Rev 1997; 18: 26–45.

    CAS  PubMed  Google Scholar 

  24. Kawaguchi N, Toriyama K, Nicodemou-Lena E, Inou K, Torii S, Kitagawa Y . De novo adipogenesis in mice at the site of injection of basement membrane and basic fibroblast growth factor. Proc Natl Acad Sci USA 1998; 95: 1062–1066.

    Article  CAS  Google Scholar 

  25. Sang QX . Complex role of matrix metalloproteinases in angiogenesis. Cell Res 1998; 8: 171–177.

    Article  CAS  Google Scholar 

  26. Lee J, Chae K, Ha J, Park BY, Lee HS, Jeong S et al. Regulation of obesity and lipid disorders by herbal extracts from Morus alba, Melissa officinalis, and Artemisia capillaris in high-fat diet-induced obese mice. J Ethnopharmacol 2008; 115: 263–270.

    Article  Google Scholar 

  27. Krüger EA, Figg WD . Protein binding alters the activity of suramin, carboxyamidotriazole, and UCN-01 in an ex vivo rat aortic ring angiogenesis assay. Clin Cancer Res 2001; 7: 1867–1872.

    PubMed  Google Scholar 

  28. Nicosia RF, Bonanno E, Villaschi S . Large-vessel endothelium switches to a microvascular phenotype during angiogenesis in collagen gel culture of rat aorta. Atherosclerosis 1992; 95: 191–199.

    Article  CAS  Google Scholar 

  29. Liu L, Meydani M . Angiogenesis inhibitors may regulate adiposity. Nutr Rev 2003; 61: 384–387.

    Article  Google Scholar 

  30. Pierleoni C, Verdenelli F, Castellucci M, Cinti S . Fibronectins and basal lamina molecules expression in human subcutaneous white adipose tissue. Eur J Histochem 1998; 42: 183–188.

    CAS  PubMed  Google Scholar 

  31. Sadowski T, Dietrich S, Koschinsky F, Sedlacek R . Matrix metalloproteinase 19 regulates insulin-like growth factor-mediated proliferation, migration, and adhesion in human keratinocytes through proteolysis of insulin-like growth factor binding protein-3. Mol Biol Cell 2003; 14: 4569–4580.

    Article  CAS  Google Scholar 

  32. Lijnen HR . Angiogenesis and obesity. Cardiovasc Res 2008; 78: 286–293.

    Article  CAS  Google Scholar 

  33. Arner P . Regional differences in protein production by human adipose tissue. Biochem Soc Trans 2001; 29: 72–75.

    Article  CAS  Google Scholar 

  34. Park HY, Kwon HM, Lim HJ, Hong BK, Lee JY, Park BE et al. Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro. Exp Mol Med 2001; 33: 95–102.

    Article  CAS  Google Scholar 

  35. Lijnen HR, Demeulemeester D, Van Hoef B, Collen D, Maquoi E . Deficiency of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) impairs nutritionally induced obesity in mice. Thromb Haemost 2003; 89: 249–255.

    Article  CAS  Google Scholar 

  36. Armstrong LC, Bornstein P . Thrombospondins 1 and 2 function as inhibitors of angiogenesis. Matrix Biol 2003; 22: 63–71.

    Article  CAS  Google Scholar 

  37. Stetler-Stevenson WG . Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest 1999; 103: 1237–1241.

    Article  CAS  Google Scholar 

  38. Anand-Apte B, Pepper MS, Voest E, Montesano R, Olsen B, Murphy G et al. Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3. Invest Ophthalmol Vis Sci 1997; 38: 817–823.

    CAS  PubMed  Google Scholar 

  39. Hiraoka N, Allen E, Apel IJ, Gyetko MR, Weiss SJ . Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins. Cell 1998; 95: 365–377.

    Article  CAS  Google Scholar 

  40. Johnson MD, Kim HR, Chesler L, Tsao-Wu G, Bouck N, Polverini PJ . Inhibition of angiogenesis by tissue inhibitor of metalloproteinase. J Cell Physiol 1994; 160: 194–202.

    Article  CAS  Google Scholar 

  41. Itoh T, Tanioka M, Yoshida H, Yoshioka T, Nishimoto H . Itohara SReduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res 1998; 58: 1048–1051.

    CAS  PubMed  Google Scholar 

  42. O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M et al. a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 79: 315–328.

    Article  Google Scholar 

  43. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88: 277–285.

    Article  Google Scholar 

  44. Croissandeau G, Chrétien M, Mbikay M . Involvement of matrix metalloproteinases in the adipose conversion of 3T3-L1 preadipocytes. Biochem J 2002; 364: 739–746.

    Article  CAS  Google Scholar 

  45. Demeulemeester D, Collen D, Lijnen HR . Effect of matrix metalloproteinase inhibition on adipose tissue development. Biochem Biophys Res Commun 2005; 329: 105–110.

    Article  CAS  Google Scholar 

  46. Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K et al. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 1998; 101: 1354–1361.

    Article  CAS  Google Scholar 

  47. de Souza CJ, Eckhardt M, Gagen K, Dong M, Chen W, Laurent D et al. Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance. Diabetes 2001; 50: 1863–1871.

    Article  CAS  Google Scholar 

  48. Kissebah AH . Central obesity: measurement and metabolic effects. Diabetes Rev 1997; 5: 8–20.

    Google Scholar 

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Acknowledgements

We thank Dr Roger Lijnen for his invaluable comments. This study was supported by a grant from The Ministry for Health, Welfare and Family affairs (A040159), National Research Foundation of Korea (No. 2009-0083990 and No. 2009-0069150), and The Ministry of Knowledge Economy, Republic of Korea (70007823).

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Authors and Affiliations

  1. AngioLab, Inc., Daejeon, Korea

    M-Y Kim, B Y Park, H S Lee, E K Park & J C Hahm

  2. Department of Life Sciences, Mokwon University, Daejeon, Korea

    J Lee, Y Hong, S Choi, D Park, H Lee & M Yoon

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  1. M-Y Kim
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Correspondence to M-Y Kim or M Yoon.

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Kim, MY., Park, B., Lee, H. et al. The anti-angiogenic herbal composition Ob-X inhibits adipose tissue growth in obese mice. Int J Obes 34, 820–830 (2010). https://doi.org/10.1038/ijo.2010.13

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