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Thromb Haemost 2013; 109(02): 319-327
DOI: 10.1160/TH12-09-0696
Animal Models
Schattauer GmbH

Obesity with insulin resistance increase thrombosis in wild-type and bone marrow-transplanted Zucker fatty rats

Rodrigo Hernández Vera
1   Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau (UAB), CIBERobn Pathophysiology of Obesity and Nutrition, Barcelona, Spain
,
Gemma Vilahur
1   Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau (UAB), CIBERobn Pathophysiology of Obesity and Nutrition, Barcelona, Spain
,
Lina Badimon
1   Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau (UAB), CIBERobn Pathophysiology of Obesity and Nutrition, Barcelona, Spain
2   Cardiovascular Research Chair, UAB, Barcelona, Spain
› Author Affiliations
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Publication History

Received: 26 September 2012

Accepted after major revision: 13 November 2012

Publication Date:
29 November 2017 (online)

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Summary

Obesity induces metabolic and inflammatory alterations that contribute to the presentation of cardiovascular events. Although obesity is a risk factor for atherosclerosis and vascular disease, its role on thrombosis has not been directly explored. Therefore, we aimed to investigate the mechanisms by which obesity affects thrombosis. Thrombus formation was monitored by real-time intravital microscopy in Zucker Fatty rats (ZF) and lean controls (ZC). Crossed bone marrow (BM) transplants between ZF and ZC were performed. Intravital microscopy showed that ZF had significantly shorter occlusion times (OTs) than ZC, reflecting a three-fold higher thrombotic risk. Transplantation of ZC-BM to ZF recipients significantly reduced thrombosis, reducing their thrombotic risk to one third of that observed in non-transplanted ZF. Wild-type ZF showed increased platelet counts and increased platelet size compared to wild-type ZC and platelet number remained unaltered after transplantation. However, ZF-BM produced a significant increase in platelet size in ZC recipients. Thrombotic risk was found to be inversely correlated with both weight and insulin levels and directly correlated to HOMA-IR, while platelet number and size were directly correlated with weight. Thus, our data shows that obesity with insulin resistance significantly increases thrombosis and that alterations in BM-derived cells significantly contribute to this prothrombotic behaviour. Importantly, the reduction of insulin resistance was associated with reduced thrombotic risk even in the presence of obesity.

Keywords

Obesity - thrombosis - bone marrow - insulin resistance
 

  • References

  • 1 Fontaine KR, Redden DT, Wang C. et al. Years of life lost due to obesity. J Am Med Assoc 2003; 289: 187-193.
    CrossrefPubMedSearch in Google Scholar
  • 2 Hu FB, Willett WC, Li T. et al. Adiposity as Compared with Physical Activity in Predicting Mortality among Women. N Engl J Med 2004; 351: 2694-2703.
    CrossrefPubMedSearch in Google Scholar
  • 3 Poirier P, Giles TD, Bray GA. et al. Obesity and Cardiovascular Disease: Pathophysiology, Evaluation, and Effect of Weight Loss. Circulation 2006; 113: 898-918.
    CrossrefPubMedSearch in Google Scholar
  • 4 Yusuf S, Hawken S, Ounpuu S. et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364: 937-952.
    CrossrefPubMedSearch in Google Scholar
  • 5 Darvall KA, Sam RC, Silverman SH. et al. Obesity and thrombosis. Eur J Vasc Endovasc Surg 2007; 33: 223-233.
    CrossrefPubMedSearch in Google Scholar
  • 6 Lavie CJ, Milani RV, Ventura HO. Obesity and cardiovascular disease: risk factor, paradox, and impact of weight loss. J Am Coll Cardiol 2009; 53: 1925-1932.
    CrossrefPubMedSearch in Google Scholar
  • 7 Alberti KG, Eckel RH, Grundy SM. et al. Harmonising the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120: 1640-1645.
    CrossrefPubMedSearch in Google Scholar
  • 8 Mottillo S, Filion KB, Genest J. et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010; 56: 1113-1132.
    CrossrefPubMedSearch in Google Scholar
  • 9 Onat A. Metabolic syndrome: nature, therapeutic solutions and options. Expert Opin Pharmacother 2011; 12: 1887-1900.
    CrossrefPubMedSearch in Google Scholar
  • 10 Ford ES, Li C, Sattar N. Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care 2008; 31: 1898-1904.
    CrossrefPubMedSearch in Google Scholar
  • 11 Konstantinides S, Schafer K, Koschnick S. et al. Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. J Clin Invest 2001; 108: 1533-1540.
    CrossrefPubMedSearch in Google Scholar
  • 12 Nakata M, Yada T, Soejima N. et al. Leptin promotes aggregation of human platelets via the long form of its receptor. Diabetes 1999; 48: 426-429.
    CrossrefPubMedSearch in Google Scholar
  • 13 Alessi MC, Lijnen HR, Bastelica D. et al. Adipose tissue and atherothrombosis. Pathophysiol Haemost Thromb 2003; 33: 290-297.
    CrossrefPubMedSearch in Google Scholar
  • 14 McDermott MM, Green D, Greenland P. et al. Relation of levels of haemostatic factors and inflammatory markers to the ankle brachial index. Am J Cardiol 2003; 92: 194-199.
    PubMedSearch in Google Scholar
  • 15 Reiner AP, Siscovick DS, Rosendaal FR. Haemostatic risk factors and arterial thrombotic disease. Thromb Haemost 2001; 85: 584-595.
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 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: 800-803.
    CrossrefPubMedSearch in Google Scholar
  • 17 Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res 2005; 96: 939-949.
    CrossrefPubMedSearch in Google Scholar
  • 18 Furukawa S, Fujita T, Shimabukuro M. et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004; 114: 1752-1761.
    CrossrefPubMedSearch in Google Scholar
  • 19 Higdon JV, Frei B. Obesity and oxidative stress: a direct link to CVD?. Arterioscler Thromb Vasc Biol 2003; 23: 365-367.
    CrossrefPubMedSearch in Google Scholar
  • 20 Oáate B, Vilahur G, Ferrer-Lorente R. et al. The subcutaneous adipose tissue reservoir of functionally active stem cells is reduced in obese patients. FASEB J 2012; 26: 4327-4336.
    CrossrefPubMedSearch in Google Scholar
  • 21 Nilsson C, Raun K, Yan F-F. , et al. Laboratory animals as surrogate models of human obesity. Acta Pharmacol Sin 2012; 33: 173-181.
    CrossrefPubMedSearch in Google Scholar
  • 22 Phillips MS, Liu Q, Hammond HA. et al. Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet 1996; 13: 18-19.
    CrossrefPubMedSearch in Google Scholar
  • 23 White BD, Martin RJ. Evidence for a central mechanism of obesity in the Zucker rat: role of neuropeptide Y and leptin. Proc Soc Exp Biol Med 1997; 214: 222-232.
    CrossrefPubMedSearch in Google Scholar
  • 24 Hajer GR, van Haeften TW, Visseren FL. Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J 2008; 29: 2959-2971.
    CrossrefPubMedSearch in Google Scholar
  • 25 Hernández Vera R, Vilahur G, Ferrer-Lorente R. et al. Platelets derived from the bone marrow of diabetic animals show dysregulated endoplasmic reticulum stress proteins that contribute to increased thrombosis. Arterioscler Thromb Vasc Biol 2012; 32: 2141-2148.
    CrossrefPubMedSearch in Google Scholar
  • 26 Bath PM, Butterworth RJ. Platelet size: measurement, physiology and vascular disease. Blood Coagul Fibrinolysis 1996; 07: 157-161.
    CrossrefPubMedSearch in Google Scholar
  • 27 Greisenegger S, Endler G, Hsieh K. et al. Is elevated mean platelet volume associated with a worse outcome in patients with acute ischemic cerebrovascular events?. Stroke 2004; 35: 1688-1691.
    CrossrefPubMedSearch in Google Scholar
  • 28 Martin JF, Trowbridge EA, Salmon G. et al. The biological significance of platelet volume: its relationship to bleeding time, platelet thromboxane B2 production and megakaryocyte nuclear DNA concentration. Thromb Res 1983; 32: 443-460.
    CrossrefPubMedSearch in Google Scholar
  • 29 Bavbek N, Kargili A, Kaftan O. et al. Elevated concentrations of soluble adhesion molecules and large platelets in diabetic patients: are they markers of vascular disease and diabetic nephropathy?. Clin Appl Thromb Haemost 2007; 13: 391-397.
    CrossrefPubMedSearch in Google Scholar
  • 30 Watala C, Boncler M, Gresner P. Blood platelet abnormalities and pharmacological modulation of platelet reactivity in patients with diabetes mellitus. Pharmacol Rep 2005; 57 Suppl 42-58.
    PubMedSearch in Google Scholar
  • 31 Gasparyan AY, Ayvazyan L, Mikhailidis DP. et al. Mean platelet volume: a link between thrombosis and inflammation?. Curr Pharm Des 2011; 17: 47-58.
    CrossrefPubMedSearch in Google Scholar
  • 32 Ishibashi T, Kimura H, Uchida T. et al. Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. Proc Natl Acad Sci USA 1989; 86: 5953-5957.
    CrossrefPubMedSearch in Google Scholar
  • 33 Kaushansky K. The molecular mechanisms that control thrombopoiesis. J Clin Invest 2005; 115: 3339-3347.
    CrossrefPubMedSearch in Google Scholar
  • 34 Yudkin JS, Kumari M, Humphries SE. et al. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?. Atherosclerosis 2000; 148: 209-214.
    CrossrefPubMedSearch in Google Scholar
  • 35 Heilbronn LK, Noakes M, Clifton PM. Energy restriction and weight loss on very-low-fat diets reduce C-reactive protein concentrations in obese, healthy women. Arterioscler Thromb Vasc Biol 2001; 21: 968-970.
    CrossrefPubMedSearch in Google Scholar
  • 36 Nicoletti G, Giugliano G, Pontillo A. et al. Effect of a multidisciplinary program of weight reduction on endothelial functions in obese women. J Endocrinol Invest 2003; 26: RC5-8.
    CrossrefPubMedSearch in Google Scholar
  • 37 Kaser A, Brandacher G, Steurer W. et al. Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood 2001; 98: 2720-2725.
    CrossrefPubMedSearch in Google Scholar
  • 38 van der Loo B, Martin JF. A role for changes in platelet production in the cause of acute coronary syndromes. Arterioscler Thromb Vasc Biol 1999; 19: 672-679.
    CrossrefPubMedSearch in Google Scholar
  • 39 Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med 2007; 262: 157-172.
    CrossrefPubMedSearch in Google Scholar
  • 40 Hess K, Grant PJ. Inflammation and thrombosis in diabetes. Thromb Haemost 2011; 105 (Suppl. 01) S43-54
    Thieme ConnectPubMedSearch in Google Scholar
  • 41 Vazzana N, Ranalli P, Cuccurullo C. et al. Diabetes mellitus and thrombosis. Thromb Res 2012; 129: 371-377.
    CrossrefPubMedSearch in Google Scholar