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Ectopic visceral fat: A clinical and molecular perspective on the cardiometabolic risk

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Abstract

Worldwide, cardiovascular diseases (CVDs) are a leading cause of mortality. While in many westernized societies there has been a decrease prevalence of smoking and that a special emphasis has been put on the urgency to control the, so called, classical risk factors, it is more and more recognized that there remains a residual risk, which contributes to the development of CVDs. Imaging studies conducted over two decades have highlighted that the accumulation of ectopic visceral fat is associated with a plethora of metabolic dysfunctions, which have complex and intertwined interactions and participate to the development/progression/events of many cardiovascular disorders. The contribution of visceral ectopic fat to the development of coronary artery disease (CAD) is now well established, while in the last several years emerging evidence has pointed out that accumulation of harmful ectopic fat is associated with other cardiovascular disorders such as calcific aortic valve disease (CAVD), atrial fibrillation and left ventricular dysfunction. We review herein the key molecular processes linking the accumulation of ectopic fat to the development of CVDs. We have attempted, whenever possible, to use a translational approach whereby the pathobiology processes are linked to clinical observations.

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References

  1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics–2011 update: a report from the American heart association. Circulation. 2011;123(4):e18–e209.

    Article  PubMed  Google Scholar 

  2. Despres JP, Lemieux I, Bergeron J, et al. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol. 2008;28(6):1039–49.

    Article  CAS  PubMed  Google Scholar 

  3. Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444(7121):881–7.

    Article  CAS  PubMed  Google Scholar 

  4. Mathieu P, Pibarot P, Larose E, et al. Visceral obesity and the heart. Int J Biochem Cell Biol. 2008;40(5):821–36.

    Article  CAS  PubMed  Google Scholar 

  5. Hamer M, Stamatakis E. Metabolically healthy obesity and risk of all-cause and cardiovascular disease mortality. J Clin Endocrinol Metab. 2012;97(7):2482–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Wilson PW, D’Agostino RB, Sullivan L, et al. Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch Intern Med. 2002;162(16):1867–72.

    Article  PubMed  Google Scholar 

  7. Lemieux I, Pascot A, Prud’homme D, et al. Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity. Arterioscler Thromb Vasc Biol. 2001;21(6):961–7.

    Article  CAS  PubMed  Google Scholar 

  8. Arsenault BJ, Lemieux I, Despres JP, et al. The hypertriglyceridemic-waist phenotype and the risk of coronary artery disease: results from the EPIC-Norfolk prospective population study. CMAJ. 2010;182(13):1427–32.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Grundy SM. Metabolic syndrome: a multiplex cardiovascular risk factor. J Clin Endocrinol Metab. 2007;92(2):399–404.

    Article  CAS  PubMed  Google Scholar 

  10. Mauriege P, Despres JP, Moorjani S, et al. Abdominal and femoral adipose tissue lipolysis and cardiovascular disease risk factors in men. Eur J Clin Invest. 1993;23(11):729–40.

    Article  CAS  PubMed  Google Scholar 

  11. Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab. 1998;83(3):847–50.

    CAS  PubMed  Google Scholar 

  12. Mathieu P, Lemieux I, Despres JP. Obesity, inflammation, and cardiovascular risk. Clin Pharmacol Ther. 2010;87(4):407–16.

    Article  CAS  PubMed  Google Scholar 

  13. Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425–32.

    Article  CAS  PubMed  Google Scholar 

  14. Parhami F, Tintut Y, Ballard A, et al. Leptin enhances the calcification of vascular cells: artery wall as a target of leptin. Circ Res. 2001;88(9):954–60.

    Article  CAS  PubMed  Google Scholar 

  15. Zeadin M, Butcher M, Werstuck G, et al. Effect of leptin on vascular calcification in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2009;29(12):2069–75.

    Article  CAS  PubMed  Google Scholar 

  16. Slawik M, Vidal-Puig AJ. Lipotoxicity, overnutrition and energy metabolism in aging. Ageing Res Rev. 2006;5(2):144–64.

    Article  CAS  PubMed  Google Scholar 

  17. Summers SA. Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res. 2006;45(1):42–72.

    Article  CAS  PubMed  Google Scholar 

  18. Lee Y, Wang MY, Kakuma T, et al. Liporegulation in diet-induced obesity. the antisteatotic role of hyperleptinemia. J Biol Chem. 2001;276(8):5629–35.

    Article  CAS  PubMed  Google Scholar 

  19. Kim JK, Gavrilova O, Chen Y, et al. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem. 2000;275(12):8456–60.

    Article  CAS  PubMed  Google Scholar 

  20. Mathieu P, Boulanger MC. Basic Mechanisms of calcific aortic valve disease. Can J Cardiol. 2014;30(9):982–93.

    Article  PubMed  Google Scholar 

  21. Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54(23):2129–38.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Despres JP. Inflammation and cardiovascular disease: is abdominal obesity the missing link? Int J Obes Relat Metab Disord. 2003;27 Suppl 3:S22–4.

    Article  PubMed  Google Scholar 

  23. Blackburn P, Despres JP, Lamarche B, et al. Postprandial variations of plasma inflammatory markers in abdominally obese men. Obesity (Silver Spring). 2006;14(10):1747–54.

    Article  CAS  Google Scholar 

  24. Degerman E, Landstrom TR, Wijkander J, et al. Phosphorylation and activation of hormone-sensitive adipocyte phosphodiesterase type 3B. Methods. 1998;14(1):43–53.

    Article  CAS  PubMed  Google Scholar 

  25. Carmen GY, Victor SM. Signalling mechanisms regulating lipolysis. Cell Signal. 2006;18(4):401–8.

    Article  CAS  PubMed  Google Scholar 

  26. Bastard JP, Maachi M, Lagathu C, et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw. 2006;17(1):4–12.

    CAS  PubMed  Google Scholar 

  27. Arsenault BJ, Pibarot P, Despres JP. The quest for the optimal assessment of global cardiovascular risk: are traditional risk factors and metabolic syndrome partners in crime? Cardiology. 2009;113(1):35–49.

    Article  PubMed  Google Scholar 

  28. Arsenault BJ, Cartier A, Cote M, et al. Body composition, cardiorespiratory fitness, and low-grade inflammation in middle-aged men and women. Am J Cardiol. 2009;104(2):240–6.

    Article  PubMed  Google Scholar 

  29. Du Clos TW, Mold C. C-reactive protein: an activator of innate immunity and a modulator of adaptive immunity. Immunol Res. 2004;30(3):261–77.

    Article  PubMed  Google Scholar 

  30. Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis. Circulation. 2003;107(3):398–404.

    Article  CAS  PubMed  Google Scholar 

  31. Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation. 2001;103(9):1194–7.

    Article  CAS  PubMed  Google Scholar 

  32. Torzewski J, Torzewski M, Bowyer DE, et al. C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol. 1998;18(9):1386–92.

    Article  CAS  PubMed  Google Scholar 

  33. Okamoto Y, Arita Y, Nishida M, et al. An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls. Horm Metab Res. 2000;32(2):47–50.

    Article  CAS  PubMed  Google Scholar 

  34. Ouchi N, Kihara S, Funahashi T, et al. Obesity, adiponectin and vascular inflammatory disease. Curr Opin Lipidol. 2003;14(6):561–6.

    Article  CAS  PubMed  Google Scholar 

  35. Cote M, Mauriege P, Bergeron J, et al. Adiponectinemia in visceral obesity: impact on glucose tolerance and plasma lipoprotein and lipid levels in men. J Clin Endocrinol Metab. 2005;90(3):1434–9.

    Article  CAS  PubMed  Google Scholar 

  36. Maahs DM, Ogden LG, Kinney GL, et al. Low plasma adiponectin levels predict progression of coronary artery calcification. Circulation. 2005;111(6):747–53.

    Article  CAS  PubMed  Google Scholar 

  37. Mohty D, Pibarot P, Cote N, et al. Hypoadiponectinemia is associated with valvular inflammation and faster disease progression in patients with aortic stenosis. Cardiology. 2011;118(2):140–6.

    Article  CAS  PubMed  Google Scholar 

  38. Denzel MS, Scimia MC, Zumstein PM, et al. T-cadherin is critical for adiponectin-mediated cardioprotection in mice. J Clin Invest. 2010;120(12):4342–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409(6818):307–12.

    Article  CAS  PubMed  Google Scholar 

  40. Reilly MP, Lehrke M, Wolfe ML, et al. Resistin is an inflammatory marker of atherosclerosis in humans. Circulation. 2005;111(7):932–9.

    Article  CAS  PubMed  Google Scholar 

  41. Mohty D, Pibarot P, Despres JP, et al. Age-related differences in the pathogenesis of calcific aortic stenosis: the potential role of resistin. Int J Cardiol. 2010;142(2):126–32.

    Article  PubMed  Google Scholar 

  42. Garrison RJ, Kannel WB, Stokes III J, et al. Incidence and precursors of hypertension in young adults: the Framingham Offspring Study. Prev Med. 1987;16(2):235–51.

    Article  CAS  PubMed  Google Scholar 

  43. Mathieu P, Poirier P, Pibarot P, et al. Visceral obesity: the link among inflammation, hypertension, and cardiovascular disease. Hypertension. 2009;53(4):577–84.

    Article  CAS  PubMed  Google Scholar 

  44. McAllister-Lucas LM, Ruland J, Siu K, et al. CARMA3/Bcl10/MALT1-dependent NF-kappaB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells. Proc Natl Acad Sci U S A. 2007;104(1):139–44.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Choudhary S, Lu M, Cui R, et al. Involvement of a novel Rac/RhoA guanosine triphosphatase-nuclear factor-kappaB inducing kinase signaling pathway mediating angiotensin II-induced RelA transactivation. Mol Endocrinol. 2007;21(9):2203–17.

    Article  CAS  PubMed  Google Scholar 

  46. Mazzolai L, Duchosal MA, Korber M, et al. Endogenous angiotensin II induces atherosclerotic plaque vulnerability and elicits a Th1 response in ApoE−/− mice. Hypertension. 2004;44(3):277–82.

    Article  CAS  PubMed  Google Scholar 

  47. Fujisaka T, Hoshiga M, Hotchi J, et al. Angiotensin II promotes aortic valve thickening independent of elevated blood pressure in apolipoprotein-E deficient mice. Atherosclerosis. 2013;226(1):82–7.

    Article  CAS  PubMed  Google Scholar 

  48. Vandanmagsar B, Youm YH, Ravussin A, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011;17(2):179–88.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Lamkanfi M, Dixit VM. Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol. 2012;28:137–61.

    Article  CAS  PubMed  Google Scholar 

  50. Derbali H, Bosse Y, Cote N, et al. Increased biglycan in aortic valve stenosis leads to the overexpression of phospholipid transfer protein via Toll-like receptor 2. Am J Pathol. 2010;176(6):2638–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Zeng Q, Jin C, Ao L, et al. Cross-talk between the Toll-like receptor 4 and Notch1 pathways augments the inflammatory response in the interstitial cells of stenotic human aortic valves. Circulation. 2012;126(11 Suppl 1):S222–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Cani PD, Osto M, Geurts L, et al. Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity. Gut Microbes. 2012;3(4):279–88.

    Article  PubMed Central  PubMed  Google Scholar 

  53. Brasier AR. The nuclear factor-kappaB-interleukin-6 signalling pathway mediating vascular inflammation. Cardiovasc Res. 2010;86(2):211–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Finco TS, Beg AA, Baldwin Jr AS. Inducible phosphorylation of I kappa B alpha is not sufficient for its dissociation from NF-kappa B and is inhibited by protease inhibitors. Proc Natl Acad Sci U S A. 1994;91(25):11884–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science. 2001;293(5535):1673–7.

    Article  CAS  PubMed  Google Scholar 

  56. Sui Y, Park SH, Xu J, et al. IKKbeta links vascular inflammation to obesity and atherosclerosis. J Exp Med. 2014;211(5):869–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. El HD, Boulanger MC. Mahmut A, et al. P2Y2 receptor represses IL-6 expression by valve interstitial cells through Akt: implication for calcific aortic valve disease. J Mol Cell Cardiol. 2014;72:146–56.

    Article  Google Scholar 

  58. Babu AN, Meng X, Zou N, et al. Lipopolysaccharide stimulation of human aortic valve interstitial cells activates inflammation and osteogenesis. Ann Thorac Surg. 2008;86(1):71–6.

    Article  PubMed  Google Scholar 

  59. Eder K, Baffy N, Falus A, et al. The major inflammatory mediator interleukin-6 and obesity. Inflamm Res. 2009;58(11):727–36.

    Article  CAS  PubMed  Google Scholar 

  60. Melendez GC, McLarty JL, Levick SP, et al. Interleukin 6 mediates myocardial fibrosis, concentric hypertrophy, and diastolic dysfunction in rats. Hypertension. 2010;56(2):225–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Pascot A, Lemieux I, Prud’homme D, et al. Reduced HDL particle size as an additional feature of the atherogenic dyslipidemia of abdominal obesity. J Lipid Res. 2001;42(12):2007–14.

    CAS  PubMed  Google Scholar 

  62. Lemieux I, Couillard C, Pascot A, et al. The small, dense LDL phenotype as a correlate of postprandial lipemia in men. Atherosclerosis. 2000;153(2):423–32.

    Article  CAS  PubMed  Google Scholar 

  63. Lamarche B, Tchernof A, Mauriege P, et al. Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease. JAMA. 1998;279(24):1955–61.

    Article  CAS  PubMed  Google Scholar 

  64. Mohty D, Pibarot P, Despres JP, et al. Association between plasma LDL particle size, valvular accumulation of oxidized LDL, and inflammation in patients with aortic stenosis. Arterioscler Thromb Vasc Biol. 2008;28(1):187–93.

    Article  CAS  PubMed  Google Scholar 

  65. Cote C, Pibarot P, Despres JP, et al. Association between circulating oxidised low-density lipoprotein and fibrocalcific remodeling of the aortic valve in aortic stenosis. Heart. 2008;94(9):1175–80.

    Article  CAS  PubMed  Google Scholar 

  66. Mahmut A, Boulanger MC, El HD, et al. Elevated expression of lipoprotein-associated phospholipase A2 in calcific aortic valve disease: implications for valve mineralization. J Am Coll Cardiol. 2014;63(5):460–9.

    Article  CAS  PubMed  Google Scholar 

  67. Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359(13):1343–56.

    Article  PubMed  Google Scholar 

  68. Goldbourt U, Yaari S, Medalie JH. Isolated low HDL cholesterol as a risk factor for coronary heart disease mortality. A 21-year follow-up of 8000 men. Arterioscler Thromb Vasc Biol. 1997;17(1):107–13.

    Article  CAS  PubMed  Google Scholar 

  69. Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res. 2005;96(12):1221–32.

    Article  CAS  PubMed  Google Scholar 

  70. Barter PJ, Nicholls S, Rye KA, et al. Antiinflammatory properties of HDL. Circ Res. 2004;95(8):764–72.

    Article  CAS  PubMed  Google Scholar 

  71. Parhami F, Basseri B, Hwang J, et al. High-density lipoprotein regulates calcification of vascular cells. Circ Res. 2002;91(7):570–6.

    Article  CAS  PubMed  Google Scholar 

  72. Mahmut A, Boulanger MC, Fournier D, et al. Lipoprotein lipase in aortic valve stenosis is associated with lipid retention and remodeling. Eur J Clin Invest. 2013;43(6):570–8.

    Article  CAS  PubMed  Google Scholar 

  73. Huang Y, DiDonato JA, Levison BS, et al. An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med. 2014;20(2):193–203.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Bots ML, Visseren FL, Evans GW, et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet. 2007;370(9582):153–60.

    Article  CAS  PubMed  Google Scholar 

  75. Rader DJ. deGoma EM. Future of cholesteryl ester transfer protein inhibitors. Annu Rev Med. 2014;65:385–403.

    Article  CAS  PubMed  Google Scholar 

  76. St-Pierre AC, Cantin B, Dagenais GR, et al. The triglyceride/high-density lipoprotein cholesterol ratio, the small dense low-density lipoprotein phenotype, and ischemic heart disease risk. Metab Syndr Relat Disord. 2004;2(1):57–64.

    Article  CAS  PubMed  Google Scholar 

  77. Nissen SE, Nicholls SJ, Wolski K, et al. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA. 2008;299(13):1547–60.

    Article  CAS  PubMed  Google Scholar 

  78. Saremi A, Schwenke DC, Buchanan TA, et al. Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors. Arterioscler Thromb Vasc Biol. 2013;33(2):393–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Lincoff AM, Wolski K, Nicholls SJ, et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298(10):1180–8.

    Article  CAS  PubMed  Google Scholar 

  80. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–71.

    Article  CAS  PubMed  Google Scholar 

  81. Endo Y, Suzuki M, Yamada H, et al. Thiazolidinediones enhance sodium-coupled bicarbonate absorption from renal proximal tubules via PPARgamma-dependent nongenomic signaling. Cell Metab. 2011;13(5):550–61.

    Article  CAS  PubMed  Google Scholar 

  82. Wing RR, Bolin P, Brancati FL, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(2):145–54.

    Article  CAS  PubMed  Google Scholar 

  83. Gogebakan O, Kohl A, Osterhoff MA, et al. Effects of weight loss and long-term weight maintenance with diets varying in protein and glycemic index on cardiovascular risk factors: the diet, obesity, and genes (DiOGenes) study: a randomized, controlled trial. Circulation. 2011;124(25):2829–38.

    Article  PubMed  Google Scholar 

  84. Glantz S, Gonzalez M. Effective tobacco control is key to rapid progress in reduction of non-communicable diseases. Lancet. 2012;379(9822):1269–71.

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The work of the authors is supported by the Heart and Stroke Foundation of Canada, Fonds de Recherche Nature et Technologie Québec and CIHR grants MOP245048, MOP114893 and the Quebec Heart and Lung Institute Fund. P. Mathieu is a research scholar from the Fonds de Recherche en Santé du Québec, Montreal, Québec, Canada.

Conflict of interest

J.P. Després has served as a speaker for Abbott Laboratories, AstraZeneca, Solvay Pharma, GlaxoSmithKline, and Pfizer Canada Inc.; has received research funding from Eli Lilly Canada; and has served on the advisory boards of Novartis, Theratechnologies, Torrent Pharmaceuticals Ltd., and Sanofi-Aventis. P. Mathieu has patent applications for the treatment of calcific aortic valve disease. M.C. Boulanger reports no conflict of interest.

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  1. Institut de Cardiologie et de Pneumologie de Québec/Quebec Heart and Lung Institute, 2725 Chemin Ste-Foy, Québec, QC, G1V-4G5, Canada

    Patrick Mathieu, Marie-Chloé Boulanger & Jean-Pierre Després

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  1. Patrick Mathieu
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Mathieu, P., Boulanger, MC. & Després, JP. Ectopic visceral fat: A clinical and molecular perspective on the cardiometabolic risk. Rev Endocr Metab Disord 15, 289–298 (2014). https://doi.org/10.1007/s11154-014-9299-3

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