Abstract
Obesity is an epidemic that threatens the health of millions of people worldwide and is a major risk factor for cardiovascular diseases, hypertension, diabetes, and dyslipidemia. There are multiple and complex mechanisms to explain how obesity can cause cardiovascular disease. In recent years, studies have shown some limitations in the way we currently define obesity and assess adiposity. This review focuses on the mechanisms involved in the cardiometabolic consequences of obesity and on the relationship between obesity and cardiovascular comorbidities, and provides a brief review of the latest studies focused on normal weight obesity and the obesity paradox.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
World Health Organization. Obesity and overweight.http://who.int/mediacentre/factsheets/fs311/en/print.html (2011). Accessed Mar 2013.
Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA. 2012;307(5):491–7.
Wang YC, McPherson K, Marsh T, Gortmaker SL, Brown M. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet. 2011;378(9793):815–25.
Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest. 1995;95(5):2111–9.
Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006;113(6):898–918.
Trayhurn P, Wang B, Wood IS. Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? Br J Nutr. 2008;100(2):227–35.
Wenger RH. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J. 2002;16(10):1151–62.
Park HS, Park JY, Yu R. Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6. Diabetes Res Clin Pract. 2005;69(1):29–35.
Ridker PM. Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: implications for longevity. Nutr Rev. 2007;65(12 Pt 2):S253–9.
Lavie CJ, Milani RV, Verma A, O'Keefe JH. C-reactive protein and cardiovascular diseases–is it ready for primetime? Am J Med Sci. 2009;338(6):486–92.
Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010;140(6):900–17.
Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance. Nature. 2002;420(6913):333–6.
Nguyen MT, Favelyukis S, Nguyen AK, et al. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem. 2007;282(48):35279–92.
Vollenweider P, Tappy L, Randin D, et al. Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest. 1993;92(1):147–54.
Wolk R, Somers VK. Obesity-related cardiovascular disease: implications of obstructive sleep apnea. Diabetes Obes Metab. 2006;8(3):250–60.
Mark AL, Agassandian K, Morgan DA, Liu X, Cassell MD, Rahmouni K. Leptin signaling in the nucleus tractus solitarii increases sympathetic nerve activity to the kidney. Hypertension. 2009;53(2):375–80.
Grassi G, Facchini A, Trevano FQ, et al. Obstructive sleep apnea-dependent and -independent adrenergic activation in obesity. Hypertension. 2005;46(2):321–5.
Vaz M, Jennings G, Turner A, Cox H, Lambert G, Esler M. Regional sympathetic nervous activity and oxygen consumption in obese normotensive human subjects. Circulation. 1997;96(10):3423–9.
Cho Y, Lee SE, Lee HC, et al. Adipokine resistin is a key player to modulate monocytes, endothelial cells, and smooth muscle cells, leading to progression of atherosclerosis in rabbit carotid artery. J Am Coll Cardiol. 2011;57(1):99–109.
Singh P, Hoffmann M, Wolk R, Shamsuzzaman AS, Somers VK. Leptin induces C-reactive protein expression in vascular endothelial cells. Arterioscler Thromb Vasc Biol. 2007;27(9):e302–7.
Yamagishi SI, Edelstein D, Du XL, Kaneda Y, Guzman M, Brownlee M. Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J Biol Chem. 2001;276(27):25096–100.
Oda A, Taniguchi T, Yokoyama M. Leptin stimulates rat aortic smooth muscle cell proliferation and migration. Kobe J Med Sci. 2001;47(3):141–50.
Huang F, Xiong X, Wang H, You S, Zeng H. Leptin-induced vascular smooth muscle cell proliferation via regulating cell cycle, activating ERK1/2 and NF-kB. Acta Biochim Biophys Sin (Shanghai). 2010;42(5):325–31.
Wolf G, Ziyadeh FN. Leptin and renal fibrosis. Contrib Nephrol. 2006;151:175–83.
Lembo G, Vecchione C, Fratta L, et al. Leptin induces direct vasodilation through distinct endothelial mechanisms. Diabetes. 2000;49(2):293–7.
Beltowski J, Wojcicka G, Jamroz-Wisniewska A, Marciniak A. Resistance to acute NO-mimetic and EDHF-mimetic effects of leptin in the metabolic syndrome. Life Sci. 2009;85(15–16):557–67.
Patel SVD, Kundra A, et al. Cardiovascular and renal actions of leptin. In: Vesely D, editor. Cardiac hormones. India; 2008. p. 111–127.
Villarreal D, Reams G, Freeman RH. Effects of renal denervation on the sodium excretory actions of leptin in hypertensive rats. Kidney Int. 2000;58(3):989–94.
Nickola MW, Wold LE, Colligan PB, Wang GJ, Samson WK, Ren J. Leptin attenuates cardiac contraction in rat ventricular myocytes. Role of NO. Hypertension. 2000;36(4):501–5.
Singh P, Peterson TE, Barber KR, et al. Leptin upregulates the expression of plasminogen activator inhibitor-1 in human vascular endothelial cells. Biochem Biophys Res Commun. 2010;392(1):47–52.
Rajapurohitam V, Izaddoustdar F, Martinez-Abundis E, Karmazyn M. Leptin-induced cardiomyocyte hypertrophy reveals both calcium-dependent and calcium-independent/RhoA-dependent calcineurin activation and NFAT nuclear translocation. Cell Signal. 2012;24(12):2283–90.
McGaffin KR, Zou B, McTiernan CF, O'Donnell CP. Leptin attenuates cardiac apoptosis after chronic ischaemic injury. Cardiovasc Res. 2009;83(2):313–24.
Barouch LA, Berkowitz DE, Harrison RW, O'Donnell CP, Hare JM. Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation. 2003;108(6):754–9.
Wang ZV, Scherer PE. Adiponectin, cardiovascular function, and hypertension. Hypertension. 2008;51(1):8–14.
Motobayashi Y, Izawa-Ishizawa Y, Ishizawa K, et al. Adiponectin inhibits insulin-like growth factor-1-induced cell migration by the suppression of extracellular signal-regulated kinase 1/2 activation, but not Akt in vascular smooth muscle cells. Hypertens Res. 2009;32(3):188–93.
Tsatsanis C, Zacharioudaki V, Androulidaki A, et al. Adiponectin induces TNF-alpha and IL-6 in macrophages and promotes tolerance to itself and other pro-inflammatory stimuli. Biochem Biophys Res Commun. 2005;335(4):1254–63.
Tsubakio-Yamamoto K, Matsuura F, Koseki M, et al. Adiponectin prevents atherosclerosis by increasing cholesterol efflux from macrophages. Biochem Biophys Res Commun. 2008;375(3):390–4.
Ouchi N, Kihara S, Arita Y, et al. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation. 1999;100(25):2473–6.
Kumada M, Kihara S, Ouchi N, et al. Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation. 2004;109(17):2046–9.
Tao L, Gao E, Jiao X, et al. Adiponectin cardioprotection after myocardial ischemia/reperfusion involves the reduction of oxidative/nitrative stress. Circulation. 2007;115(11):1408–16.
Chow WS, Cheung BM, Tso AW, et al. Hypoadiponectinemia as a predictor for the development of hypertension: a 5-year prospective study. Hypertension. 2007;49(6):1455–61.
Lago F, Dieguez C, Gomez-Reino J, Gualillo O. The emerging role of adipokines as mediators of inflammation and immune responses. Cytokine Growth Factor Rev. 2007;18(3–4):313–25.
Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA. 2004;291(14):1730–7.
Wolk R, Berger P, Lennon RJ, Brilakis ES, Davison DE, Somers VK. Association between plasma adiponectin levels and unstable coronary syndromes. Eur Heart J. 2007;28(3):292–8.
Schulze MB, Shai I, Rimm EB, Li T, Rifai N, Hu FB. Adiponectin and future coronary heart disease events among men with type 2 diabetes. Diabetes. 2005;54(2):534–9.
Beltowski J, Jamroz-Wisniewska A, Widomska S. Adiponectin and its role in cardiovascular diseases. Cardiovasc Hematol Disord Drug Targets. 2008;8(1):7–46.
Antoniades C, Antonopoulos AS, Tousoulis D, Stefanadis C. Adiponectin: from obesity to cardiovascular disease. Obes Rev. 2009;10(3):269–79.
Shetty S, Kusminski CM, Scherer PE. Adiponectin in health and disease: evaluation of adiponectin-targeted drug development strategies. Trends Pharmacol Sci. 2009;30(5):234–9.
Okumura H, Nagaya N, Enomoto M, Nakagawa E, Oya H, Kangawa K. Vasodilatory effect of ghrelin, an endogenous peptide from the stomach. J Cardiovasc Pharmacol. 2002;39(6):779–83.
Soeki T, Kishimoto I, Schwenke DO, et al. Ghrelin suppresses cardiac sympathetic activity and prevents early left ventricular remodeling in rats with myocardial infarction. Am J Physiol Heart Circ Physiol. 2008;294(1):H426–32.
Schwenke DO, Tokudome T, Kishimoto I, et al. Early ghrelin treatment after myocardial infarction prevents an increase in cardiac sympathetic tone and reduces mortality. Endocrinology. 2008;149(10):5172–6.
Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes. 2001;50(4):707–9.
Lambert E, Lambert G, Ika-Sari C, et al. Ghrelin modulates sympathetic nervous system activity and stress response in lean and overweight men. Hypertension. 2011;58(1):43–50.
Arcaro G, Zamboni M, Rossi L, et al. Body fat distribution predicts the degree of endothelial dysfunction in uncomplicated obesity. Int J Obes Relat Metab Disord. 1999;23(9):936–42.
Westerbacka J, Vehkavaara S, Bergholm R, Wilkinson I, Cockcroft J, Yki-Jarvinen H. Marked resistance of the ability of insulin to decrease arterial stiffness characterizes human obesity. Diabetes. 1999;48(4):821–7.
Nielsen S, Guo Z, Johnson CM, Hensrud DD, Jensen MD. Splanchnic lipolysis in human obesity. J Clin Invest. 2004;113(11):1582–8.
Arcaro G, Cretti A, Balzano S, et al. Insulin causes endothelial dysfunction in humans: sites and mechanisms. Circulation. 2002;105(5):576–82.
Brook RD, Bard RL, Glazewski L, et al. Effect of short-term weight loss on the metabolic syndrome and conduit vascular endothelial function in overweight adults. Am J Cardiol. 2004;93(8):1012–6.
Pontiroli AE, Frige F, Paganelli M, Folli F. In morbid obesity, metabolic abnormalities and adhesion molecules correlate with visceral fat, not with subcutaneous fat: effect of weight loss through surgery. Obes Surg. 2009;19(6):745–50.
Lorenzet R, Napoleone E, Cutrone A, Donati MB. Thrombosis and obesity: cellular bases. Thromb Res. 2012;129(3):285–9.
Schneiderman J, Sawdey MS, Keeton MR, et al. Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci U S A. 1992;89(15):6998–7002.
Nakata M, Yada T, Soejima N, Maruyama I. Leptin promotes aggregation of human platelets via the long form of its receptor. Diabetes. 1999;48(2):426–9.
Verhagen SN, Visseren FL. Perivascular adipose tissue as a cause of atherosclerosis. Atherosclerosis. 2011;214(1):3–10.
Chaowalit N, Somers VK, Pellikka PA, Rihal CS, Lopez-Jimenez F. Adipose tissue of atrial septum as a marker of coronary artery disease. Chest. 2007;132(3):817–22.
Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation. 1983;67(5):968–77.
Romero-Corral A, Montori VM, Somers VK, et al. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies. Lancet. 2006;368(9536):666–78.
Lopez-Jimenez F, Wu CO, Tian X, et al. Weight change after myocardial infarction—the Enhancing Recovery in Coronary Heart Disease patients (ENRICHD) experience. Am Heart J. 2008;155(3):478–84.
Bardia A, Holtan SG, Slezak JM, Thompson WG. Diagnosis of obesity by primary care physicians and impact on obesity management. Mayo Clin Proc. 2007;82(8):927–32.
• Singh S, Lopez-Jimenez F. Medically diagnosed overweight and weight loss in a US national survey. Prev Med. 2010;51(1):24–6. This article reminds us of the importance of the diagnosis of overweight, especially in individuals at risk of CVD. Moreover, these results show that the diagnoses of overweight and obesity are also important to stimulate weight loss in patients.
Lopez-Jimenez F, Malinski M, Gutt M, et al. Recognition, diagnosis and management of obesity after myocardial infarction. Int J Obes (Lond). 2005;29(1):137–41.
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.
Coutinho T, Goel K, de Sa Correa D, et al. Central obesity and survival in subjects with coronary artery disease: a systematic review of the literature and collaborative analysis with individual subject data. J Am Coll Cardiol. 2011;57(19):1877–86.
•• Coutinho T, Goel K, de Sa Correa D, et al. Combining body mass index with measures of central obesity in the assessment of mortality in subjects with coronary disease: role of "normal weight central obesity". J Am Coll Cardiol. 2013;61(5):553–60. This article demonstrates that central obesity assessed with the waist-to-hip ratio in the presence of normal body weight conveys the highest mortality risk in patients with coronary disease. These results suggest that the distribution of adipose tissue is perhaps more important than total body adiposity and that the assessment of adiposity needs to go beyond the BMI.
Zimmet P, Alberti G. The metabolic syndrome: progress towards one definition for an epidemic of our time. Nat Clin Pract Endocrinol Metab. 2008;4(5):239.
Krum H, Abraham WT. Heart failure. Lancet. 2009;373(9667):941–55.
Wanahita N, Messerli FH, Bangalore S, Gami AS, Somers VK, Steinberg JS. Atrial fibrillation and obesity—results of a meta-analysis. Am Heart J. 2008;155(2):310–5.
Rosengren A, Hauptman PJ, Lappas G, Olsson L, Wilhelmsen L, Swedberg K. Big men and atrial fibrillation: effects of body size and weight gain on risk of atrial fibrillation in men. Eur Heart J. 2009;30(9):1113–20.
Tedrow UB, Conen D, Ridker PM, et al. The long- and short-term impact of elevated body mass index on the risk of new atrial fibrillation the WHS (Women's Health Study). J Am Coll Cardiol. 2010;55(21):2319–27.
Filardo G, Hamilton C, Hamman B, Hebeler Jr RF, Grayburn PA. Relation of obesity to atrial fibrillation after isolated coronary artery bypass grafting. Am J Cardiol. 2009;103(5):663–6.
Lavie CJ, Milani RV, Artham SM, Patel DA, Ventura HO. The obesity paradox, weight loss, and coronary disease. Am J Med. 2009;122(12):1106–14.
Benoit SR, Mendelsohn AB, Nourjah P, Staffa JA, Graham DJ. Risk factors for prolonged QTc among US adults: third national health and nutrition examination survey. Eur J Cardiovasc Prev Rehabil. 2005;12(4):363–8.
Lalani AP, Kanna B, John J, Ferrick KJ, Huber MS, Shapiro LE. Abnormal signal-averaged electrocardiogram (SAECG) in obesity. Obes Res. 2000;8(1):20–8.
Perseghin G. The role of non-alcoholic fatty liver disease in cardiovascular disease. Dig Dis. 2010;28(1):210–3.
Sunny NE, Parks EJ, Browning JD, Burgess SC. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab. 2011;14(6):804–10.
Lomonaco R, Ortiz-Lopez C, Orsak B, et al. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology. 2012;55(5):1389–97.
Ndumele CE, Nasir K, Conceicao RD, Carvalho JA, Blumenthal RS, Santos RD. Hepatic steatosis, obesity, and the metabolic syndrome are independently and additively associated with increased systemic inflammation. Arterioscler Thromb Vasc Biol. 2011;31(8):1927–32.
Bonapace S, Perseghin G, Molon G, et al. Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. Diabetes Care. 2012;35(2):389–95.
Malhotra A, White DP. Obstructive sleep apnoea. Lancet. 2002;360(9328):237–45.
Li C, Ford ES, Zhao G, Croft JB, Balluz LS, Mokdad AH. Prevalence of self-reported clinically diagnosed sleep apnea according to obesity status in men and women: national health and nutrition examination survey, 2005–2006. Prev Med. 2010;51(1):18–23.
Phillips BG, Kato M, Narkiewicz K, Choe I, Somers VK. Increases in leptin levels, sympathetic drive, and weight gain in obstructive sleep apnea. Am J Physiol Heart Circ Physiol. 2000;279(1):H234–7.
Lopez-Jimenez F, Sert Kuniyoshi FH, Gami A, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. Chest. 2008;133(3):793–804.
Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med. 2001;163(1):19–25.
Namtvedt SK, Hisdal J, Randby A, et al. Impaired endothelial function in persons with obstructive sleep apnoea: impact of obesity. Heart. 2013;99(1):30–4.
Lavie L, Lavie P. Molecular mechanisms of cardiovascular disease in OSAHS: the oxidative stress link. Eur Respir J. 2009;33(6):1467–84.
Zhang XL, Yin KS, Li C, Jia EZ, Li YQ, Gao ZF. Effect of continuous positive airway pressure treatment on serum adiponectin level and mean arterial pressure in male patients with obstructive sleep apnea syndrome. Chin Med J (Engl). 2007;120(17):1477–81.
Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005;365(9464):1046–53.
•• Romero-Corral A, Somers VK, Sierra-Johnson J, et al. Normal weight obesity: a risk factor for cardiometabolic dysregulation and cardiovascular mortality. Eur Heart J. 2010;31(6):737–46. This article demonstrates that normal weight obesity, defined as the combination of normal BMI and high body fat content, is associated with a high prevalence of cardiometabolic dysregulation, metabolic syndrome, and cardiovascular risk factors. Furthermore, it shows that normal weight obesity is independently associated with increased risk of cardiovascular mortality in women.
Oreopoulos A, Padwal R, Norris CM, Mullen JC, Pretorius V, Kalantar-Zadeh K. Effect of obesity on short- and long-term mortality postcoronary revascularization: a meta-analysis. Obesity (Silver Spring). 2008;16(2):442–50.
Sierra-Johnson J, Wright SR, Lopez-Jimenez F, Allison TG. Relation of body mass index to fatal and nonfatal cardiovascular events after cardiac rehabilitation. Am J Cardiol. 2005;96(2):211–4.
Lavie CJ, De Schutter A, Patel D, Artham SM, Milani RV. Body composition and coronary heart disease mortality—an obesity or a lean paradox? Mayo Clin Proc. 2011;86(9):857–64.
Acknowledgments
Prachi Singh, Virend K. Somers, Ondrej Sochor, and Francisco Lopez-Jimenez were supported by the European Regional Development Fund, project FNUSA-ICRC (Z.1.05/1.1.00/02.0123). Ondrej Sochor was also supported by the Internal Grant Agency of the Ministry of Health of the Czech Republic (IGA MZČR; NT 13434-4/2012). Prachi SIngh is funded by 11SDG726004 from American Heart Association (AHA).
Conflict of Interest
Virend K. Somers has been a consultant to Neu Pro, Apnex Medical, Respicardia, Medtronic, and ResMed.
Carlos M. Diaz-Melean, Juan Pablo Rodriguez-Escudero, Prachi Singh, Ondrej Sochor, Ernesto Manuel Llano, and Francisco Lopez-Jimenez declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is part of the Topical Collection on Clinical Trials and Their Interpretations
Rights and permissions
About this article
Cite this article
Diaz-Melean, C.M., Somers, V.K., Rodriguez-Escudero, J.P. et al. Mechanisms of Adverse Cardiometabolic Consequences of Obesity. Curr Atheroscler Rep 15, 364 (2013). https://doi.org/10.1007/s11883-013-0364-2
Published:
DOI: https://doi.org/10.1007/s11883-013-0364-2