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Obesity increases the risk of cardiovascular disease and premature death. Adipose tissue releases a large
number of bioactive mediators that influence not only body weight homeostasis but also insulin resistance
— the core feature of type 2 diabetes — as well as alterations in lipids, blood pressure, coagulation,
fibrinolysis and inflammation, leading to endothelial dysfunction and atherosclerosis. We are now beginning
to understand the underlying mechanisms as well as the ways in which smoking and dyslipidaemia increase,
and physical activity attenuates, the adverse effects of obesity on cardiovascular health.
Obesity is a fast growing problem that is reaching epidemic propor- cell products such as intercellular adhesion molecule-1 (ICAM-1)13. Ciga-
tions worldwide1, and is associated with an increased risk of prema- rette smoking may also influence cytokines: it causes a dose-dependent
ture death2. Individuals with a central deposition of adipose tissue can increase in plasma ICAM-1 (ref. 14) and decrease in adiponectin lev-
experience elevated cardiovascular morbidity and mortality, including els15,16, thereby inducing endothelial dysfunction. Whether these effects
stroke, congestive heart failure, myocardial infarction and cardiovas- are direct effects of nicotine, carbon monoxide or other components of
cular death, and this is independent of the association between obesity tobacco smoke is unclear. Both hydrogen peroxide and nicotine sup-
and other cardiovascular risk factors3,4. Weight gain during adult life5 press adiponectin expression in adipocytes15. Furthermore, smoking may
or even during childhood and adolescence6 seems to have a great effect directly regulate adiponectin concentration through lipolysis. Nicotinic
on diabetes and cardiovascular risk, even within the normal body mass acetylcholine receptors may be involved in the regulation of adipokine
index (BMI) range. (also known as adipocytokine) release in adipocytes in vitro17.
Owing to the increasing rates of childhood obesity, the global life Smoking may also increase levels of tumour necrosis factor-α (TNF-α),
expectancy in the United States will, for the first time in recent history, a powerful cytokine that might decrease adiponectin levels and induce
decline7, and the American Heart Association (AHA) has reclassified insulin resistance. Lower adiponectin levels found in chronic smokers
obesity as a ‘major, modifiable risk factor’ for coronary heart disease confirm earlier findings that chronic smokers are insulin resistant18.
(CHD)8. Cigarette smoking may also enhance the oxidative stress (production of
Different mechanisms linking obesity to cardiovascular disease have reactive oxygen species, ROS) resulting from obesity owing to the direct
been postulated, adding weight to classical risk factors. Obesity also effects of the free radicals present in smoke, as well as the inflammatory
increases the prevalence of less conventional risk factors. Adipose tissue response it can induce19. Endothelial dysfunction, an early marker of
is an active endocrine and paracrine organ that releases a large number atherosclerosis and present early in obesity, has also been observed in
of cytokines and bioactive mediators, such as leptin, adiponectin, inter- chronic cigarette smokers14. This could occur either directly or through
leukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), that influence the effect of smoking on interleukin-6 (IL-6) secretion from adipocytes
not only body weight homeostasis but also insulin resistance, diabetes, and subsequent C-reactive protein (CRP) burst. Figure 1 depicts how
lipid levels, tension, coagulation, fibrinolysis, inflammation and athero- smoking might have additional negative effects in obese individuals.
sclerosis9. Various morphological adaptations in cardiac structure and Dyslipidaemia in obesity is characterized by increased levels of very
haemodynamic function also occur in obese individuals10. low-density lipoprotein (VLDL) cholesterol, triacylglycerols and total
Here we describe and discuss classical and less conventional risk fac- cholesterol, an increase in small dense LDL particles, and lower high-
tors within the scope of insulin resistance as a major contributing factor density lipoprotein (HDL) cholesterol levels20. As to the effect of lipopro-
to the obesity-associated cardiovascular risk. teins among conventional risk factors, there is little evidence that LDL
cholesterol — known to be a major risk factor for CHD — is enhanced
Risk factors in obesity, among patients with visceral obesity in particular. Other lipo-
Classical cardiovascular risk factors include smoking, high low-density proteins, such as the apolipoprotein (Apo) B/A1 ratio21, small dense
lipoprotein (LDL) cholesterol, hypertension and dysfunctions in glu- LDL particles and low HDL cholesterol, are predictive for cardiovascular
cose metabolism. The extent to which these factors might contribute disease endpoints in people with visceral adiposity.
to an independent, additional risk among obese individuals is unclear. It is not clear whether hypercholesterolaemia further increases the risk
When compared with non-obese smokers, obese smokers have a clear of cardiovascular disease in obese individuals. But the insulin-resistant
reduction in life expectancy11,12, so smoking clearly confounds consid- state of abdominal obesity adds substantially to the CHD risk of patients
erations based on BMI alone. with familial hypercholesterolaemia22. Obesity also limits the beneficial
Obesity induces several cytokines and inflammatory markers that effects of lipid-lowering strategies23. However, aggressive reduction of
might contribute to the cardiovascular outcome in overweight and lipids with the use of statins can have a beneficial effect on coronary
obese people. It is also associated with increased levels of endothelial plaque development in obese individuals23.
1
University of Antwerp, Faculty of Medicine, Department of Diabetology, Metabolism and Clinical Nutrition, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem (Antwerp), Belgium.
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INSIGHT REVIEW NATURE|Vol 444|14 December 2006
RBP4 is an adipocyte-secreted molecule that is elevated in the serum increased myocardial oxygen consumption. In humans, myocardial
before the development of diabetes and seems to signal the presence triacylglycerol content increases with increasing BMI53.
of insulin resistance and associated cardiovascular risk factors38. RBP4 In peripheral vessels, high amounts of perivascular fat cells could con-
seems to be involved in impairing insulin signalling in muscles and tribute mechanically to the increased vascular stiffness seen in obesity.
inducing the expression of gluconeogenic enzymes in the liver, contrib- Periadventitional adipose tissue in particular may regulate the arterial
uting to insulin resistance39. tone of mesenteric arteries54, with increased arterial stiffness as a conse-
When adipocytes exceed their storage capacity and the process of quence. In addition, increased adipose paracrine secretion may lead to
fat-cell proliferation fails, fat begins to accumulate in tissues not suited vascular smooth muscle cell (VSMC) growth induced by growth factors.
for lipid storage, leading to the formation of specific metabolites that This is certain to occur in the absence of adiponectin, which is known
inhibit insulin signal transduction40. to reduce VSMC proliferation and migration55.
leptin seems to enhance the calcification of vascular cells, making the Pro-coagulation and hypofibrinolysis
arterial wall a target of leptin. The prothrombotic state in the atherosclerotic process encompasses
Adiponectin has important anti-atherogenic, antidiabetic and anti- platelet hyperaggregability, hypercoagulability and hypofibrinolysis.
inflammatory properties, and is expressed abundantly in adipocytes9,16. In obesity and metabolic syndrome, fibrinogen, von Willebrand factor
Unlike most other adipokines, adiponectin is decreased in obesity, dia- (vWF) and PAI-1 have been most extensively studied as markers of the
betes and other insulin-resistant states. The mechanism by which plasma haemostatic and fibrinolytic system and as possible predictors for the
levels are reduced in individuals with visceral fat accumulation has not development of cardiovascular disease and type 2 diabetes64. In obese
yet been clarified, but an increase in TNF-α secretion from accumulated individuals, only PAI-1 levels were increased in those with metabolic
visceral fat seems to have a role. Co-culture with visceral fat cells inhibits syndrome29 (Fig. 2). PAI-1 is expressed in visceral adipose tissue. It is
adiponectin secretion from subcutaneous adipocytes, suggesting that mainly expressed in stromal cells, including monocytes, smooth muscle
some inhibiting factors for adiponectin synthesis or secretion are cells and pre-adipocytes65. Visceral adipose tissue seems to have up
secreted from visceral adipose tissue. The negative correlation between to five times the number of PAI-1-producing stromal cells compared
visceral adiposity and adiponectin levels might be explained by the with subcutaneous adipose tissue. Plasma PAI-1 levels are more closely
increased secretion of TNF-α from accumulated visceral fat. related to fat accumulation and PAI-1 expression in the liver than in
Adiponectin increases the expression of messenger RNA and pro- adipose tissue66, suggesting that in insulin-resistant individuals the fatty
tein production of tissue inhibitor of metalloproteinase in macrophages liver is an important site of PAI-1 production. This confirms the central
through the induction of IL-10 synthesis59, and selectively suppresses role of the liver in these processes. The fibrinolytic system could have a
endothelial cell apoptosis60. This suggests that adiponectin protects role in the regulation of adipose tissue development and insulin signal-
plaque rupture by the inhibition of matrix metalloproteinase function. ling in adipocytes67.
Endothelium-dependent vasoreactivity is impaired in people with Fibrinogen, vWF and PAI-1 are also considered to be markers of the
hypoadiponectinaemia, which might be at least one cause of hyperten- acute-phase reaction of inflammation, and thrombosis has been closely
sion in visceral obesity61.The protein inhibits the expression of adhe- linked to inflammation68. Fibrinogen clusters with inflammation vari-
sion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), ables rather than with markers of pro-coagulation or metabolic factors69.
ICAM-1 and E-selectin, through the inhibition of nuclear factor-κB CRP increases PAI-1 expression and activity in human aortic endothelial
(NF-κB) activation; it also suppresses foam-cell formation. cells70. Figure 2 shows how disturbances in haemostasis and fibrinolysis
Visfatin is a visceral-fat-specific protein that is probably involved in the relate to metabolic syndrome and its different components.
development of obesity-related diseases. Visfatin levels correlate strongly
with an individual’s amount of visceral fat62, exert insulin-mimetic effects Oxidative stress
in culture cells, and have a potent insulin-like activity of adipogenesis. Oxidative stress has been proposed to be a potential pathogenic
Because of visfatin’s possible — but already controversial63 — origin in mechanism linking obesity and insulin resistance with endothelial
visceral adipose tissue, it is thought that future research might reveal an dysfunction71. However, it is not clear whether obesity itself or obes-
independent role of visceral fat in cardiovascular diseases. ity-associated conditions lead to oxidative stress. Several pathways
Figure 3 | Both abdominal (visceral) fat and insulin resistance may inflammation (CRP) and endothelial dysfunction. Insulin resistance
contribute to cardiovascular disease in obesity. Visceral fat in particular induced by cytokines (IL-6, TNF-α and adiponectin), NEFA and retinol-
contributes to endothelial dysfunction through the direct effect of binding protein 4 (RBP-4) may induce oxidative stress and subsequent
adipokines, mainly adiponectin and TNF-α, which are secreted by fat endothelial dysfunction (PAI-1 and ICAM-1). Fat accumulation, insulin
tissue after macrophage recruitment (through monocyte chemoattractant resistance, liver-induced inflammation and dyslipidaemic features may all
protein-1, MCP-1). Indirect effects of TNF-α and IL-6 might influence lead to the premature atherosclerotic process.
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©2006 Nature Publishing Group
NATURE|Vol 444|14 December 2006 INSIGHT REVIEW
Box 1 | Insulin resistance and left ventricle remodelling Visceral and ectopic fat, its fatty acid behaviour, local adipokine sec-
Potential mechanisms by which insulin resistance and its correlates retion and low-grade inflammation in the context of an insulin-resistant
might be involved in left ventricle remodelling and contractile obese patient, might explain the development of endothelial dysfunction
dysfunction (data from refs 80, 81). and early cardiovascular disease.
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INSIGHT REVIEW NATURE|Vol 444|14 December 2006
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