Brief Reviews |
From the Departments of Human Nutrition (G.F., T.M.), Medicine (T.M.), and Pharmacology (T.M.), University of Illinois at Chicago.
Correspondence to Theodore Mazzone, MD, Section of Endocrinology, Diabetes & Metabolism, University of Illinois at Chicago, 1819 W Polk St (M/C 797), Chicago, IL 60612. E-mail tmazzone{at}uic.edu
| Abstract |
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The increasing prevalence of obesity in the United States will have a direct impact on atherosclerosis and subsequent rates of cardiovascular disease. This article considers potential mechanisms for the adverse effect of excess adipose tissue on the vessel wall, the importance of different adipose tissue depots, and the evidence that reduction of adipose tissue can reverse atherosclerosis risk.
Key Words: obesity atherosclerosis adipocytokines lipoprotein metabolism visceral fat
| Introduction |
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30 kg/m2. Extreme obesity (defined as a BMI
40 kg/m2) affects 2.8% of men and 6.9% of women in the United States. Many studies have demonstrated that obesity increases mortality from all causes, including cardiovascular death. This review focuses on the contribution of excess adipose tissue to the major underlying cause of cardiovascular death, large vessel atherosclerosis. Studies measuring the effect of obesity on direct measures of large vessel atherosclerosis in humans are considered, along with evidence regarding potential mechanisms by which excess adipose tissue could adversely affect the vessel wall. | Obesity and Atherosclerosis |
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| Excess Adipose Tissue and the Vessel Wall: Mechanisms of Injury |
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There are multiple mechanisms by which obesity can influence systemic lipid and lipoprotein metabolism.15 Increased release of fatty acids from adipose tissue in obesity with increased flux to the liver can increase very-low-density lipoprotein, apolipoprotein B (apoB), and triglyceride secretion.15–18 Other factors secreted by adipose tissue may cause adverse effects on circulating lipids. For example, in a study of white men with BMI values ranging from 22 to 35 kg/m2, adiponectin was the most significant predictor of plasma very-low-density lipoprotein apoB concentration.19 Tumor necrosis factor expression is increased in adipose tissue from obese subjects and could have multiple effects on lipid metabolism via both paracrine effects on adipocytes, as well as on effects in the liver.15,20,21 Adipose tissue can also influence systemic lipoprotein metabolism and function by secreting apolipoproteins. ApoE is highly expressed in adipose tissue and its expression increased by treatment with peroxisome proliferator-activated receptor-
agonists.22,23 ApoE is a key apolipoprotein involved in the systemic and cellular lipoprotein metabolism, and apoE secreted by extrahepatic tissue can have a profound effect on systemic lipoprotein metabolism.24 Endogenous expression of apoE in adipocytes has also been shown to play an important role in adipocyte triglyceride turnover and adipocytokine expression.25 Serum amyloid A is both an inflammatory cytokine and an apolipoprotein produced by multiple cell types, including adipocytes.14 Its level of expression is highly correlated with BMI, and weight loss produces significant decreases in serum amyloid A levels, as does treatment with peroxisome proliferator-activated receptor-
agonists.26 In inflammatory conditions, serum amyloid A becomes an important surface constituent of HDL and thereby has a number of important effects on the metabolism and function of HDL.27–29 Two other apolipoproteins are also produced in adipocytes, apoC1 and apoD,15 but their impact on systemic lipoprotein metabolism or cellular lipid flux is less well defined.
Increased free fatty acid release from adipose tissue in obesity may also accelerate atherosclerosis by mechanisms not directly related to lipids. Evidence for this is provided by the results of a prospective study of 3315 subjects followed for 5.3 years. Free fatty acid levels in these subjects independently predicted all-cause and cardiovascular mortality after adjustment for age, sex, BMI, triglycerides, HDL, LDL, homeostasis model assessment of insulin resistance, hypertension, smoking, C-reactive protein (CRP), homocysteine, creatinine, statin use, and β-blocker.30 Excess free fatty acid delivery to peripheral tissues may worsen insulin resistance and may play a role in activating inflammatory processes, possibly through activation of Toll-like receptor 4.14,31,32 Free fatty acids have also been shown to induce endothelial cell apoptosis and to impair endothelium-dependent vasodilatation.33–35
A number of cytokines and adipokines secreted by adipose tissue may also influence vessel wall directly. Resistin is highly expressed in the fat tissue of rodents, and its level is elevated in models of obesity and insulin resistance.36 Some, but not all, studies have shown that resistin levels are also increased in human obesity and diabetes.37,38 In humans, resistin is expressed primarily in inflammatory cells, where its expression is increased by treatment with endotoxin and proinflammatory cytokines.39–41 Recently, the level of resistin in humans has been shown to positively correlate with increasing coronary atherosclerosis measured by coronary artery calcium after adjustment for established cardiac risk factors.42 On the other hand, recent data from Kunnari et al showed no relationship between resistin levels and another marker of atherosclerosis/cardiovascular risk, carotid intima/media thickness.43 High levels of resistin may negatively influence the atherosclerotic process through several mechanisms. Resistin directly activates the endothelium through upregulation of adhesion molecules, an effect that is antagonized by adiponectin (see below).44,45 Resistin also induces production of the proinflammatory cytokines endothelin-1, monocyte chemoattractant protein (MCP)-1, and pentraxin by endothelial cells.44,45 It also promotes migratory activity of vascular smooth muscle cells.41 In macrophages, resistin increases expression of CD36 and facilitates lipid accumulation, thereby promoting formation of foam cells; this effect is also antagonized by adiponectin.46,47 Furthermore, resistin induces production of the proinflammatory cytokines tumor necrosis factor-
and interleukin (IL)-12 by macrophages through activation of nuclear factor
B.48
Leptin is a product of adipocytes, and plasma leptin levels increase with obesity. Plasma leptin levels have been positively associated with cardiovascular complications in humans, and this effect has been observed independent of BMI and traditional cardiac risk factors.14 A recent study in type 2 diabetes demonstrated that hyperleptinemia was associated with coronary atherosclerosis, as measured by coronary artery calcium, and this association was independent of insulin resistance.49 In animal models, recombinant leptin has been shown to promote atherosclerosis and thrombosis in apoE-deficient mice.50 This adverse effect on vascular disease was observed in spite of the metabolic benefits associated with leptin treatment. Other studies have shown that leptin may have a role in neointimal formation in response to arterial injury.51 Leptin has multiple effects on cells of the artery wall; many of which are similar to those described for resistin. In endothelial cells, leptin induces oxidative stress, increases production of MCP-1 and endothelin-1, and potentiates proliferation.52–55 In smooth muscle cells, leptin promotes migration, proliferation and hypertrophy, this latter effect being mediated by activation of p38 mitogen-activated protein kinase.56 Leptin also contributes to increased activation of and cytokine production by macrophages, neutrophils, and T lymphocytes.57–59 Finally, leptin promotes calcification of cells of the vascular wall60 and facilitates thrombosis by increasing platelet aggregation.61 Although these effects of leptin point to a proatherogenic role for this adipokine, it is important to note that obesity is associated with leptin resistance, which leads to a reduced biological response to leptin. Leptin resistance, probably mediated by alterations in leptin receptor signaling pathways and originally reported in the hypothalamus of obese subjects and experimental animals,62 has been shown to extend to the peripheral effects of leptin, including those on platelets and the vascular wall.62,63
Adiponectin is a product of adipocytes, and its level in humans is decreased in obese and diabetic subjects.14 Levels of adiponectin increase with weight loss or with pharmacological treatment of insulin resistance. Adiponectin plays a role in regulating systemic substrate metabolism, and several recent publications have suggested a role for adiponectin in modulating vessel wall health. Adiponectin circulates in 3 different oligomers, and each of these may has a different biologic function.64,65 HDL cholesterol and high-molecular-weight adiponectin level are positively correlated, and both total serum adiponectin and high-molecular-weight adiponectin levels correlate negatively with triglyceride, homeostasis model assessment of insulin resistance, and circulating inflammatory markers.64,65 Serum high-molecular-weight adiponectin level is significantly lower in men with coronary artery disease,66 independent of other cardiac risk factors. Rewers and colleagues studied the progression of coronary artery calcification over 2.6 years in a group of patients with type 1 diabetes and nondiabetic subjects aged 19 to 59 years.67 Adiponectin levels were inversely correlated to progression of coronary artery calcium in both diabetic and nondiabetic subjects. Adiponectin levels after treatment with insulin sensitizers have also been shown to be the best predictor of an improvement in carotid arterial wall stiffness in a group of subjects with type 2 diabetes.68 Mutations of the adiponectin gene are strongly associated with impaired glucose tolerance, diabetes mellitus, and coronary artery disease in humans.68 In adiponectin knockout mice, a high-fat and high-sucrose diet leads to marked elevation of plasma glucose and insulin levels, insulin resistance, and an increase in intimal smooth muscle cell proliferation after injury in the aorta; however, these alterations have not been observed in all of the adiponectin knockout strains that have been developed to date.69,70 Treatment of apoE-deficient mice with an adiponectin adenovirus has been shown to reduce plaque formation in the aortic sinus by 30%.69 As might be expected based on the above observations, adiponectin promotes an antiatherogenic and antiinflammatory program of gene expression and function in vessel wall cells. Adiponectin downregulates expression of adhesion molecules on endothelial cells through inhibition of nuclear factor
B activation71 and thereby reverses the effects of resistin.45 Adiponectin also reduces endothelial oxidative stress and proliferation while stimulating nitric oxide synthase activity.72–73 However, both induction and suppression of chemokine production by endothelial cells have been reported in response to adiponectin.74,75 In vascular smooth muscle cells, adiponectin reduces proliferation in a receptor-independent fashion by binding to, and inhibiting, the activity of growth factors, such as heparin-binding epidermal growth factor, basic fibroblast growth factor, and platelet-derived growth factor-BB.76,77 In macrophages, adiponectin reduces lipid accumulation and downregulates expression of scavenger receptors.78 Similar to what was reported in endothelial cells, controversy remains regarding the role of adiponectin for macrophage cytokine production.79–81
Obesity leads to increased expression of additional inflammatory mediators in adipose tissue, including MCP-1. Adipocyte expression of MCP-1 increases in obesity, and increased circulating MCP-1 levels have been shown to increase the number of circulating CD11B-positive monocytes in mice.82 CD11B is a component of MAC-1 and is involved in binding of monocyte/macrophages to the vascular wall. The expression of adipose tissue IL-6 is increased in human obesity, and up to one-third of plasma IL-6 is believed to be derived from adipose sites. In humans, IL-6 produces elevation of plasma free fatty acids and increased levels of hepatic CRP expression. CRP may also be produced in adipose tissue, and recent data suggest that CRP may be directly involved in atherogenesis at the vessel wall.14,83,84 Angiotensinogen, angiotensin-converting enzyme, and plasminogen activator inhibitor-1 are also produced by adipose tissue, where their level of expression is increased in obesity.14 Angiotensin II produces vasoconstrictive effects and may also promote systemic inflammation.14 Plasminogen activator inhibitor-1 can promote atherothrombosis.14
| Differences in Atherosclerotic Risk Based on Adipose Tissue Distribution |
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, or adiponectin. It also did not produce significant changes in blood pressure, plasma glucose, insulin, or lipid concentrations. On the other hand, a number of studies have shown that a reduction in visceral fat in animals and humans is associated with increased in insulin sensitivity, HDL cholesterol, and decreased in triglyceride and blood pressure.88–91 Thorne et al randomized 50 subjects with a BMI>35 kg/m2 to adjustable gastric banding alone, or this plus surgical removal of the greater omentum.88 Metabolic parameters were compared before surgery and 2 years after surgery. There were no significant differences between control and omentectomized patients at baseline. At 2-year followup, there was a decrease in weight and improved metabolic profile in both groups. Omentectomized subjects lost more weight than control subjects, but the difference was not statistically significant. Subjects who underwent omentectomy, however, had a statistically significant improvement in oral glucose tolerance, insulin sensitivity, fasting plasma glucose, and insulin levels independent of the change in BMI. There were no differences in blood lipids between the 2 groups. Several recent studies have reported on the influence of adipose tissue distribution on direct measures of macrovascular disease. In a cross-sectional analysis of 1356 women, 60 to 85 years of age,92 aortic calcification (as an index of atherosclerosis) was evaluated. Peripheral fat mass showed an independent and dominant antiatherogenic effect in elderly women. Ferreira et al investigated 336 subjects (175 women) who were apparently healthy and examined the relationship among truncal fat, peripheral fat, and estimates of the stiffness of large arteries.93 Central fat was positively associated with stiffness of the carotid and femoral arteries, whereas peripheral fat was inversely associated with stiffness of the brachial and carotido-femoral segment. In a study of more than 5000 middle-aged women aged 30 to 69 years, a subsample of 310 participants underwent measurement of carotid intima/media thickness. An increase in carotid intima/media thickness was observed in abdominally obese (elevated waist-to-hip ratio) women to lean women.94 Morricone et al studied 55 patients undergoing coronary angiography,95 and multivariate regression analyses showed that coronary artery disease was significantly correlated with visceral adipose tissue as measured by abdominal CT. No relationship was found between coronary artery disease and BMI.
Although the basis for the apparent difference in vascular risk conferred by different adipose tissue depots remains under active investigation, patterns of gene expression between peripheral subcutaneous and visceral fat are consistent with a more proatherogenic influence of the latter.14 Vohl et al recently performed a microarray analysis of genes differentially expressed in subcutaneous versus visceral adipose tissue of obese subjects and identified 347 genes that were differentially expressed in the 2 depots, of which 131 genes were expressed at higher levels in subcutaneous adipose tissue and 216 were more abundant in visceral fat.96 Compared with subcutaneous tissue, visceral adipose tissue produces higher levels of several factors that have been implicated in cardiovascular disease and metabolic disturbances, including IL-6, IL-8, MCP-1, vascular endothelial growth factor, and plasminogen activator inhibitor-1.97–99 Many of these factors are produced by the stromovascular fraction of adipose tissue, mostly by macrophages, which infiltrate adipose tissue in greater number in obese compared with lean subjects.100 Increased levels of the chemokine MCP-1 in visceral adipose tissue attract more monocytes/macrophages, thereby creating a self-sustaining inflammatory cycle.31,100 In addition to creating a more proinflammatory environment, products of visceral adipose tissue—cytokines, free fatty acids, and hormones—also gain a direct access to the liver through the portal circulation (Figure 1), likely magnifying the adverse consequences of excess visceral adipose tissue.101 Leptin, on the other hand, has been shown to be produced at higher levels in subcutaneous compared with visceral adipose tissue.102
| Cardiovascular Benefits of Weight Loss |
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There have been multiple studies demonstrating improvement in metabolic or inflammatory markers with short-term weight loss.12,13,85,108–110 There have, however, been fewer reports of the effects of weight loss on direct measures of macrovascular disease. Dengel et al have recently studied 12 overweight individuals without known diabetes or vascular disease and measured parameters of vascular structure, function, and mechanical properties using ultrasound.108 An intravenous glucose-tolerance test, blood pressure, body composition, and lipids were also measured. During weight loss, there were significant reductions in BMI and percentage of body fat. There were the expected improvements in total cholesterol, LDL cholesterol, triglyceride, and insulin sensitivity. After 6 months, there were also significant improvements in brachial artery compliance and distensibility; however, endothelial function and arterial intima/media thickness did not change. Ziccardi et al reported that after 1 year of weight loss, the vascular response to L-arginine improved in obese women.109 Balkestein et al reported that 3 months of negative caloric balance improved carotid distensibility in obese men.110 Overall, the results of studies evaluating the effect of weight loss on measures of macrovascular disease are mixed, and longer-term studies with sustained weight loss are needed.
As compared with medical therapy, surgical intervention can produce more substantial long-term weight loss. Sjostrom et al recently reported on a prospective controlled study involving obese subjects who underwent gastric surgery compared with a matched conventionally treated obese control group.111 After 10 years, weight had increased by 1.6% in the control group and decreased by16.1% in the surgery group. Two- and 10-year rates of recovery from diabetes, hypertriglyceridemia, low HDL, hypertension, and hyperuricemia were more favorable in the surgery group. The surgical group also had lower 2- and 10-year incidence of diabetes, hypertriglyceridemia, and hyperuricemia. There were no differences in the incidence of hypercholesterolemia or hypertension between the groups. This study is important because it demonstrates that the improvements in the metabolic parameters that have been repeatedly demonstrated in short-term weight loss are durable for up to 10 years. However, there were no direct measures of macrovascular disease reported for this study.
| Conclusion |
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Important questions for additional research remain for successfully meeting the challenge presented by the epidemic of obesity. The development and evaluation of additional tools for prevention and treatment of obesity and its vascular complications are critical. The use of surrogate vascular end points can be useful not only for investigating the mechanistic relationship between excess adipose tissue and macrovascular atherosclerosis but also for evaluating the effect of weight loss sustained over a shorter period of time than that needed for measuring changes in cardiovascular events. Additional work is also needed to further explore adipocyte and adipose tissue biology. The recent recognition that adipose tissue is an active endocrine and metabolic organ, with a major role in regulating organismal substrate flux and metabolism and in influencing systemic inflammatory state112,113 provides new opportunities for investigations that could lead to more effective approaches for preventing and/or treating obesity and its vascular complications.
| Acknowledgments |
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Sources of Funding
G.F. is supported by NIH grants DK 061483 and DK 068035, and T.M. is supported by NIH grants HL 39653 and DK 71711.
Disclosures
None.
| Footnotes |
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