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Obesity, Inflammation, and Cardiovascular Risk P Mathieu1,2, I Lemieux1 and J-P Després1,3 Obesity, a highly prevalent condition, is heterogeneous with regard to its impact on cardiovascular disease (CVD) risk. Epidemiological observations and metabolic investigations have consistently demonstrated that the accumulation of excess visceral fat is related to an increased risk of CVD as well as several metabolic and inflammatory perturbations. In the past decade, data from several studies have served to emphasize that atherosclerosis has an inflammatory component that may contribute to several key pathophysiological processes. Study data have also highlighted the finding that the expanded visceral fat is infiltrated by macrophages that conduct “cross-talk” with adipose tissue through several significant mechanisms. In this review, we provide, in the context of CVD risk, an up-to-date account of the complex interactions that occur between a dysfunctional adipose tissue phenotype and inflammation.
Obesity, a highly prevalent condition in Westernized societies and a growing problem in developing countries, is heterogeneous with respect to its metabolic features. For instance, numerous studies conducted over the past three decades have provided solid evidence that the regional distribution of adipose tissue is the key factor explaining the relationship between adiposity and cardiometabolic risk. Many metabolic investigations have shown that excess visceral adiposity is a key feature of a phenomenon referred to as ectopic fat deposition, which has been shown to be associated with a plethora of metabolic dysfunctions. Key features associated with excess visceral fat/ectopic fat accumulation include insulin resistance, atherogenic dyslipidemia, hypertension, impaired fibrinolysis/increased risk of thrombosis, and inflammation.1,2 It should be pointed out that these metabolic features, most commonly found in the viscerally obese patient, are often referred to collectively as the metabolic syndrome, which is linked to the development of cardiovascular disease (CVD). The metabolic syndrome of visceral obesity has been described as a “multiplex” additional modifiable CVD risk factor that—when added to traditional risk factors (age, sex, smoking, blood pressure, low-density-lipoprotein (LDL) cholesterol, highdensity-lipoprotein (HDL) cholesterol, diabetes, and family history of premature CVD)—determines global “cardiometabolic risk” (Figure 1).3 It is now beyond dispute that inflammation is one of the important causes of CVD and a key player in the development of atherothrombosis, leading to adverse clinical events.4 Inflammation is also considered to be at the center stage of metabolic dysfunction. For instance, insulin resistance is strongly influenced by
several proinflammatory signals. In the past decade or so, data from studies by various investigators have underscored the fact that chronic low-grade inflammation, such as is encountered in individuals with an excess of visceral/ectopic fat, plays an important role in several cardiovascular disorders. In addition to atherosclerosis, in which the involvement of inflammation is well known, other cardiovascular disorders—such as calcific aortic stenosis, aortic aneurysms, and atrial fibrillation, to name a few—are strongly influenced by the inflammatory components of visceral obesity.2 In terms of its proinflammatory and metabolic features (which have intricate and reciprocal relationships), visceral obesity is an emergent powerful but modifiable risk factor for CVD. Therefore, we must admit that the late Professor Björntorp, who coined the term “civilization syndrome,” foresaw the plague of a new era well before the turn of the century.5 In this article, we provide an update on the topic of obesity and inflammation in light of recent investigations linking cardiometabolic risk to inflammation and the underlying pathophysiology of cardiovascular disorders. The Inflammation of Visceral Obesity: an Imbalance Between Overconsumption of Energy and Dysfunctional Adipocytes?
Although the metabolic dysfunctions that are traditionally related to obesity are determined by several factors, it should be emphasized that two of them may be particularly important. First, the regional distribution and metabolism of adipose tissue are crucial factors that determine the existence/absence of a dysmetabolic state under the conditions of a sedentary, affluent
1Quebec Heart and Lung Institute/Research Center, Québec, Québec, Canada; 2Department of Surgery, Laval University, Québec, Québec, Canada; 3Division of
Kinesiology, Department of Social and Preventive Medicine, Laval University, Québec, Québec, Canada. Correspondence: P Mathieu (email@example.com) Received 14 December 2009; accepted 22 December 2009; advance online publication 3 March 2010. doi:10.1038/clpt.2009.311 Clinical pharmacology & Therapeutics | VOLUME 87 NUMBER 4 | APRIL 2010
Visceral AT/ ectopic fat
Visceral AT/ ectopic fat
A new CVD risk factor
Others (including family history)
Others (including family history)
Global CVD risk from traditional risk factors
Global cardiometabolic risk = Global CVD risk
Figure 1 The concept of global cardiometabolic risk. This simplified scheme shows the added contribution of excess visceral adiposity/ectopic fat to global cardiometabolic risk, which is the cardiovascular disease (CVD) risk resulting from the presence of traditional and emerging risk factors/markers. AT, adipose tissue; HDL, high-density lipoprotein; LDL, low-density lipoprotein. Adapted from ref. 1.
lifestyle that promotes body fat accumulation and, ultimately, obesity (Figure 2). The biology of subcutaneous fat cells differs from that of visceral fat cells in many respects. Experimental studies have demonstrated that, as compared with their sub cutaneous counterparts, visceral adipocytes are hyperlipolytic and have a distinct secretion profile of cytokines (often referred to as adipokines). Experimental evidence also indicates that subcutaneous fat tissue may be considered a “metabolic sink” that prevents accumulation of harmful ectopic visceral fat. Second, differentiation of preadipocytes into mature adipocytes is a key process contributing to the biology of adipose tissue. Therefore, if the differentiation of preadipocytes is hampered in the context of a positive energy balance, it will promote, at some stage, the formation of larger, dysfunctional adipocytes.6 As a result, these hypertrophied adipocytes with large triglyceride stores will have a high lipolytic rate; they will produce more leptin and less adiponectin, two important adipokines that influence inflammation and overall carbohydrate and lipid metabolism. Another important consequence of fat cell hypertrophy is the infiltration of adipose tissue by macrophages. It is believed that cross-talk between adipocytes and macrophages contributes to the production of cytokines as well as to the exacerbation of the metabolic activity of the adipose tissue itself. These processes also contribute to systemic inflammation and insulin resistance. Inflammation and Adipose Tissue Cytokines
Several studies have documented significant associations between the amount of visceral adipose tissue and circulating levels of interleukin (IL)-6, tumor necrosis factor-α (TNF-α), 408
Lack of physical activity/exercise
Energy-dense diet Energy excess
“Dysfunctional” metabolic sink “Inflamed” adipose tissue
Hypertrophic obesity Altered cytokine secretion profile •↓ Adiponectin •↑ TNF-α •↑ IL-6 ICAM-1 Selectins HSPs, etc. Endothelium and other cells
IL-6 "Messenger" cytokine
Atherosclerosis and CVD
Figure 2 The “inflamed” adipose tissue of visceral obesity. It is proposed that the inability of subcutaneous adipose tissue to adapt to caloric overload by hyperplasia of preadipocytes leads to exaggerated fat cell hypertrophy, macrophage infiltration, apoptosis of some adipose cells, and an altered production of proinflammatory cytokines. In this model, elevated concentrations of circulating CRPs are often a marker of such a “dysfunctional” adipose tissue phenotype. CRP, C-reactive protein; CVD, cardiovascular disease; HSPs, heat-shock proteins; ICAM-1, intercellular adhesion molecule-1; IL-6, interleukin-6; SAA, serum amyloid A; TNF-α, tumor necrosis factor-α.
and C-reactive protein (CRP).7–9 In the past decade, a series of studies have contributed to shedding light on possible mechanisms through which expansion of the visceral adipose depot VOLUME 87 NUMBER 4 | aPRIL 2010 | www.nature.com/cpt
Crp: a Simple Convenient Inflammation Marker Associated with Excess Visceral/Ectopic Fat?
Elevated CRP levels have been documented in obese subjects. We have shown that the highest CRP levels were found in individuals who had elevated levels of both total and visceral adipose tissue (Figure 3a). We developed an inflammation score that Clinical pharmacology & Therapeutics | VOLUME 87 NUMBER 4 | APRIL 2010
3.0 2.5 2.0 1.5 (2)
1.0 0.5 0.0
<167 ≥167 Visceral adipose tissue (cm2)
b 60 % With inflammation score ≥3
may contribute to inflammation. Although the picture is far from being entirely clear, some factors have emerged, with two key processes shown to be involved. First, macrophages are present within adipose tissue, and their density increases with obesity, particularly with hypertrophic obesity, which is associated with a reduced production of an anti-inflammatory adipokine, adiponectin, by the hypertrophied adipose tissue (Figure 2).10,11 On the other hand, hyperplastic adipose tissue (in which the expanded adipose depot is explained mainly by an increase in the number of fat cells of smaller size) remains quite active in the production of adiponectin, which could protect against macrophage infiltration leading to the overproduction of inflammatory cytokines such as IL-6 and TNF-α.12 The number of macrophages within the adipose tissue has been shown to correlate well with insulin resistance—a phenomenon that is clearly concordant with the insulin-resistant state of hypertrophic obesity. Second, the interplay between macrophages and adipocytes contributes, to a large extent, to several inflammatory and metabolic dysfunctions encountered in obesity.13 Large adipocytes, such as those encountered in a state of chronic positive energy balance, produce more free fatty acids (FFAs), which are potent activators of the Toll-like receptor-4 (ref. 14). It is worthwhile to point out that the Toll receptors, discovered in the 1990s, are a subset of the pattern recognition receptors and play a central role in the innate immune response. In addition, the discovery that the Toll receptors are involved not only in the recognition of pathogens, but also in that of endogenous molecules, has shed light on the mechanisms through which inflammation might be triggered and sustained in several human disorders such as obesity and atherosclerosis. Hence, it has been proposed that endogenous molecules could be considered as “danger signals” that contribute to maintaining a detrimental response in conditions of sustained stimulation.14 In this regard, FFAs derived from adipocytes and also from the diet induce (through Tolllike receptors) the activation of the NF-κB pathway and, in the end, contribute to the synthesis and production of cytokines such as TNF-α.15 Cross-talk between adipocytes and macrophages will then promote positive feedback loops and result in the amplification of a detrimental metabolic/inflammatory response. For instance, TNF-α activates lipolysis as well as the synthesis of IL-6 and macrophage chemoattractant protein-1 (MCP-1), a potent chemokine that allows the recruitment of more macrophages.16 In addition, IL-6 is a key driver of production of CRP by the liver.17 Moreover, visceral fat is infiltrated by macrophages to a greater extent than is subcutaneous fat; given the location of abdominal fat, and drainage to the portal system, cytokines produced by this fat depot have direct access to the liver, where they may promote the production of acute-phase proteins, including CRP.
50 40 30 20 ≥130
25–30 ≥30 Body mass index (kg/m2)
se po di 2 ) a al cm <130 er e ( sc u Vi tiss
Figure 3 Impact of visceral adipose tissue on inflammation. (a) Plasma C-reactive protein (CRP) levels in male subjects, classified on the basis of their total adiposity and visceral fat accumulation. The 50th percentile values of the distribution of both variables were used as the arbitrary cutoff to classify individuals into two groups: those with “low” levels of both variables and those with “high” levels of both variables. 1, 2, 3: Significantly different from the corresponding subgroups. (b) Severity of an inflammation score as a function of increasing visceral adiposity. The inflammation score was defined as the sum of the number of inflammatory markers >50th percentile (C-reactive protein, tumor necrosis factor-α, and interleukin-6) or <50th percentile for adiponectin. Adapted from Lemieux, I. et al., Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity, Arterioscler. Thromb. Vasc. Biol. 21, 961–967 (2001), and ref. 18.
included CRP and inflammatory cytokines; we found that, for any given body mass index (BMI) value, the highest inflammation scores were observed in individuals with high levels of visceral adipose tissue (Figure 3b).18 In addition, circulating CRP concentrations have been shown to be clearly associated with features of the metabolic syndrome.19 In other words, the more severe the metabolic syndrome, the higher the CRP levels are. Despite the fact (as numerous studies have shown) that elevated CRP concentrations predict an increased CVD risk even after controlling for traditional risk factors, some questions remain. Does this residual relationship between CRP and CVD provide evidence of a direct role for CRP in the pathophysiology of CVD? Would this apparently independent CRP–CVD relationship still hold good after properly controlling for features of the metabolic syndrome, including visceral/ectopic fat deposits as measured directly? Some lines of evidence suggest that CRP may capture, at least to a significant extent, the risk associated with excess visceral adiposity/ectopic fat. First, it is well known that CRP levels increase with age (Figure 4). However, when we recently compared nonobese middle-aged individuals with young nonobese 409
Before matching for visceral fat P < 0.0001
1.0 0.5 0.0
1.98 CRP (mg/l)
After matching for visceral fat
2.0 1.5 1.0 0.5
Figure 4 Plasma C-reactive protein (CRP) levels in young vs. middle-aged male subjects before and after controlling for visceral adiposity. These results suggest that the age-related increase in CRP can be prevented by maintaining normal levels of visceral adiposity. NS, nonsignificant. Adapted from Cartier, A. et al., Age‑related differences in inflammatory markers in men: contribution of visceral adiposity, Metabolism 58, 1452–1458 (2009).
Crp: a Risk Marker/Innocent Bystander Or an Active Atherothrombotic Molecule?
The preceding section suggests that the relationship between CRP and CVD events may not necessarily reflect a cause–effect association and that an elevated CRP may often be a marker of a dysmetabolic state associated with “fat stored in the wrong place.” However, there is evidence that CRP may also be a biologically active protein that may play a role in atherothrombotic events. In this regard, in vitro studies with endothelial cells have documented that CRP promotes the production of adhesion 410
1,2 % With inflammation score ≥3
adults who had the same amount of visceral adipose tissue, the age-related difference in CRP was no longer observed, thereby suggesting that the rise is CRP with age is not inevitable, and that it is explained entirely by the age-related increase in visceral adiposity. Second, it is also well known that individuals with poor cardiorespiratory fitness have higher CRP levels.20 However, when we compared individuals with poor fitness levels with those with high fitness levels on the basis of their visceral adipose tissue, the differences in CRP and in composite inflammatory scores between the two groups (Figure 5) were eliminated, suggesting again that visceral adiposity is a key correlate of inflammation, as reflected by CRP levels. Finally, there are numerous factors that influence CRP levels, including steroid hormones. For instance, there is the apparent paradox that women, who are generally at lower CVD risk than men, have higher CRP levels.21 We have recently shown that this genderrelated difference can be explained entirely in terms of the greater accumulation of “healthy” subcutaneous fat in women than in men. Therefore, a given CRP concentration does not imply the same absolute CVD risk in women as in men, and additional studies will be required to derive gender-specific cutoff values for CRP concentration, similar to the gender-specific ones pertaining to HDL-cholesterol levels. Finally, another line of evidence relates CRP to the quality of adipose tissue; thiazolidinediones (TZDs) are known to induce hyperplasia of adipose tissue, boost adiponectin production by adipose cells, and markedly reduce CRP levels.22 Taken together, these results suggest that the relationship between CRP and CVD can be explained, at least to a large extent, by the fact that CRP is a good marker of a dysmetabolic state resulting from visceral adiposity/ectopic fat and of the quality (hyperplastic vs. hypertrophic) of adipose tissue.
60 50 40 30 (2)
20 10 0
2 Visceral adipose tissue (cm )
≥10.7 nes fit ry to ) <10.7 a g ir sp /k re pm dio (k r Ca
Figure 5 Proportion of male individuals with an elevated inflammation score classified on the basis of their levels of cardiorespiratory fitness (50th percentile value) and visceral adipose tissue. The results suggest that the increased inflammation scores found in individuals with poor fitness levels are entirely explained by the fact that these individuals have increased levels of visceral adipose tissue. The inflammation score was defined as the sum of the number of inflammatory markers >50th percentile (C-reactive protein, tumor necrosis factor-α, and interleukin-6) or <50th percentile for adiponectin. 1, 2: Significantly different from the corresponding subgroups. Adapted from ref. 20.
molecules, IL-6, and plasminogen activator inhibitor-1, a potent inhibitor of fibrinolysis and a prothrombotic protein.23,24 Furthermore, CRP is suspected to be involved in the activation of the complement cascade. In fact, experimental evidence suggests that enzymatically modified LDL, which is present in atherosclerotic plaques, may, under certain conditions and with the help of CRP, trigger complement activation.14 In addition, CRP binds to the phosphatidylcholine group of ox-LDL and may thereby promote, at high concentrations, the formation of foam cells by macrophages through the Fcγ receptor. It is therefore likely that visceral adipose tissue—by participating in the recruitment of macrophages, producing cytokines, and activating the liver-derived acute-phase protein, CRP—contributes to an intricate set of inflammatory and metabolic perturbations having, at least in part, interactions with the vascular wall and a role in the development of atherosclerosis. Adipokines and inflammation
Adipokines are specific adipose tissue–derived peptides; they represent a heterogeneous family of molecules having associations with metabolism, inflammation, and possibly CVD. Some of these adipose tissue–derived peptides, such as leptin, have VOLUME 87 NUMBER 4 | aPRIL 2010 | www.nature.com/cpt
state a broad range of actions. Leptin, for instance, in addition to its neuroendocrine functions, is actively involved in energy homeostasis and inflammation. Leptin receptors have been documented to exist on the surfaces of immune cells such as monocytes/macrophages, T cells, and natural killer cells. Patients deficient in leptin are immunodeficient and have a low T-cell count, thymus atrophy, and an impairment of delayedtype hypersensitivity.14,25 In isolated monocytes/macrophages, leptin induces the production of TNF-α and IL-6. In vivo, however, the role of leptin in atherogenesis is far from being clear and fully elucidated. Leptin-deficient ob/ob mice exhibit earlyonset obesity yet are resistant to diet-induced atherosclerosis; however, exogenous administration of leptin reduces adiposity in leptin-deficient children, whereas it has been shown to induce vascular neointimal proliferation in rodents. The West of Scotland Coronary Prevention Study reported that in humans leptin was an independent predictor of CVD.26 However, other studies, including the Quebec Cardiovascular Study, have not found evidence of a significant association between plasma levels of leptin and CVD.27 These inconsistencies may arise from the fact that leptin reflects the amount of total body fat and is a poor marker of regional fat distribution; the latter is certainly a key factor in determining the cardiovascular risk of overweight/ obesity. One view is that leptin levels are relatively low in some obese states (such as in visceral obesity in men as compared with subcutaneous obesity in women) and may not protect against the accumulation of harmful ectopic fat. In this regard, it is important to note that leptin promotes the oxidation of FFAs in various tissues. It is suspected, therefore, that in states of relative leptin deficiency, such as in visceral obesity with low levels of subcutaneous adipose tissue, accumulation of fat occurs in various organs such as the liver, kidneys, and heart.2 Hence, it is possible that, in some individuals, resistance to leptin and/ or a relative deficiency in the production of this adipokine may promote the accumulation of ectopic/visceral fat. Again, such a model is consistent with the absence of ectopic fat in massively obese but “metabolically healthy” women with subcutaneous obesity and with very high plasma leptin levels. It is thus possible that leptin may have an important role the development of CVD, but more investigations are needed to tease out the key mechanisms involved in these processes. Adiponectin is another adipose tissue–specific peptide with a wide array of functions. Over the past decade, a growing number of investigations have underscored the finding that adiponectin has potent anti-inflammatory activity as well as antiatherosclerotic properties.28 Production of adiponectin by fat cells is reduced by TNF-α and vice versa. In addition, circulating adiponectin levels are negatively correlated with visceral adiposity and not with total adiposity.29 In vitro, in isolated leukocytes, adiponectin promotes a Th2 type of response, which is protective against the development of atherosclerosis.30 More specifically, it has been documented that adiponectin lowers interferon-γ production whereas it increases the synthesis of IL-10 and the tissue inhibitor of metalloproteinase-1. In addition, adipo nectin prevents the formation of foam cells by decreasing the expression of class A scavenger receptors. In univariate Clinical pharmacology & Therapeutics | VOLUME 87 NUMBER 4 | APRIL 2010
analyses, epidemiological studies have generally reported that lower adiponectin levels are associated with an increased risk of myocardial infarction in men and with the progression of coronary artery calcification score. A recent study also showed that, in patients with established coronary heart disease, plasma adiponectin concentrations were positively and independently related to the risk of cardiovascular events.31 These discrepancies from clinical observations might be explained by several factors. First, the regulation of adiponectin synthesis may differ between those with established coronary heart disease and those without. Second, the measurement of total or oligomeric forms of adiponectin may explain some variation. In fact, adiponectin circulates in the blood in three main oligomeric forms: a lowmolecular-weight form, a medium-molecular-weight form, and a high-molecular-weight form. It has been found that the ratio of high-molecular-weight/medium-molecular-weight is increased after a weight loss program, whereas the low-molecular-weight level is decreased. Therefore, in addition to patients’ characteristics, there are measurement issues that are unresolved regarding this potentially important adipokine. For instance, several factors remain to be elucidated with regard to the function and levels of the various oligomeric forms of adiponectin in obese patients with or without documented CVD. Resistin, another recently discovered adipose tissue–produced peptide, has been shown to induce insulin resistance in mice, whereas the existence of a corresponding effect in humans is still a contentious issue.32 In mice, resistin is, to a large extent, produced by adipocytes, but in humans it is also secreted by monocytes/macrophages. Resistin is a potent proinflammatory peptide. When injected into the joints of mice it induces arthritis, and it has been documented to be a strong inducer of TNF-α and IL-6 production by monocytes/macrophages through the NF-κB pathway.33 In line with these observations, resistin also promotes the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. Interestingly, resistin is found in atherosclerotic plaques, and its plasma levels correlate with coronary artery calcification scores.34 In calcific aortic valve disease in elderly patients, plasma levels of resistin have been found to correlate with the extent of valvular inflammation.35 Although the biology of resistin and its role in pathological states are not fully understood, several pieces of evidence indicate that it has proinflammatory activity along with possible metabolic implications; however, these remain to be fully understood. PPARγ: a central regulator of adipose tissue distribution, morphology, and metabolic/inflammatory responses
Peroxisome proliferator–activated receptor-γ (PPARγ) is one of a group of lipid-sensing ligand-activated transcription factors that are involved in glucose homeostasis, lipid metabolism, and the control of inflammation. Natural agonists of PPARγ have recently been identified, including metabolites of the polyunsaturated fatty acids such as 13-hydroxyoctadecadienoic acid and 15-deoxy-Δ12,14-prostaglandin J2. Several studies have helped to elucidate some crucial functions of PPARγ in atherosclerosis. PPARγ is present in human atherosclerotic plaques. In animal models, the absence of PPARγ in macrophages exacerbates 411
atherosclerosis, whereas the administration of TZDs, which are potent synthetic PPARγ agonists, results in a lower incidence of atherosclerotic lesions.36 It should be emphasized that PPARγ is also involved in the control of inflammation. In this context, investigations have repeatedly shown that activation of PPARγ decreases the expression of inducible nitric oxide synthase, metalloproteinase-9, IL-1β, IL-6, and TNF-α. Of utmost importance is the finding that PPARγ is an important regulator of adipocyte development (a process that continues even in adult life).10 The ability of adipose tissue to expand by increasing the number of adipocytes (hyperplasia) is a normal response to a chronic state of positive energy balance. Mechanisms that may hamper this response could lead to the accumulation of large and dysfunctional adipocytes (hypertrophy). According to one model, the development of adipose tissue, particularly in the subcutaneous compartment, is a crucial response enabling the body to cope with excess energy intake. Accordingly, experiments conducted with the fatless A-Zip mice, which have no subcutaneous fat depot and are insulin resistant, have been particularly instructive. The injection of mesenchymal white adipocyte precursor cells into lipodystrophic A-Zip mice resulted in the formation of a subcutaneous fat depot, along with normalization of plasma glucose and insulin levels.37 Remarkably, a recent work has documented the presence of PPARγ+ CD24+ adipocyte precursor cells in the vasculature of the adipose tissue.38 Taken together, therefore, these findings suggest that hyperplasia of subcutaneous fat cells from precursor progenitor cells, a process that is under the control of the transcriptional factor PPARγ, is a protective response when energy intake is greater than expenditure. On the contrary, one can assume that processes that would block this latter mechanism during chronic positive energy balance would translate into the accumulation of harmful visceral fat tissue. Accordingly, the administration of TZDs to diabetic patients is associated with an increased accumulation of subcutaneous fat, lower plasma glucose level, increased production of adiponectin by adipose tissue, and a marked reduction in circulating CRP levels, which serve as a marker of inflammation.39 However, it should be emphasized that, despite the overall positive metabolic effects of TZDs, their role in mediating cardiovascular events remains uncertain. Whereas the administration of pioglitazone to patients with type 2 diabetes has been shown to lower the rate of cardiovascular events and death, treatment with rosiglitazone has been associated, in a meta-analysis, with an increase in the rate of cardiovascular-related mortality; however, the methodology of this analysis has been questioned.40 Whether these findings are related to a well-documented side effect of TZDs, namely, precipitation of congestive heart failure in predisposed patients, or whether they are related to a molecule-specific response remains unresolved. Another intriguing phenomenon remains unexplained: if TZDs are so powerful in reducing inflammation and improving several features of the insulin resistance/metabolic syndrome and are associated only with hyperplasia of unharmful subcutaneous adipose tissue, why have the clinical trials conducted to date failed to report spectacular reductions in cardiovascular event rates? Even in the best scenario, the difference between the cardiovascular 412
morbidity/mortality associated with the use of TZDs and that associated with other antidiabetic medications has remained rather modest. A trial (Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE)) currently under way will also test whether there are differences between the two TZDs available in clinical practice. HDL, atherosclerosis, and inflammation
HDLs are a group of heterogeneous particles with a vast array of effects that may protect against atherothrombosis. Most epidemiological studies have reported an association between low plasma HDL-cholesterol levels and coronary heart disease.41 However, it should be pointed out that a low HDL-cholesterol level is rarely observed in isolation in clinical practice, and that it is often associated with the presence of visceral obesity, insulin resistance, and hypertriglyceridemia. Hence, a low HDL-cholesterol concentration is usually an indicator of a dysmetabolic state resulting from the presence of excess visceral/ectopic fat. Among the various biological functions of HDL, reverse cholesterol transport is certainly the one that has received the greatest attention. In fact, apolipoprotein (apo) A1, a major constituent of the HDL particle, interacts with the ATP-binding cassette protein-1 and, in so doing, promotes the efflux of cholesterol from macrophages. Although this efflux of cholesterol to the liver is considered one of the main functions of HDL, recent investigations have contributed to highlighting the complex role of the HDL particle in the inflammatory process.42 In this context, HDL prevents the release of TNF-α and IL-1β from activated monocytes. In addition, apoA1–deficient mice have an increased burden of atherosclerotic lesions along with a higher production of MCP-1. Although these facts point toward an overall beneficial effect of HDL, other observations have cast light on a more complex picture. During the acutephase response, HDLs are proinflammatory and promote the activation and migration of monocytes induced by LDL.43 It is noteworthy that patients with coronary artery disease and normal/high plasma levels of HDL have dysfunctional particles with a reduced anti-inflammatory activity. Furthermore, in patients with excess visceral fat, HDLs have a core enriched in triglycerides and depleted in cholesteryl esters, leading to the formation of small HDL particles that also have lower antioxidative properties. In addition, oxidative modification of apoA1 reduces the efficiency of reverse cholesterol transport. Recently, a randomized trial with torcetrapib, a cholesteryl ester transfer protein inhibitor that substantially raises HDL-cholesterol levels, has thrown a glimmer of light on the complex biology and role of HDLs. In this trial, despite a spectacular elevation of HDL-cholesterol concentration, treatment with torcetrapib was associated with an increase in mortality rate.44 Although this appeared to be explained by an off-target effect of torcetrapib on blood pressure, it is also possible that the very large HDL particles generated by cholesteryl ester transfer protein inhibition were dysfunctional after the treatment. A major question that arises from these observations is whether HDL is just a surrogate marker or an active player with a possible dual role in atherosclerosis: one in preventing and the other in promoting VOLUME 87 NUMBER 4 | aPRIL 2010 | www.nature.com/cpt
Renin angiotensin, a complex, integrated system linking obesity, inflammation, hypertension, and insulin resistance
One consistent observation is that visceral obesity is associated with hypertension, an important cardiovascular risk factor.45 Several mechanisms, which have clinical implications, could explain this relationship. Among these mechanisms, the renin–angiotensin system deserves attention because it plays an important role in the regulation of blood pressure. Seminal studies have brought to light the fact that fat cells produce angiotensinogen, which is ultimately used to form angiotensin II, a powerful vasoconstrictor. In turn, angiotensin II has been demonstrated to prevent the differentiation of preadipocytes into well-differentiated mature adipocytes.45 By this process, the activated renin–angiotensin system in viscerally obese subjects could promote the hypertrophy of the fat cells. In turn, large adipocytes are hyperlipolytic and secrete more angiotensinogen. Under this model, visceral obesity and the renin–angiotensin system are engaged in a vicious circle leading to deleterious consequences such as inflammation, hypertension, and a dysmetabolic state. In apoE−/− mice, a model prone to atherosclerosis, elevated angiotensin II levels were shown to promote the development of vulnerable plaques with a larger lipid core and higher cellular inflammatory content.46 Similarly, the administration of angiotensin II in rats stimulated a T-helper 1 type of response, which could be explained by the presence of angiotensin II type 1 receptor on immune cells. Whether or not the excess visceral fat is a critical component of the hypertensive state is still being debated, but accumulating evidence indicates that it is certainly one of the major players. In the Quebec Health Survey, which involved 1,844 adult subjects, it was clearly shown that variation in waist circumference had a much greater impact on the blood pressure than BMI did (Figure 6).47 Furthermore, it was found that the relationship between blood pressure and fasting insulinemia, as a convenient marker of insulin resistance, was completely explained by the concomitant variation in waist circumference as an epidemiological marker of abdominal adiposity. These observations, along with more recent results from our laboratory, suggest that metabolic processes that are related to an excess of visceral adipose tissue contribute to the elevated blood pressure observed in sedentary individuals with poor levels of cardiorespiratory fitness.48 An equally important finding emerged from a study by Engeli et al. In a cohort of women undergoing a weight-loss program, the decline in blood pressure was related to the reduction in waist circumference and not to the reduction in BMI.49 That same study produced the particularly insightful finding Clinical pharmacology & Therapeutics | VOLUME 87 NUMBER 4 | APRIL 2010
<88 cm ≥88 cm 135 Systolic blood pressure (mm Hg)
deleterious atheroinflammatory responses. This “Janus face” of HDL, which makes it a potential friend or foe, may account for some of the discrepancies between epidemiological observations and results of pharmacological interventions. However, it should be stressed that, until data from further studies are available on pharmacologically induced HDL elevation and associated CVD risk, a low HDL-cholesterol level should continue to be considered a convenient, reliable, and powerful blood marker of a dysmetabolic state and an elevated CVD risk.
120 115 110
BMI tertiles (kg/m2)
Figure 6 Systolic blood pressure in male subjects, classified on the basis of their body mass index (BMI, index of total adiposity) and waist circumference (marker of abdominal adiposity). 1, 2, 3: Significantly different from the corresponding subgroups. Adapted from ref. 47.
that the decline in angiotensinogen was, to a large extent, explained by the decrease in waist circumference. Together, these studies provide evidence that expanded visceral adipose tissue could make a direct contribution to variation in blood pressure, leading to hypertension. These results may explain why the renin–angiotensin system has also been related to insulin resistance.45 Integrating Visceral Adiposity Into the Inflammation–Cvd Paradigm: Clinical Implications
In the mid-twentieth century, Jean Vague, a French physician, made an important clinical observation that went largely unnoticed at the time. He noticed that body fat distribution, rather than excess body weight per se, was one of the key components associated with the presence of diabetes mellitus and CVD.50 Even at that time, he had put forward the concept that android obesity (upper body obesity) was associated with the risk of developing metabolic dysfunction conditions such as diabetes, CVD, and gout. Of course, obesity per se does increase the risk of developing insulin resistance and glucose intolerance, but in the majority of overweight/obese patients the risk of developing type 2 diabetes is clearly more closely related to the amount of visceral adipose tissue. Although many studies had shown the added value of measuring waist circumference as a simple but useful approach to estimating abdominal-fat accumulation, some investigators remained skeptical about the feasibility of implementing a reliable measurement of waist circumference in clinical practice. To address this issue, an international study was conducted, involving 6,400 primary care physicians in 63 countries (the IDEA (International Day for the Evaluation of Abdominal Obesity) study).51 In the course of the IDEA study, physicians were asked to measure their patients’ weight and height and to report their clinical status. Furthermore, they received a video presentation describing the proper method of measuring waist circumference. In this simple but large-scale international study, which evaluated 168,000 patients on five continents, it was clearly found that, independent of BMI, 413
Frequency with diabetes (%)
waist circumference, which is a crude marker of abdominal fat accumulation, was consistently associated with the prevalence of type 2 diabetes (Figure 7). In addition, at any given BMI value, patients with diabetes had a higher waist circumference, showing once again the clear discriminating value of the waist measurement. Studies that have used imaging techniques such as computed tomography or magnetic resonance have revealed that this association between risk of diabetes and enlarged waist circumference is attributable mainly to visceral adipose tissue accumulation, which has been shown to be a major risk factor for the development of type 2 diabetes.52 In this regard, an elevated CRP concentration as a marker of inflammation has been shown to be predictive of an increased risk of diabetes.53 However, the question remains: is inflammation per se related to the risk of diabetes, or is it rather a specific form of inflammation, related to visceral obesity/ectopic fat deposition, that predicts diabetes risk? Several studies have underscored the fact that FFAs, TNF-α, and IL-6 prevent the phosphorylation of insulin receptors and thereby hamper the insulin cascade signaling pathway.54 In skeletal muscle,
FFAs and acyl‑coA derivatives such as ceramide prevent the phosphorylation of Akt and thereby limit the action of insulin. Also, TNF-α contributes to insulin resistance by preventing the synthesis of several key molecules such as glucose transporter type 4 (GLUT-4), PPARγ, and adiponectin, to name a few. Paradoxically, insulin resistance is often associated with increased gluconeogenesis; this is promoted by the FFAs and by TNF-α, possibly through the protein kinase-c and c-jun N-terminal kinase-1, respectively. In animals, the administration of adiponectin lowers glycemia and plasma levels of FFAs, and it enhances glucose utilization by skeletal muscle and the liver.55 In the liver, adiponectin decreases glucose production, whereas it increases the oxidation of FFAs, the translocation of GLUT-4, and the expression of sterol-regulatory-element binding protein 1C, a critical transcription factor that controls the genes involved in lipid synthesis. Although insulin is elevated in abdominal obesity, at least during the initial phase, it is widely accepted that type 2 diabetes is related to a dual mechanism of insulin resistance and a relative deficit in insulin secretion. Consequently, in the presence of insulin resistance, decreased pancreatic β-cell function is also a crucial feature of type 2 diabetes. Chronically elevated levels of TNF-α and FFAs are known to lower insulin secretion by pancreatic β-cells.56 Among the proposed mechanisms, the accumulation of FFAs and the long-chain fatty acyl-CoA allow the opening of potassium channels and the expression of uncoupling protein 2, which limits the availability of ATP for β-cells, two factors known to decrease insulin production. The increase in the levels of FFAs also contributes to apoptosis of β-cells through a decreased expression of antiapoptotic factor Bcl-2; this, in turn, translates into a loss of insulin-producing cells. Hence, it is likely that inflammation and dysfunctional visceral adipose tissue are jointly involved in promoting insulin resistance/diabetes through several mechanisms involving inflammation and a hyperlipolytic state.
20 15 10 5 0
Waist circumference (cm)
2) ≥30 25–30 kg/m ( y r o eg cat MI
Figure 7 Prevalence of diabetes in subjects of the IDEA study, classified on the basis of their body mass index (BMI) and waist circumference. IDEA, International Day for the Evaluation of Abdominal Obesity. Adapted from ref. 51.
Inflammation ↑ CRP
↑ Risk of type 2 diabetes and cardiovascular disease
Visceral obesity/ectopic fat
Figure 8 Schematic summary of the concept that the relationship between inflammation (as globally assessed by C-reactive protein (CRP) in clinical practice) and the risk of developing diabetes and cardiovascular disease may not necessarily reflect a cause–effect relationship but rather may be the consequence of an unfavorable adipose tissue phenotype (excess visceral obesity/ectopic fat) leading to both inflammation and diabetes/cardiovascular disease. 414
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state On the basis of these complex interactions, it remains uncertain whether a chronic state of inflammation, in the absence of visceral obesity/excess ectopic fat, truly increases the risk of type 2 diabetes and CVD (Figure 8). Regarding inflammation and CVD, a landmark study was the JUPITER trial, in which more than 16,000 asymptomatic individuals with “normal” LDLcholesterol but elevated CRP levels were randomized to receive either a statin (rosuvastatin) or a placebo.57 Because of a marked benefit of statin therapy on CVD outcomes, the trial was prematurely interrupted by the safety monitoring committee. The study showed that asymptomatic individuals in whom both LDL-cholesterol and CRP levels were lowered benefited the most from rosuvastatin therapy. Given that statins have both LDLcholesterol-lowering and anti-inflammatory properties, we do not know whether reducing CRP levels without concomitantly reducing LDL-cholesterol would translate into clinical benefits. However, because the JUPITER study validated the hypothesis that a large segment of asymptomatic and apparently low-risk individuals could benefit from statin therapy if they had elevated CRP concentrations, these results have forced the medical community to debate the role of statins in the primary prevention of CVD in apparently low-risk individuals with evidence of inflammation. In the context of this review, it would be important to achieve a better understanding of the key drivers of elevated CRP concentrations in the JUPITER population. Although numerous correlates of CRP levels have been identified, it should be kept in mind that abdominal obesity associated with excess visceral adipose tissue/ectopic fat, and with features of what has been called the metabolic syndrome, is by far the most prevalent cause of increased CRP levels. Lifestyle-modification studies have clearly shown that weight loss can reduce CRP levels. Therefore, the question remains: should we put a large proportion of our asymptomatic sedentary adult population who are unfit/overweight/viscerally obese on statin therapy, or should we attempt to vigorously improve their physical activity/nutritional habits? Conclusion
On the basis of what we have learned over the past two decades about the metabolic/endocrine properties of adipose tissue, it is hoped that the medical community and other health professionals will better recognize that excess visceral adiposity/ectopic fat is probably the key missing link between inflammation and CVD and type 2 diabetes (Figure 8). The landscape of modifiable risk factors has changed over the past 50 years. There have been reductions in blood pressure, smoking, and cholesterol levels but marked increases in the incidence of sedentary lifestyles and overconsumption of calories, leading to an epidemic of obesity and type 2 diabetes. Against this background, reducing excess adiposity, visceral obesity, and ectopic fat is probably the key therapeutic target to achieve a reduction in the residual burden of CVD associated with present-day sedentary lifestyles. Conflict of Interest The authors declared no conflict of interest. © 2010 American Society for Clinical Pharmacology and Therapeutics
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Although the metabolic dysfunctions that are traditionally related to obesity are determined by several factors, it should be emphasized tha...