Obesity, Inflammation, and Cardiovascular Risk

state nature publishing group art Obesity, Inflammation, and Cardiovascular Risk P Mathieu1,2, I Lemieux1 and J-P Després1,3 Obesity, a highly prev...
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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 protected]) 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

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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

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Hypertrophic obesity Altered cytokine secretion profile •↓ Adiponectin •↑ TNF-α •↑ IL-6 ICAM-1 Selectins HSPs, etc. Endothelium and other cells

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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

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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

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3.0 2.5 2.0 1.5 (2)

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≥27.0

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