Inflammation, Insulin Resistance, and Obesity Patrizia Ferroni, MD, PhD, Stefani Basili, MD, Angela Falco, MD, and Giovanni Davì, MD*
Address *Center of Excellence on Aging, Via colle dell’Ara, 66013 Chieti, Italy. E-mail:
[email protected] Current Atherosclerosis Reports 2004, 6:424–431 Current Science Inc. ISSN 1523-3804 Copyright © 2004 by Current Science Inc.
Obesity, in particular visceral obesity, has strong associations with cardiovascular disease and is related to many factors that are constituents of the metabolic syndrome. Increasing evidence suggests that features of the metabolic syndrome, including visceral obesity, are associated with a low-grade inflammatory state. Indeed, visceral fat is a source of several molecules, such as leptin, adiponectin, tumor necrosis factor-α, and interleukin 6, that are collectively called adipokines. All of them may induce a proinflammatory state and oxidative damage, leading to initiation and progression of atherosclerosis. Reducedenergy diets might represent an effective and healthful approach for long-term weight loss in patients with metabolic syndrome by reducing the underlying inflammatory condition.
Introduction The prevalence of obesity is increasing rapidly in the developed world, where it constitutes a major public health challenge. Overweight and obesity are commonly defined on the basis of body mass index (BMI), which is computed as body weight (kilograms) divided by height (meters) squared, because this measurement correlates strongly with total body fat content in adults [1]. However, BMI fails to consider body fat distribution. The importance of the central distribution of body fat has been known since the 1950s, when Morris [2] described increased cardiac deaths in London bus drivers with large belt sizes, in contrast to leaner, more active bus conductors. In 1956, Vague [3] suggested that android (central and upper body) distribution of fat contributed to diabetes and atherosclerosis. Since then, many studies suggested that visceral fat (referred to as visceral or central obesity) is the most predictive factor of the metabolic syndrome and increased cardiovascular risk and, because of this association, it has been pro-
posed to use the waist-to-hip ratio (WHR) in addition to, or instead of, BMI [1]. Increased WHR ratios have been associated with stroke and ischemic heart disease in men [4,5] and were found to be the strongest anthropometric predictors of cardiovascular disease (CVD) and death in women [6,7]. The data for men and women were also combined (with statistical adjustment for different methods) to support the hypothesis that visceral fat distribution might explain the sex difference in the frequency of heart attacks [8]. This is an issue that has been recently reconsidered by Welborn et al. [9], who confirmed that WHR ratio is the major obesity-related determinant of CVD-related death, and that this measure accounts for much of the sex difference in incidence of CVD [9]. The relationship between visceral obesity and CVD appears to develop at a relatively young age, as demonstrated by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study [10], organized in 1985 to examine the effects of risk factors for adult CVD on atherosclerosis in autopsied persons aged 15 to 34 years who died of external causes. This study demonstrated that obesity in young men, as defined by BMI, is associated with the incidence of coronary lesions. The potential importance of visceral obesity compared with peripheral obesity was not appreciated when this study began, thus no specific measures were included. However, the results obtained clearly demonstrated that the effect of BMI on coronary lesions was greater among men with a thick panniculus adiposus (ie, men with a central pattern of adiposity) [10]. The Bogalusa Heart study [11] showed positive associations between obesity in childhood and/or adolescence and an adverse cardiovascular risk profile at young adulthood, whereas other reports showed that childhood obesity is positively related to cardiovascular morbidity and mortality years hereafter [12]. Visceral obesity is associated with a litany of factors that are constituents of the metabolic syndrome, many of which are independent risk factors for CVD [1]. Obesity has been associated with increased coagulability, endothelial dysfunction, and inflammation, as well as more conventional CVD risk factors such as insulin resistance [1]. This article discusses obesity as a trigger of low-grade inflammation, linking obesity to the insulin resistance and dyslipidemic syndrome commonly known as the “metabolic syndrome.”
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The Metabolic Syndrome Many organizations have recommended clinical criteria for the diagnosis of the metabolic syndrome [13–15,16••]. Their criteria are similar in many aspects, but they also reveal fundamental differences in positioning of the predominant causes of the syndrome (Table 1), which is mainly characterized by visceral obesity, insulin resistance with or without glucose intolerance, and dyslipidemia.
Visceral obesity Obesity, in particular visceral obesity, correlates with metabolic risk factors. Adipose tissue is recognized as a source of several molecules (Fig. 1) that apparently exacerbate these risk factors, such as nonesterified fatty acids (NEFA), cytokines, α-1 acid glycoprotein, serum amyloid A3, adiponectin, and plasminogen activator inhibitor-1 (PAI-1) [16••]. However, the mechanisms underlying the association between visceral obesity and the metabolic syndrome are complex and not yet fully understood. It has been assumed that elevated plasma concentrations of NEFA overload muscle and liver with lipids, which enhances insulin resistance. High C-reactive protein (CRP) levels accompanying obesity may signify cytokine excess and a proinflammatory state. An elevated PAI-1 contributes to a prothrombotic state, whereas low adiponectin levels that accompany obesity correlate with worsening of metabolic risk factors. Other proteins are also associated with obesity. Resistin is an adipocyte-secreted hormone that impairs glucose homeostasis and insulin action in the mouse. Although specifically seen in rodents, there are related types of this protein seen in fat cells in humans [17]. Adiponectin, a recently described adipokine of emerging importance, is distinct from other known adipokines in that it alone among them appears to improve insulin sensitivity and inhibits vascular inflammation [18]. Serum adiponectin levels are low in obese patients but increase upon weight loss [19]. Leptin has also been implicated in insulin resistance [20], and Guagnano et al. [21] have recently suggested that it might have proatherogenic effects in vivo, with a mechanism involving endothelial cell activation. Furthermore, serum leptin levels are directly related to 24hour blood pressure levels in normotensive women with visceral fat distribution, independent of BMI [22]. More recently, it has been demonstrated that fasting plasma levels of ghrelin, an orexigenic peptide that antagonizes leptin action, are associated with visceral obesity or insulin resistance [23]. Insulin resistance Insulin resistance is widely believed to be at the heart of the metabolic syndrome. Numerous studies documented the inverse relationship between BMI and insulin sensitivity, suggesting that obesity is a cause of insulin resistance. Nonetheless, many investigators have placed a greater priority on insulin resistance than on obesity in the definition of metabolic syndrome, arguing that insulin resistance or
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its accomplice, hyperinsulinemia, directly causes other metabolic risk factors [14]. The metabolic abnormalities associated with insulin resistance favor proliferation, inflammation, and plaque formation through two essential cell pathways. The first is the phosphatidylinositol 3-kinase pathway, which is associated with the metabolism of insulin (causing glucose transport, glycogen synthesis, and lipid metabolism) and also plays a role in the anti-inflammatory effects of insulin and the release of nitric oxide, leading to vasodilatation [24]. The second is the mitogen-activated protein kinase, which is associated with cell growth and proliferation. With insulin resistance, the effects of the former are reduced, whereas the latter is unchanged, thus shifting the balance toward cell proliferation and increased inflammation [24]. Signaling molecules secreted by adipose tissue may play a major role in the development of insulin resistance. This was first appreciated in the mid 1990s with the discovery of leptin. That other secretory products of the adipocyte, including the inflammatory cytokine tumor necrosis factor-α (TNF-α), might control insulin sensitivity was lately suggested by the work of Hotamisligil [25•], who demonstrated that when TNF-α activity is blocked in obesity, either biochemically or genetically, the result is improved insulin sensitivity. Thus, dissociation of obesity and primary insulin resistance in patients with metabolic syndrome is still difficult [14].
Dyslipidemia An atherogenic switch of the lipid pattern in the metabolic syndrome manifests in routine lipoprotein analysis by elevated concentrations of triglycerides and low levels of high-density lipoprotein (HDL) cholesterol. A more detailed analysis may reveal other lipoprotein abnormalities, such as increased remnant lipoproteins, elevated apolipoprotein B, small low-density lipoprotein (LDL) particles, and small HDL particles. All of these abnormalities have been implicated as being independently atherogenic [16••]. Underlying, major, and emerging risk factors These components of the metabolic syndrome constitute a particular combination of what the National Cholesterol Education Program’s Adult Treatment Panel III report (NCEP-ATP III) terms underlying, major, and emerging risk factors. According to this report, underlying risk factors for CVD are obesity (especially visceral obesity), physical inactivity, and atherogenic diet. Major risk factors are cigarette smoking, hypertension, elevated LDL cholesterol, low HDL cholesterol, family history of premature CVD, and aging. Emerging risk factors include elevated triglycerides, small LDL particles, insulin resistance, glucose intolerance, proinflammatory state, and prothrombotic state. Among these, NCEP-ATP III identified six components of the metabolic syndrome that relate to CVD: 1) visceral obesity, 2) atherogenic dyslipidemia, 3) raised blood
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Table 1. Clinical criteria for the identification of the metabolic syndrome NCEP-ATP III
World Health Organization
AACE
Abdominal obesity defined as a waist circumference > 102 cm in men and > 88 cm in women Triglycerides > 150 mg/dL HDL cholesterol < 40 mg/dL in men and < 50 mg/dL in women BP ≥ 130 / ≥ 85 mm Hg Fasting glucose ≥ 110 mg/dL
Type 2 diabetes Impaired fasting glucose, impaired glucose tolerance, plus any 2 of the following: BP ≥ 140 / ≥ 90 mm Hg or antihypertensive drugs Triglycerides ≥ 150 mg/dL HDL cholesterol < 35 mg/dL in men and < 39 mg/dL in women BMI > 30 and/or WHR > 0.9 in men, > 0.85 in women Urinary albumin excretion rate ≥ 20 µg/min or albumin:creatinine ratio ≥ 30 mg/g
Obesity defined as BMI ≥ 25 Triglycerides ≥ 150 mg/dL HDL cholesterol < 40 mg/dL in men and < 50 mg/dL in women BP ≥ 130 / ≥ 85 mm Hg 2-hour post-glucose challenge > 140 mg/dL Fasting glucose between 110 and 126 mg/dL Family history of type 2 diabetes, hypertension, or CVD; sedentary lifestyle, advancing age
AACE—American Association of Clinical Endocrinologists; BMI—body mass index; BP—blood pressure; CVD—cardiovascular disease; HDL—high-density lipoprotein; NCEP-ATP III—National Cholesterol Education Program Adult Treatment Panel III; WHR—waist-to-hip ratio. Figure 1. Visceral fat represents an important source of bioactive molecules that might contribute to insulin resistance (IR) and impaired glucose homeostasis, as well as inflammation. Among them, tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) play a pivotal role in determining a low-grade inflammatory response. Moreover, other molecules (ie, resistin and adiponectin) have been related to vascular inflammation in obesity, eventually leading to IR. The latter has been also associated with increased production of orexigenic peptides produced by adipocytes, such as leptin and ghrelin, although their mechanisms of action are incompletely understood. On the other hand, the release of large amounts of nonesterified fatty acids (NEFA) may result in resistance to insulin signaling in skeletal muscle and liver because of lipid overload. Elevated levels of plasminogen activator inhibitor-1 (PAI-1) contribute to establish a prothrombotic condition acting in concert with the endothelial dysfunction driven by inflammatory cytokines.
pressure, 4) insulin resistance with or without glucose intolerance, 5) proinflammatory state, and 6) prothrombotic state [13]. Visceral obesity, recognized by increased waist circumference, is the first criterion listed, and its inclusion reflects the priority given to this factor as a contributor to the metabolic syndrome. However, NCEPATP III criteria for metabolic syndrome differ somewhat from those of other organizations (Table 1). The World Health Organization (WHO) also recognizes CVD as the primary outcome of the syndrome; however, it viewed insulin resistance as the main contributor [14]. Furthermore, BMI (or increased WHR) was used instead of waist circumference. The American Association of Clinical Endocrinologists [15] proposes a third set of clinical criteria for the insulin resistance syndrome, similar to those of NCEP-ATP III and WHO classification.
However, no defined number of risk factors is specified and diagnosis is left to clinical judgment (Table 1). Consequently, the National Heart, Lung, and Blood Institute, in collaboration with the American Heart Association, convened a conference to examine scientific issues related to definition of the metabolic syndrome [16••]. For this conference, Framingham investigators were asked to examine their extensive database for the relation between metabolic syndrome and future development of both CVD and diabetes. The results of this analysis indicated that no advantage is gained in risk assessment by adding the unique risk factors of the NCEP-ATP III metabolic syndrome to the usual Framingham risk factors [16••]. On the other hand, when the risk for new-onset diabetes was examined for the Framingham cohort in both men and women, the presence of the metabolic syndrome
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was highly predictive of new-onset diabetes. Conference participants agreed that CVD is the primary clinical outcome of metabolic syndrome, and that therapeutic lifestyle change, with emphasis on weight reduction, constitutes first-line therapy for metabolic syndrome [16••]. In this context, NCEP-ATP III criteria were acknowledged as a practical tool to identify patients at increased risk for CVD.
Inflammation: The Link Between Obesity and Insulin Resistance As reported here, the development of the concept of inflammation in relation to metabolic conditions, such as obesity and insulin resistance, started with the pioneering work of Hotamisligil et al. [26] in 1993, which demonstrated that adipocytes of obese animals constitutively express TNF-α and that neutralization of TNF-α by its soluble receptor also leads to a decrease in insulin resistance in these animals. These observations provided the first link between an increase in the expression of a proinflammatory cytokine and insulin resistance. Later data showed that the adipose tissue in humans also expressed TNF-α constitutively and that its expression fell after weight loss [27]. Similar observations were made with respect to plasma TNF-α concentrations [28]. Since then, increasing evidence is accumulating suggesting that features of the insulin resistance syndrome, including visceral obesity, are associated with a low-grade inflammatory state, as indicated by increased CRP levels [29]. CRP, an acute-phase reactant, is currently recognized as one of the key features of metabolic syndrome [14] and an important atherothrombotic risk factor [30]. In nondiabetic subjects enrolled in the Insulin Resistance Atherosclerosis Study (IRAS) [31], CRP levels were significantly correlated with BMI, waist circumference, systolic blood pressure, fasting glucose, fasting insulin, and insulin sensitivity. In addition, the level of CRP was strongly correlated with the number of metabolic disorders (dyslipidemia, upper body adiposity, insulin resistance, and hypertension) [31]. Impaired insulin sensitivity may lead to enhanced CRP expression by counteracting the physiologic effect of insulin on hepatic acute-phase synthesis [32]. Alternatively, the expanded abdominal fat depot may be responsible for a lowgrade inflammatory state, by providing a source of increased production of interleukin 6 (IL-6), a potent stimulus to CRP synthesis by the liver (Fig. 1). Indeed, abdominal vein concentrations of IL-6 were found to be three- to fourfold higher than arterial concentrations [33], leading the authors to speculate that if IL-6 production is similar in all adipose regions, one can estimate that up to one third of circulating IL-6 in healthy subjects might derive from adipose tissue [34]. Novel data have now appeared showing that the concomitant presence of promoter polymorphisms of TNF-α (G-308A) and IL-6 (C-124G) in obese subjects with impaired glucose tolerance carry twice the risk of conver-
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sion to type 2 diabetes when compared with other genotypes [35]. A G-308A mutation of the TNF-α promoter is associated with increased plasma TNF-α concentrations and a twofold higher risk of developing diabetes compared with noncarriers, whereas a C-124G mutation of the IL-6 promoter increases the risk for insulin resistance [36•]. One other mechanism that might connect insulin resistance and atherosclerosis is the anti-inflammatory and potential anti-atherosclerotic effect of insulin, which in the presence of resistance will lead to a proinflammatory state. As stated previously, insulin exerts an anti-inflammatory effect at the cellular and molecular level both in vitro and in vivo, as demonstrated by the experimental finding that a low-dose infusion of insulin reduces reactive oxygen species generation by mononuclear cells, suppresses nuclear transcription factor-κB binding, and induces the expression of the inhibitory protein IκB, thus preventing the transcription of inflammation-related oxidant-sensitive genes [36•]. It is interesting in this light that insulin sensitizers of the thiazolidinedione class are also antiinflammatory, because they are capable of decreasing the plasma concentrations of both TNF-α and CRP [36•]. The pivotal role of excess body fat (especially visceral fat) in determining a low-grade inflammatory condition is also supported by observations of Hotamisligil [37] on the “fat body” of the fruit fly Drosophila melanogaster, a rather unique organ that functions at once as liver and hematopoietic/immune system, and that also appears as the mammalian homologue of adipose tissue. In an elegant study, Tong et al. [38] demonstrated that despite substantial changes in the architecture and the molecular complexity of adipose tissue, the biology of GATA transcription factors at this site has been preserved from the fruit fly to the mouse. The individualization of the hepatic, adipose, and hematopoietic/immune organs occurred during phylogeny, but the function of a common network of functional and molecular pathways were retained in all, which might account for the presence of so many overlapping pathways in the hepatocyte, adipocyte, and macrophage. Depending on the cell type, the action of these overlapping pathways will produce end points, such as insulin resistance (adipocyte), atherosclerosis (macrophage), or hyperlipidemia (hepatocyte) [37]. Two recent articles by Xu et al. [39••] and Weisberg et al. [40••] report that macrophages infiltrate adipose tissue in states of obesity. These findings contribute to the current notion of a role for adipocytes in inflammatory pathways, demonstrating that fat tissue from obese mice had a gene expression profile reminiscent of that of macrophages. Moreover, the largest class of genes significantly regulated in obesity was related to macrophage biology. Importantly, Weisberg et al. [40••] also provide evidence that macrophage infiltration of adipose tissue is characteristic of human obesity, demonstrating that both BMI and average adipocyte size were significant predictors of macrophage accumulation in adipose tissue. Whether
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macrophage infiltration is a cause or effect of obesity is unclear from these studies, although at present it is conceivable to hypothesize that it reflects a response to the abnormal fat metabolism caused by the increasing adiposity. As stated previously, visceral fat is currently recognized as an important source of bioactive molecules. Among them, adiponectin is thought to inhibit adhesion of macrophages to endothelial cells, a crucial step in the pathogenesis of atherosclerosis. Furthermore, leptin promotes cholesterol ester synthesis in macrophages under hyperglycemic conditions, an important process in the formation of foam cells in fatty streaks and advanced lesions. Finally, complement factor C3, a macrophage chemotaxin, is highly expressed in adipocytes, as it is in the case of monocyte chemotactic protein-1 [39••]. Once macrophage activation and infiltration is initiated, the inflammatory response proceeds with further lymphokine production and secretion, eventually leading to increased adipocyte lipolysis, production of NEFA, and resistance to insulin signaling in skeletal muscle and liver [16••]. Another exciting hypothesis could be that the significant changes in the turnover rate of other bioactive substances released by the fat cells expose the vasculature in adipose tissue to oxidative injury or endothelial dysfunction to which macrophages respond [41]. Finally, we must also consider that a low-grade inflammatory state, such as that found in obesity and insulin resistance and characterized by increased levels of proinflammatory molecules and acute phase proteins, is also associated with an elevated procoagulant activity and a reduced fibrinolytic potential that may enhance the risk for cardiovascular events [30,34]. Indeed, Romano et al. [42] have recently provided evidence of a close relationship between insulin sensitivity and coagulative activation in obesity and have suggested that inflammatory cytokines may represent a biochemical link between insulin resistance, prothrombotic state, and an increased risk for cardiovascular disease.
Obesity and Oxidative Stress Oxidative damage has been indicated as a feature of many risk factors for premature atherosclerosis, such as diabetes, hypertension, and smoking, as well as obesity [43]. To date, measurement of F2-isoprostanes is the most accurate method to quantify oxidant stress in humans [44]. Levels of 8-iso-prostaglandin F 2α (8-iso-PGF 2α) are most frequently measured in human body fluids, such as plasma or urine, but the ex vivo artifactual formation of unmetabolized compounds resulting from auto-oxidation of lipids is less likely in urine than in plasma, making the former a more suitable marker of in vivo lipid peroxidation [44]. BMI was highly associated with urinary 8-iso-PGF 2α excretion in nearly 3000 subjects from the Framingham Heart Study [45]. The effect of BMI was minimally affected by blood glucose and diabetes, a finding consistent with an
important role of oxidative stress in the deleterious impact of obesity on cardiovascular disease [45]. In a study in 2002, we [46] tested the hypothesis that lipid peroxidation and platelet activation are increased in obese women in the absence of other known cardiovascular risk factors. Obese women had higher levels of lipid peroxidation and platelet activation when compared with age-matched non-obese women. Android obesity was associated with fourfold higher rate of thromboxane (TX) metabolite excretion than measured in non-obese women, with a linear relationship between the excretion rates of 8-iso-PGF2α and 11-dehydro-TXB2. Similar findings were obtained by Urakawa et al. [47], who showed that circulating levels of 8-iso-PGF2α are related to adiposity and insulin resistance in men [47]. Although both hyperinsulinemia and increased leptin production may trigger increased generation of oxygen radicals, possibly contributing to enhanced lipid peroxidation, a multiple regression analysis indicated that CRP levels and WHR predicted the rate of 8-iso-PGF2α excretion independently of insulin and leptin levels [46]. Furthermore, when plasma CRP concentrations were divided into quartiles, the excretion rates of 8-iso-PGF2α and 11dehydro-TXB2 significantly increased from the first to the fourth quartile [46]. Of interest, the association found between CRP and 8-iso-PGF 2α was sustained by the presence of visceral obesity and was less evident in women with gynoid obesity (Fig. 2). Thus, taken together, these observations suggest that a low-grade inflammatory state associated with abdominal adiposity may be the primary trigger of TX-dependent platelet activation mediated, at least in part, through enhanced lipid peroxidation.
Effects of Weight Loss on Inflammation and Oxidative Stress Further evidence for a cause-and-effect relationship between obesity and persistent low-grade inflammation was obtained through diet-induced weight-loss programs. Obesity guidelines stress the need for weight reduction using behavioral change to reduce caloric intake and increasing physical activity. Years of study and clinical experience suggest that reduced-energy diets, consisting of a modest 500- to 1000-cal/d reduction, represent an effective and healthful approach for long-term weight loss. A realistic goal for weight reduction is to reduce body weight by 7% to 10% over a period of 6 to 12 months. In the study cited previously, we examined the shortterm effects of a weight-loss program by assessing in android obese women changes in oxidant stress and inflammatory markers associated with caloric restriction [46]. Successful weight loss was associated with statistically significant reductions in CRP levels and in urinary 8-iso-PGF2α and 11-dehydro-TXB2 excretion rates [46]. Failure to achieve a significant weight loss provided an interesting control group that demonstrated the
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Figure 2. Spearman rank correlation analysis of C-reactive protein (CRP) plasma levels and urinary excretion rates of 8-iso-prostaglandin F2a (8-isoPGF2a) in obese women with gynoid (panel A) or android (panel B) obesity. A marked correlation between lipid peroxidation (evidenced by increased levels of 8-iso-PGF2a) and inflammation (evidenced by increased levels of CRP) is detected in women with android obesity, whereas only a trend to correlate is observed in women with gynoid obesity, thus corroborating the current idea that android (ie, visceral) more than gynoid (ie, peripheral) obesity is related to oxidant stress and low-grade inflammation, eventually leading to increased cardiovascular risk.
reproducibility of these biochemical indexes over time in the presence of constant body weight. A randomized controlled trial of lifestyle changes was subsequently designed by Esposito et al. [48] to obtain a sustained and long-term reduction of body weight (by 10% or more maintained for 2 years) for evaluating the effect of weight loss on markers of vascular inflammation. The results obtained demonstrated that there was a significant decrease of serum concentrations of IL-6, IL-18, and CRP accompanied by an increase of adiponectin levels after 2 years of follow-up. However, this study provided a multidisciplinary approach, combining a low-energy Mediterranean-style diet and increased physical activity, and the population recruited consisted of healthy premenopausal obese women. This may explain the different results obtained by You et al. [49], who sought to investigate whether a hypocaloric diet with and without exercise training is effective in reducing plasma CRP, IL-6, and TNF-α in obese postmenopausal women (diet alone, n = 17; diet plus exercise, n = 17). The authors showed that diet plus exercise, but not diet alone, is effective in reducing chronic inflammation in obese postmenopausal women, as indicated by a significant reduction of plasma CRP and IL-6 levels [49]. The effects of diet-induced weight loss and exercise on markers of chronic inflammation were also investigated by Nicklas et al. [50] on overweight or obese men and women aged 60 years or more. In this study, the diet-induced weight-loss intervention resulted in significantly higher reductions in CRP and IL-6 concentrations than did no weight-loss treatment. On the other hand, exercise training did not have a significant effect on these inflammatory biomarkers, leading the authors to suggest that a dietary intervention designed to elicit weight loss does reduce overall inflammation in older obese persons.
It should be pointed out that in all these studies [48–50], overweight and obesity were defined on the basis of BMI and no information was given on the percentages of subjects with central or peripheral obesity. Thus, apparent discrepancies among the various studies might be explained by a different prevalence within the recruited subjects of visceral obesity, which is associated with a stronger proinflammatory condition than peripheral obesity (Fig. 2) [46]. Additional studies are still needed to assess the effects of weight loss on obesityassociated low-grade inflammation.
Conclusions Visceral obesity and insulin resistance are predisposing factors for the development of type 2 diabetes and CVD. Adipose tissue is biologically active and produces chemical messengers (such as adiponectin, resistin, leptin, or ghrelin) and cytokines such as TNF-α and IL-6 that may affect CVD risk factors through a low-grade inflammation and possible switch toward a prothrombotic condition. Additional research will be necessary to explore the molecular mechanisms. However, present data point to a pivotal role of chronic adipose inflammation in determining systemic insulin resistance. These observations strengthen the epidemiologic observation on the contribution of visceral obesity to increased cardiovascular risk. Furthermore, they provide a biologic basis to the recommendations of NCEP-ATP III that recognize visceral obesity as the main contributor to the metabolic syndrome and suggest that therapeutic lifestyle changes, with emphasis on weight reduction, constitute first-line treatment of this syndrome. Multidisciplinary approaches of long-term weight loss and increased physical activity may, in fact, help in reducing markers of vascular inflammation and insulin resistance, ultimately leading to decreased cardiovascular risk in
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obese patients. Taken together, all these findings demand that researchers consider novel approaches to improve the current understanding of causes, prevention, and treatment of obesity.
Acknowledgments P. Feroni can be contacted at the Department of Experimental Medicine & Pathology, University of Rome, in Italy. S. Basili can be contacted at the Department of Medical Therapy, University of Rome, in Italy. A. Falco can be contacted at the Center of Excellence on Aging, in Chieti, Italy.
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