332 Journal of Atherosclerosis and Thrombosis　Vol.17, No.4

Review

333Adipose Tissue and Atherosclerosis

Adipose Tissue, Inflammation and Atherosclerosis

Birgit Gustafson

The Lundberg Laboratory for Diabetes Research, Center of Excellence for Metabolic and Cardiovascular Research, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Metabolic syndrome is associated with dysfunctional adipose tissue that is most likely a consequence of the enlargement of adipocytes and infiltration of macrophages into adipose tissue. Obesity and ectopic lipid deposition are major risk factors for diseases ranging from insulin resistance to type 2 diabetes and atherosclerosis. Enlargement of adipocytes, due to impaired adipocyte differentiation, leads to a chronic state of inflammation in the adipocytes and adipose tissue with a reduction in the secretion of adiponectin and increase in the secretion of proinflammatory cytokines such as interleu-kin (IL)-6, IL-8 and monocyte chemoattractant protein (MCP)-1. The secretion of cytokines like tumour necrosis factor (TNF)-α, mainly from macrophages, enhances local inflammation. These proinflammatory cytokines might also substantially affect cardiovascular function and morphology. Furthermore, a proinflammatory state in adipose tissue can lead to local insulin resistance with an impaired inhibitory effect of insulin on the release of FFAs and endothelial dysfunction that clearly promotes cardiovascular diseases and type 2 diabetes. The underlying mechanisms of ectopic fat accumulation in various tissues and the impact on metabolic syndrome and its association with insu-lin resistance are discussed.

J Atheroscler Thromb, 2010; 17:332-341.

Key words; Obesity, Insulin resistance, Cytokines, Vascular injury

tissue biology and endocrine function. Obesity, char-acterized by enlarged adipocytes, and insulin resistance are associated with impaired adipogenesis and a low-grade chronic inflammation that to a large extent emanates from adipose tissue2). The secretion of bio-active molecules from adipose tissue might have an effect on insulin sensitivity in the liver and peripheral tissues, and have a negative impact on the cardiovas-cular system. In this review, current knowledge of low-grade chronic inflammation in adipose tissue with local and systemic effects will be discussed.

Adipose Tissue

Adipose tissue in mammals can be divided into white and brown adipose tissue (WAT and BAT). WAT is not homogenous, and can be divided into subcutaneous and visceral adipose tissue. Subcutane-ous adipose tissue stores excess calories and can be fur-ther divided into upper and lower body obesity, while visceral adipose tissue (omental and mesenteric) sup-plies the inner organs with energy. There is 3 to 4

Introduction

For many years, adipose tissue was regarded merely as a heat insulator and a store of excess free fatty acids (FFAs) that could be released when needed. However, following the identification of adipokines, adipose tissue is now recognized to play a central role in the pathophysiology of insulin resistance and meta-bolic syndrome1). Waist circumference, an easy-to-measure marker of metabolic risk and used to define metabolic syndrome, has been shown to correlate with different components of the syndrome supporting the notion that visceral obesity plays an important role in the development of cardiovascular diseases as well as insulin resistance and type 2 diabetes. Several recent studies have increased the understanding of adipose

Address for correspondence: Birgit Gustafson, Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Blå Stråket 3, 413 45 Göteborg, SwedenE-mail: birgit@medic.gu.seReceived: September 15, 2009Accepted for publication: October 6, 2009

332 Journal of Atherosclerosis and Thrombosis　Vol.17, No.4

Review

333Adipose Tissue and Atherosclerosis

times more subcutaneous than visceral adipose tis-sue3), and it appears that these two tissue types can interact in a coordinated and compensatory manner4).

Although WAT and BAT share many metabolic characteristics, WAT stores energy whereas BAT dissi-pates energy. The role of BAT in adult humans is unclear but it has been recently proposed that it can be induced to increase glucose uptake5). Furthermore, genes characteristic of human BAT have been shown to negatively correlate with obesity and insulin sensi-tivity6, 7).

Adipose Tissue as an Endocrine Organ

Adipose tissue is a key endocrine organ with autocrine regulation. It has a central role in obesity-associated complications such as dyslipidemia, insulin resistance and type 2 diabetes as well as low-grade inflammation and increased risk of cardiovascular dis-ease and metabolic syndrome8). It is now established that adipose tissue comprises ~50% adipocytes and ~50% other cells including preadipocytes, vascular, neural and immune cells and leucocytes9). The adipo-cytes, preadipocytes and macrophages within adipose tissue secrete a wide range of hormones and cytokines, including interleukin (IL)-6, IL-8, IL-1β and mono-cyte chemoattractant protein (MCP)-12). It is now evident that many of these adipokines have the ability to influence other tissues such as the liver and muscle. Furthermore, the adipokine leptin affects appetite reg-ulation, and others have an important impact on inflammation and vascular biology (Fig.1).

The Adipocyte

The adipocyte is a very complex cell. Under nor-mal conditions, it is involved in lipid synthesis, stor-age and secretion of anti-inflammatory molecules, but it can also be induced to secrete a number of inflam-matory factors such as MCP-1 and IL-6. By acting as transmitters of endocrine or paracrine signals, the secreted adipokines can promote either inflammation or altered insulin sensitivity of the adipocyte (Fig.2).

Fat mass is dependent on both adipocyte cell number and size. The number of adipocytes is deter-mined during early adulthood and changes in fat mass are attributed to changes in adipocyte cell size10). The adipocyte turnover rate in humans was recently estab-lished to be ~10% per year10).

Fat cell mass increases with increasing body fat to a maximum of ~0.7−0.8 μg lipids per cell, and there-after there is a more rapid increase in fat cell num-ber11). In subjects with obesity, adipose tissue has a lower capacity for the recruitment of new adipo-cytes12). Tschoukalova et al. found that the number of committed preadipocytes was decreased in patients with obesity independent of fat location13). In a recently published study from our laboratory, we found that the number of mesenchymal precursor cells was increased in obese individuals but differentia-tion of preadipocytes into adipocytes was decreased, suggesting an impaired differentiation of preadipo-cytes in obesity2). Therefore, it appears that most adult-onset obesity is related to the hypertrophy of adipo-cytes, and enlarged adipocytes is the best obesity-fac-

Fig.1. Cross-talk between adipose tissue and other organs.

Adipose tissue is a key endocrine organ that releases several adipo-kines capable of affecting other tissues and playing an important role in the pathophysiology of insulin resistance and metabolic syndrome.

Fig.2. Enlargement of adipocytes causes alterations in secre-tion of adipokines.

Under normal conditions, the adipocyte is a site of lipid synthesis, uptake and storage. Secreted adipokines function as either endo-crine, paracrine or autocrine mediators. Increases in adipocyte size can lead to deleterious alterations in insulin sensitivity caused by a decrease in adiponectin secretion, an increase in the release of FFAs and the induction of inflammatory mediators.

334 Gustafson 335Adipose Tissue and Atherosclerosis

tor in correlation with insulin resistance compared with other factors related to obesity1, 14).

Large adipocytes are more insulin-resistant and lipolytic, and release more inflammatory cytokines and less adiponectin (Fig.2)15). They are also more frequently found in individuals with obesity-related metabolic disorders11). Thus, the relative number of large adipocytes might be the most important deter-minant of metabolic activity and the response to envi-ronmental changes.

Features of Metabolic Syndrome

The term “metabolic syndrome” includes hyper-tension, dyslipidemia, glucose intolerance and insulin resistance, variables that all are associated with obe-sity16). Dysfunctional adipose tissue with low-grade, chronic and systemic inflammation links the meta-bolic and vascular pathogenesis including dyslipid-emia, low-grade inflammation and insulin resistance and is a hallmark of disorders such as type 2 diabetes and cardiovascular disease (Fig.3). However, lifestyle factors and, to a lesser degree, genetic factors, are also involved17).

Visceral and Subcutaneous Adipose Tissue

A high level of visceral fat is an independent risk factor for glucose intolerance, insulin resistance, and cardiovascular disease. Visceral fat refers to the intra-peritoneal fat composed of the greater and lesser omentum and mesenteric adipose tissue. Visceral fat accounts for ~20% of total body fat in men compared

with only ~6% in pre-menopausal women. A male risk profile has been characterized in women with abdominal obesity11). Enlarged adipocytes in the vis-cera are characterized by an increased lipolytic state and are resistant to the anti-lipolytic effects of insu-lin18).

Waist circumference is an index of the body’s periarterial and periarteriolar fat. It is an easy-to-mea-sure marker of metabolic risk and is used to identify individuals with metabolic syndrome. However, the adverse and contributing effects of abdominal subcu-taneous fat should not be overlooked as up to 80% of total adipose tissue can be composed of subcutaneous fat19).

Visceral and subcutaneous adipose tissue deposits have constitutive biological differences that are charac-teristic of their physiological roles. Even though both deposits serve as energy reservoirs to maintain sys-temic equilibrium, there are differences in levels of lipid mobilization, adipokine production and adipo-cyte differentiation that might be of importance in responses to diet and exercise20). Visceral fat secretes higher levels of complement factors, adiponectin, and inflammatory markers such as IL-6, IL-8, angioten-sinogen and plasminogen activator inhibitor-14, 21, 22).

Rates of FFA lipolysis are approximately 50% greater in obese individuals than in healthy subjects, and higher in subjects with upper body obesity than those with lower body obesity. However, abdominal subcutaneous fat is probably the main source of increased levels of circulating FFA20). The altered FFA metabolism and endocrine function in visseral obese individuals imply that visceral adipose tissue is involved in the pathophysiology of metabolic syndrome but this does not exclude a contribution from subcutane-ous adipose tissue.

TNFα and IL-6

Several studies suggest that tumour necrosis fac-tor (TNF)α and IL-6 are both involved in obesity-related insulin resistance and that TNFα is one of the most important mediators of inflammation23). In con-trast to IL-6, TNFα is secreted not by adipocytes but instead by infiltrating macrophages in adipose tissue, and functions as a paracrine and/or autocrine fac-tor24, 25). It has been shown that adipose tissue is a sig-nificant source of circulating IL-6 and also related to BMI and adipocyte size15). TNFα and IL-6 are known to promote lipolysis and the secretion of FFA, which contribute to an increase in hepatic glucose produc-tion and insulin resistance26). Both cytokines impair adipocyte differentiation and instead promote inflam-

Fig.3. Features of metabolic syndrome.

Metabolic syndrome refers to several known risk factors including insulin resistance, obesity, dyslipidemia and hypertension. The conditions are interrelated and share underlying mediators. Indi-viduals who have the same underlying malfunctions are at high risk of developing type 2 diabetes and cardiovascular disease.

334 Gustafson 335Adipose Tissue and Atherosclerosis

mation27). Furthermore, IL-6 promotes inflammation not only in adipose tissue but in endothelial cells and liver cells28). IL-6 also promotes insulin resistance by interfering with the insulin signaling in adipose tis-sue29).

In a recent study in obese individuals, adipokine levels in the radial artery were compared with those in the portal circulation to evaluate the possibility that visceral fat supports systemic inflammation by secret-ing inflammatory cytokines into the portal circulation that drains visceral fat22). The authors found a 50% increase in the secretion of IL-6 into the portal vein, but no other differences among the inflammatory adipokines tested. They also found a direct correla-tion between the concentrations of IL-6 and systemic C-reactive protein (CRP) in the portal vein. These findings indicate that visceral fat is an important site for IL-6 secretion and provide a potential link between visceral fat and systemic inflammation in individuals with abdominal obesity22).

A further study in overweight men showed that circulating levels of IL-6 were associated with visceral adiposity, whereas TNFα showed an association with overall obesity30). These results support the hypothesis that IL-6 mediates the hyperinsulinemic state related to excess visceral fat while TNFα seems to contribute to the insulin resistance of overall obesity30).

Ectopic Fat Accumulation

Ectopic fat is defined as the deposition of triglyc-erides within cells of non-adipose tissue that normally contain only small amounts of fat. A positive energy balance produces a pattern similar to lipodystrophy with the accumulation of excess lipids in the liver, skeletal muscle and pancreas indicating that adipose tissue is not capable of sequestering nutritional lipids away from these organs31). The accumulation of fat in skeletal muscle and viscera is associated with insulin resistance and cardiovascular disease.

Lipid accumulation in liver and muscle is an early hallmark of type 2 diabetes. In the pancreas, lipid accumulation has been shown to precede sup-pressed glucose-mediated insulin production32). In the lipid-overloaded heart, metabolic dysregulation may induce insulin resistance resulting in impaired glucose oxidation and, ultimately, heart failure33). The accu-mulation of ectopic fat is now considered part of met-abolic syndrome. However, although the evidence for its deleterious effects is strong, whether ectopic lipid accumulation precedes or succeeds insulin resistance is not clear.

Epicardial Adipose Tissue

Epicardial adipose tissue is metabolically active and a source of FFA and several bioactive adipokines such as adiponectin, TNFα, IL-1, IL-6, neural growth factor and resistin34, 35). Some of these factors might substantially affect cardiovascular function and mor-phology and, thereby, directly contribute to the devel-opment of the cardiovascular complications of increased adiposity as well as insulin resistance34, 35). Epicardial fat reflects cardiac and visceral adiposity and is related to intima-media thickness, an increase in vascular stiffness, and inflammation which plays a major part in disease progression36, 37). Individuals with coronary artery disease show increased macro-phage infiltration into epicardial fat, suggesting a state of chronic inflammation38).

Epicardial adipose tissue may also affect the coro-nary arteries and myocardium through paracrine and/or direct secretion of pro-inflammatory adipo-kines. Epicardial fat has a higher rate of FFA and tria-cylglycerol uptake than subcutaneous fat, but also a higher rate of fatty acid breakdown39).

Perivascular Fat

Perivascular adipose tissue (PAT) surrounds blood vessels in changing amounts and is produced from the vascular lamina adventitia in response to circulating factors and local stimuli40). PAT has been considered largely a passive structural support for arteries. However, it can play an active role in regulat-ing vascular tone and releases adipocytederived vascu-lar relaxation factors into blood vessels41). Excess calo-ries and inactivity enlarge PAT depots with potentially unfavorable consequences and an increase in PAT is suggested to mediate morphologic changes associated with an increase in vascular stiffness seen in obesity42).

Insulin Resistance

Large adipocytes are more frequently found in subjects with impaired glucose tolerance and type 2 diabetes than those with a similar degree of adiposity but with normal glucose tolerance, and impaired adi-pocyte differentiation appears to be one of the most important factors in the progression of type 2 diabe-tes1). Insulin has several functions, including the trans-port of nutrients into cells, the regulation of gene expression and energy homeostasis. It acts on a num-ber of target tissues and through many different intra-cellular signaling cascades. Elevated levels of intracel-lular FFAs can blunt the response to insulin and sub-

336 Gustafson 337Adipose Tissue and Atherosclerosis

sequent metabolic effects43).Insulin receptor substrate (IRS)-1 is a key mole-

cule in the insulin signaling pathway, and failure to activate IRS-1 leads to systemic insulin resistance44). Inhibitory phosphorylation of IRS-1 can be induced through inflammatory agents such as TNFα and IL-6, but also through activation of receptors such as the Toll-like receptors (TLR), or intracellular molecules such as lipids and reactive oxygen species (ROS). Acti-vation of the TNFα and IL-6 receptors induces activa-tion of important activators of inflammation i.e. IκB kinase (IKKβ) and Janus kinase (JNK). JNK is also activated by FFAs and endoplasmatic reticulum stress, factors that are associated with obesity-induced activ-ity. IKKβ does not phosphorylate IRS-1 but causes insulin resistance through activation of NFκB45). Sup-pressor of cytokine signalling (SOCS) inhibits insulins actions on IRS-1 either by interfering with the tyro-sine phosphorylation or by targeting IRS-1 for proteo-somal degradation44, 46).

The consequences of decreased insulin produc-tion as a result of ectopic lipid accumulation in the pancreas combined with a diminished activation of the insulin receptor in adipocytes results in an impair-ment of insulin-stimulated glucose transport, a reduced anti-lipolytic effect, an increase in the amount of FFA released, impaired preadipocyte differentiation and a decrease in lipoprotein lipase production and activity. These effects will lead to the development of insulin resistance, type 2 diabetes and cardiovascular diseases.

Macrophage Infiltration into Adipose Tissue

There are two kinds of macrophages in adipose tissue: resident/tissue (or alternatively activated) mac-rophages and inflammatory macrophages. In severely obese individuals, the number of macrophages is higher in visceral fat than subcutaneous fat47), consis-tent with a more prominent role for visceral fat in insulin resistance48). The infiltration of monocytes/macrophages into adipocyte tissue is probably initi-ated by an increase in adipocyte size (Fig.4). Enlarge-ment of adipocytes is associated with an increase in physical stress and ROS production, and increased secretion of FFA and inflammatory cytokines2, 49). Of these cytokines, MCP-1 secreted from macrophages seems to be the most important2, 49). MCP-1 is expressed before inflammatory macrophage mark-ers50), providing evidence that cells other than macro-phages produce it. In obesity, circulating mononuclear cells are in a proinflammatory state and are key players in endothelial dysfunction. The transmigration of blood monocytes into adipose tissue is a complex mechanism that requires the expression of adherent molecules both on the monocytes and on the endo-thelial cells to which they attach51, 52). After transmi-gration into adipose tissue, the monocytes differenti-ate into inflammatory macrophages.

Infiltrating inflammatory macrophages constitute a major source of inflammatory mediators, especially TNFα, within adipose tissue, and it is likely that they

Fig.4. Inflammation in adipose tissue induces a vicious cycle.

Enlargement of adipocytes is associated with an increase in the release of FFAs, physical stress and increased ROS production. These stress factors induce production of inflamma-tory adipokines such as IL-6, serum amyloid A (SAA) and MCP-1 that are released into the circulation and mediate the recruitment of activated monocytes into adipose tissue. The monocytes differentiate into inflammatory macrophages that release TNFα. TNFα induces further inflammation in the adipocytes and recruitment of macrophages.

336 Gustafson 337Adipose Tissue and Atherosclerosis

act synergistically with adipocytes to amplify local inflammation53). Neutralizing antibodies to TNFα have been shown to inhibit inflammation in a cocul-ture of 3T3-L1 adipocytes and a macrophage cell line, suggesting that TNFα is a major macrophage-derived mediator of inflammation in adipocytes54). Resident macrophages have low levels of proinflammatory cyto-kine production but can be activated with an enhanced recruitment and activation of blood monocytes52).

The infiltration of macrophages into adipose tis-sue contributes to the local and systemic metabolic effects of obesity, however, the majority of macro-phages are distributed around necrotic adipocytes whose numbers increase dramatically in obese individ-uals. For example, Cinti et al. showed that ＞90% of all macrophages in the adipose tissue of obese individ-uals were located around dead adipocytes55). They also showed a positive correlation between adipocyte death and adipocyte size and suggested that adipocyte death helps to mediate local macrophage infiltration55). It is proposed that the inflammation in adipocytes entails a paracrine loop involving FFAs released from adipo-cytes and TNFα released from macrophages, which, together with other factors, leads to a further increase in recruitment of monocytes54).

Vasocrine Signaling

Excess intake of calories results in increased depo-sition of perivascular fat around the heart and its major branches. Conditions where there is an increased amount of adipose tissue surrounding the blood ves-sels, overproduction of adipokines, and signaling from perivascular fat deposits to the arteries, “outside-to-inside signalling”, could than lead to inflammation and atherosclerosis (Fig.5). Perivascular fat is also considered to be ectopic within adipose tissue, acting as an integrated organ responsible for both paracrine signaling and vessel-to-vessel signaling “vasocrine sig-naling”. Insulin has the rapid effect of increasing blood flow to skeletal muscle and an ability to recruit capillaries that depends on its actions to dilate precap-illary arterioles56). The most potent inhibitor of insu-lin’s actions and endothelial nitrogen oxide (NO)-dependent vasodilation among cytokines is TNFα, and it is suggested that a high local concentration of cytokines leads to a blunted activation by insulin of endothelial NO synthase and increased release of endo-thelin-1, resulting in a constriction of the arteriole40).

Fig.5. Perivascular adipose tissue and vasocrine signaling.

Increased amounts of perivascular adipose tissue around vessels secrete vasoactive sub-stances that can both generate local inflammation and alter vascular function. A balance between the perivascular adipose tissue-derived vasodilator and vasoconstriction factors is essential for maintaining normal vascular tone. Increased secretion of vasocrine substances can lead to the increased release of endothelin-1 at the expense of NO and here insulin has a dual function, modulation of NO synthesis and release of endothelin-1.

338 Gustafson 339Adipose Tissue and Atherosclerosis

Effects of Adiponectin

In 1995 and 1996, four different groups inde-pendently identified adiponectin57-59). Belonging to the complement 1q family, adiponectin forms char-acteristic multimers of which the high molecular weight (HMW) multimer seems to be the most important60, 61). The ratio of the HMW multimer to other forms is an independent risk factor for meta-bolic disorders62). Adiponectin is abundantly expressed in adipose tissue and circulating levels are high, 5 to 20 μg/mL. Adiponectin levels negatively correlate with visceral adiposity to a greater extent than with subcutaneous adiposity.

Kim et al. showed that although overexpression of adiponectin in ob/ob mice results in normalized glucose and insulin levels together with improvements in triglyceride and FFA levels, the mice became extremely obese due to adipocyte hyperplasia63). Despite the obesity, very few macrophages were pres-ent in adipose tissue, consistent with increased differ-entiation of new insulin-sensitive adipocytes63).

Adiponectin and the Vascular System

Adiponectin has effects in a number of different tissues. For example, in muscle, it counteracts insulin resistance64). In arteries, it reduces atherosclerosis and

intima media thickness65). It also has effects on capil-laries and the heart61). The actions of adiponectin are summarized in Fig.6.

Adiponectin attenuates inflammatory actions at several levels. It reduces TNFα-stimulated expres-sion of E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and IL-8 in human aortic endothelial cells66-68). It also inhibits TNFα-induced activation of nuclear factor-κB (NFκB) and prevents the prolifera-tion and migration of smooth muscle cells. Adiponec-tin inhibits foam cell formation (lipid accumulation in macrophages) as well as platelet aggregation and T-cell recruitment and accumulation69). It has been shown to inhibit Toll-like receptor-mediated activation of NFκB in mouse macrophages70). Adiponectin is also an important regulator of endothelial NO synthase, a major determinant of endothelial function and angio-genesis71).

Conclusion

Adipose tissue is a central factor in the develop-ment of insulin resistance and regulation of whole-body insulin sensitivity. It is also plays an important role in vascular complications. Adipose tissue has the ability to modulate both local and systemic processes in other tissues such as the liver, pancreas, skeletal muscle, heart and brain. An increase in adipose tissue

Fig.6. Effects of circulating adiponectin.

Adiponectin acts to prevent the deleterious effects of TNFα on endothelial cells by reduc-ing levels of adhesion molecules and inflammation. Adiponectin also prevents the recruit-ment of macrophages and formation of foam cells as well as decreases smooth muscle migration and proliferation.

338 Gustafson 339Adipose Tissue and Atherosclerosis

mass results in the infiltration of macrophages and enhanced inflammation. Adipokines produced by the adipose tissue impair insulin signalling and key pro-teins for glucose uptake. In addition, secreted adipo-kines promote endothelial dysfunction, adhesion of monocytes, vascular remodelling and foam cell forma-tion in the arterial wall, which contribute to cardio-vascular complications. The reduction in adiponectin levels with increasing adiposity contributes to obesity-associated vascular complications.

Acknowledgements

The studies referred to in the authors´ laboratory were supported by the Swedish Research Council, the Swedish Diabetes Association, the NovoNordisk Foundation, the Swedish Foundation for Strategic Research, the Torsten and Ragnar Soderberg Founda-tion and the European Union (EUGENE2 LSHM- CT-2004-512013). The author also thank Rosie Per-kins for reading and commenting on the manuscript.

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