The Inflammatory Syndrome: The Role of Adipose Tissue Cytokines in Metabolic Disorders Linked to Obesity
Brent E. Wisse
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Harborview Medical Center, University of Washington, Seattle, Washington
Correspondence to Dr. Brent E. Wisse, Harborview Medical Center, 325 Ninth Avenue, Box 359757, Seattle, WA, 98104-2499. Phone: 206-341-4620; Fax: 206-731-8522; E-mail: bewisse{at}u.washington.edu
The metabolic effects of obesity have made this highly prevalentdisease one of the most common risk factors for diabetes, hypertension,and atherosclerosis, the leading causes of end-stage renal failure.However, obesity per se, as defined by body mass index, is lesspredictive of the development of these diseases than is thepresence of a constellation of obesity-related abnormalitiesnow known as the metabolic syndrome. Recognition of this syndrome,which can readily be identified in clinical settings using definedthreshold values for waist circumference, BP, fasting glucose,and dyslipidemia, allows for earlier intervention in these high-riskpatients. Systemic insulin resistance has been implicated asone possible factor that links visceral obesity to adverse metabolicconsequences; however, the mechanism whereby adipose tissuecauses alterations in insulin sensitivity remains unclear. Infectionand inflammation are commonly associated with insulin resistance,and visceral obesity is associated with a chronic, low-gradeinflammatory state, suggesting that inflammation may be a potentialmechanism whereby obesity leads to insulin resistance. Moreover,adipose tissue is now recognized as an immune organ that secretesnumerous immunomodulatory factors and seems to be a significantsource of inflammatory signals known to cause insulin resistance.Therefore, inflammation within white adipose tissue may be acrucial step contributing to the emergence of many of the pathologicfeatures that characterize the metabolic syndrome and resultin diabetes and atherosclerosis. This review describes the roleof proinflammatory cytokines and hormones released by adiposetissue in generating the chronic inflammatory profile associatedwith visceral obesity.
Worldwide, the prevalence of obesity is increasing dramatically,and recent estimates show that nearly two thirds of the U.S.adult population is now either overweight or obese (1). Meanwhile,pediatric obesity is increasing at an even more alarming rate,suggesting that this epidemic is unlikely to abate soon (2).Although increasing body weight, as defined by body mass index(BMI), is a powerful predictor of metabolic disease risk, (3)genetic and environmental factors cause considerable variabilityin the manifestation of type 2 diabetes and atherosclerosisfor any given degree of obesity (4). One potential explanationfor these differences is that individuals with the same BMImay have vastly different amounts of visceral (also referredto as "central" or "abdominal") fat, the adipose tissue depotknown to be associated with the greatest metabolic risk (5,6).When visceral obesity is accompanied by a constellation of metabolicderangements, including insulin resistance, low HDL, elevatedtriglycerides, and raised BP (7), the predicted cardiovasculardisease risk is increased significantly (8). This adverse metabolicprofile is now referred to as the metabolic syndrome and isa highly prevalent condition in the United States, affectingnearly 25% of all adults (9). Clinically, the identificationof these high-risk, obese patients has benefited from the recentpublication of definitions by the National Cholesterol EducationProgram expert panel and the World Health Organization (10,11).Although the criteria differ slightly (Table 1), the respectivedefinitions both serve the clinical function of identifyingobese patients who are at greater risk of developing comorbidmetabolic conditions, including type 2 diabetes, hypertension,hyperlipidemia, and cardiovascular disease (12), allowing forearlier and more directed interventions. Although current theoriesfocus on insulin resistance as the prime factor linking visceralobesity with adverse metabolic changes (7), studies suggestthat the pathophysiology of the metabolic syndrome cannot beexplained by insulin resistance alone (13). Beyond glucose homeostasis,dyslipidemia, and BP, many other pathophysiologic features havebeen characterized in individuals with the metabolic syndrome.Among these, evidence of chronic systemic inflammation is oneof the most consistent (14), and numerous inflammatory markersare highly correlated with the degree of obesity and insulinresistance (15); many of these inflammatory markers are, inturn, highly predictive of vascular disease risk (16).
This review discusses the potential role of inflammation withinfat in generating the metabolic syndrome, focusing on cytokinessecreted by adipose tissue that modulate the immune system infavor of chronic systemic inflammation. The inflammatory rolesof leptin, a fat-specific cytokine crucial to the control ofenergy balance, as well as the classical proinflammatory cytokinesIL-6 and TNF-, are highlighted specifically.
The conceptual transformation of adipose tissue from a passiveorgan of energy storage to an active participant in hormonalregulation of homeostatic systems occurred relatively recently.In 1994, adipose tissue was identified as the source of thehormone leptin, opening the door for a new era of research focusedon adipocyte endocrinology (17). In the past decade, the endocrinerole of leptin has expanded to include regulation of reproduction(18) and immune function (19), and numerous other adipose tissue-derivedmolecules that have an impact on glucose homeostasis, vascularbiology, tumor development, lipoprotein metabolism, and inflammation(20) have been identified, and these inflammatory factors arelisted in Table 2. However, adipose tissue is an inhomogeneousorgan that consists of a variety of cell types, a fact thathas prompted significant debate as to the true role of the adipocyteversus stromal/vascular and immune cells in secreting some ofthese endocrine and paracrine regulators. In fact, mature adipocytesseem to lack the storage vesicles and other structural cellularcomponents usually associated with regulated release of secretedproteins by endocrine cells. In addition, the frequent use ofpre-adipocyte cell lines to study adipocyte biology in vitrohas added to this controversy because the functional characteristics(21) and transcriptional patterns of these multipotent cellsare similar to immune cells. In fact, immature fat cells cantransdifferentiate into macrophages both in vitro and in vivo.(22). Recent studies using large-scale genetic analyses to characterizegene expression patterns in adipose tissue from a variety ofobese and lean mice have begun to clarify the role of the adipocyteas a hormone and cytokine secreting cell (23,24). Surprising,in these studies, increasing adiposity in mice correlates veryhighly with the adipose tissue expression of a large clusterof genes characteristically expressed by macrophages, and bothadipocyte size and total body weight are strong predictors ofthe number of mature macrophages found within adipose tissue,the correlation being even stronger for visceral than for subcutaneousfat. These bone marrow-derived macrophages seem to invade fatin response to as-yet-unknown signals and in obese animals tendto aggregate and form giant cells characteristic of chronicinflammatory disorders, suggesting that adipose tissue is asite of active inflammation. Gene expression studies on sortedcells from adipose tissue revealed that macrophages producealmost all TNF-, whereas mature adipocytes secrete the majorityof leptin and roughly equal IL-6 gene expression was found withinmacrophages, adipocytes, and nonmacrophage stromal-vascularcells. Importantly, these studies suggest that macrophage invasionof fat and inflammation-related gene expression in adipose tissuemay be a sentinel event, preceding the development of insulinresistance in these animals. Therefore, weight gain in miceis associated with infiltration of fat by macrophages and elaborationof proinflammatory signals from adipose tissue. Notably, theseinflammatory changes are most marked within visceral fat, thefat depot associated with greatest metabolic risk, and seemto precede other features of the metabolic syndrome, includingimpaired glucose homeostasis.
Table 2. Adipose tissue-derived proteins known to affect inflammation
The existing paradigm of adipose tissue endocrinology has beenchanged significantly by introducing immune cells as a sourceof inflammatory mediators released from adipose tissue, as wellas a paracrine regulator of adipocyte function and hormone secretion,thereby potentially controlling the metabolic changes that resultfrom excess adiposity. Research designed to elucidate the signalsthat attract macrophages to fat and dissect the paracrine mechanismswhereby adipose tissue macrophages and adipocytes communicateis likely to identify therapeutic targets that may decreasefat-induced inflammation and perhaps diminish the metabolicrisk associated with obesity.
Although that macrophages infiltrate fat as a result of obesityis surprising, interactions between adipose tissue and the immunesystem are well described, and various theories have been putforth to try to address the question of why such a link shouldexist (19). White adipose tissue and bone marrow share an embryologicorigin, the mesoderm, and pre-adipocytes are potent phagocytesthat resemble macrophages in both morphology and patterns ofgene expression (21). In addition, mature adipocytes share theability to secrete cytokines and activate the complement cascademuch like mononuclear immune cells. One line of reasoning connectingfat and the immune system is based on the role of the adipocytehormone leptin in the control of energy homeostasis and immunity.During fasting/starvation, when plasma leptin levels decline,neural pathways in the hypothalamus cause appetite to increaseand energy expenditure to decrease, an attempt to restore bodyfat stores (25). In addition, the fall in plasma leptin diminishesthyroid hormone production (26) and inhibits the reproductiveaxis, both effects that save energy during nutritionally leantimes (27). However, starvation also inhibits the immune system,resulting in increased apoptosis in the thymus and decreasedmononuclear cell proliferation, effects that can be entirelyreversed by administering leptin alone in the absence of refeeding(28). Because maintaining immune function has been estimatedto account for as much as 15% of daily energy expenditure (29),here, too, leptin’s role may be taken as contributingto reducing overall energy expenditure; thus, the regulationof immunity by adipose tissue can be seen as an extension ofthe endocrine role of fat in energy homeostasis.
The second argument for fat/immune system coordination is rootedin teleology. In Drosophila, the fat body is the organ thatgoverns the innate immune system, secreting into the lymphaticsystem molecules that target ingested pathogens (30). Similarly,in vertebrates, fat may be one of the crucial alarm systemsthat rouses the innate immune system and triggers the acute-phaseresponse, the first line of defense against bacterial infection.Certainly the adipose tissue production of leptin increasesdramatically during acute infection (31), and fat may contributeto elevated circulating IL-6, TNF-, and IL-1, as well as numerousother factors that prime the immune system or participate directlyin the defense against pathogenic organisms. The question ofwhether adipose tissue plays a significant role in controllingimmune function in humans has yet to be answered conclusively;however, that adipose tissue can elaborate acute inflammatorysignals suggests that dysregulation of the inflammatory capabilityof fat could play a role in triggering or perpetuating the chronicinflammation characteristic of the metabolic syndrome. Althoughacute and chronic inflammation are dissimilar in many ways,the metabolic perturbations seen during acute infection sharemany common features with the known characteristics of the metabolicsyndrome. Most important, insulin resistance and hyperglycemiaare common to both conditions, as are hypertriglyceridemia,impaired lipolysis, and increases in nonesterified fatty acids.Leptin, IL-6, TNF-, the acute-phase reactant C-reactive protein(CRP) as well as other circulating inflammatory markers areelevated in both conditions. In addition, in rodents, more clearlythan in humans, both obesity and acute infections are associatedwith an activation of the hypothalamic-pituitary-adrenal axisand increased circulating glucocorticoid levels. During acuteinfections, these metabolic changes are thought to be adaptive,sparing fuel for the brain, activating the complement cascadeon bacterial cell surfaces, depriving bacteria of iron and othervital micronutrients, etc., but as with other adaptive physiologicprocesses, pathologic consequences may result when these acutechanges become chronic. Equating metabolic syndrome-associatedchronic inflammation with acute inflammatory responses to infectionis clearly too facile, yet it highlights the intriguing possibilitythat immune/inflammatory factors may be at the root of the metabolicperturbations associated with both obesity and acute illness.The biologic response to a given cytokine may differ betweenacute and chronic inflammatory states, and the mechanism governingsuch differential responses often remains obscure. Clearly,although similar cytokine mediators seem to be involved, thenonmetabolic features of obesity and acute inflammatory syndromesare vastly different and multiple mechanisms may account forthis variability, including differences in plasma cytokine concentration,presence of soluble cytokine receptors and receptor antagonists,balance of pro- versus anti-inflammatory cytokine networks atthe tissue level, and presence of bacterial cell wall products,to name only a few of the many potential variables. One intriguingmetabolic dissimilarity between these two conditions is worthyof mention, namely the control of appetite. Both chronic inflammatoryconditions and acute infections are usually associated withanorexia and cachexia, which are believed to be cytokine mediated(32), whereas appetite in individuals with obesity/metabolicsyndrome is not obviously diminished, despite elevations inthe circulating concentrations of cytokines associated withanorexia. Therefore, although the possibility exists that themetabolic syndrome is caused by an inflammatory response goneawry and, perhaps more specific, an inflammatory response withinadipose tissue that becomes maladaptive when chronically stimulated,the details of specific cytokine-mediated effects and the mechanisticrole of various inflammatory mediators remains to be definedclearly. The following sections summarize the potential rolesof three key adipose tissue-derived cytokines—leptin,IL-6, and TNF-—in contributing to the manifestations ofthe metabolic syndrome.
The adipocyte-derived hormone leptin is a critical mediatorof energy balance that relays information regarding the depletionor accumulation of fat stores to the brain (25,33). Althoughidentified as a classic peptide hormone, the four helix domainsin the folded structure make leptin most similar to cytokinessuch as IL-2. Moreover, the leptin receptor (lepr) bears significanthomology to type 1 cytokine receptors; therefore, the hormoneleptin is in many ways more appropriately identified as a cytokine.Although the role of leptin in controlling energy homeostasisis increasingly well defined (25,33), it remains unclear whetherleptin plays a role in the inflammatory syndrome caused by abdominalobesity. Clearly, serum leptin concentrations rise in proportionto body adiposity (34); therefore, obese individuals with themetabolic syndrome generally have higher circulating leptinconcentrations. However, obese individuals seem to be resistantto the hypothalamic effects of leptin (33); therefore, the catabolicpathways designed to reduce appetite and increase energy expenditureare not activated and excess body weight is maintained. Althoughmany of leptin’s effects result from a direct action ofleptin on hypothalamic neurons, the functional leptin receptor(long-form or leprb) is also found on many tissues outside thecentral nervous system (CNS), including immune cells (35,36).Importantly, the mechanisms that are thought to contribute tohypothalamic leptin resistance (33), e.g., defective blood-brainbarrier transport, are either moot or unproved in peripheraltissues, and no studies have documented peripheral leptin resistancein obese individuals. Therefore, immune cells may well be subjectto increased leptin effects in obese individuals, a signal that,on the basis of animal studies, may serve to activate the innateimmune system and shift the cognate immune system toward a predominanceof a proinflammatory Th1 T cell population while reducing theregulatory Th2 phenotype (19). Although the immunomodulatoryproperties of increased leptin signaling are thought to be beneficialduring acute infections in both rodents (37) and humans (38),chronically, this proinflammatory shift may be deleterious.In fact, very obese, leptin-deficient mice are protected fromatherosclerosis despite all of the metabolic risk factors, suggestingthat this hormone may contribute directly to the risk of vasculardisease (39). Moreover, in a prospective study in humans, circulatingleptin concentration was shown to be an independent risk factorin predicting cardiovascular events after anthropometric andmetabolic risk factors had been controlled for (40). Therefore,chronically elevated concentrations of leptin, as seen in obeseindividuals, may potentially predispose to progression of atherosclerosis.These data, however, are somewhat incongruent with the factthat women generally have higher leptin levels than men (34)while having lower cardiovascular disease risk. Therefore, althoughincreased serum leptin concentrations, through direct effectson the immune system, clearly may trigger a proinflammatorystate, as yet only circumstantial data from rodent studies suggestthat this cytokine contributes to the chronic low-grade inflammationassociated with the metabolic syndrome.
Most cytokines function predominantly as paracrine or autocrinefactors. However, IL-6 is unusual in that it is a true endocrinecytokine, meaning that most cellular targets of this cytokineare distant from the site of release and the effects of IL-6are correlated with the serum concentration (41). Within adiposetissue, both adipocytes and macrophages secrete IL-6 (23), andstudies measuring arteriovenous increases of serum IL-6 concentrationhave clearly shown net secretion of IL-6 from adipose tissuedepots, suggesting that fat accounts for roughly 30% of circulatingIL-6 concentrations in humans (42). Like leptin, productionof IL-6 by adipose tissue increases with increasing adiposity,and circulating IL-6 concentrations are highly correlated withpercentage of body fat (43) and with insulin resistance (44).However, like leptin, in vitro studies have shown that for agiven weight of adipose tissue, subcutaneous fat produces moreIL-6 than visceral fat, thereby weakening the link between thiscytokine and the visceral fat-dependent metabolic syndrome.Although the differential regulation of IL-6 secretion fromdifferent fat depots and from distinct adipose tissue cell typesremains to be determined, humoral (insulin, glucocorticoids),neural (sympathetic nervous system activity), and paracrine(IL-1, TNF-) signals all have been shown to regulate IL-6 productionfrom fat, and determining the factors that increase IL-6 productionfrom visceral fat remains an important research goal. AlthoughIL-6 is a highly pleiotropic cytokine, with hormonal effectson many tissues, the effects on the liver, bone marrow, andendothelium are thought to be most significant in contributingto the metabolic effects of obesity.
Circulating IL-6 is the single most important factor controllingthe hepatic acute-phase response, the rapid, coordinated physiologicreaction to tissue damage or infection designed to recruit hostdefense mechanisms, eliminate damaged cells, contain pathogens,and begin tissue repair (45). Of the many positive and negativeacute-phase reactants, perhaps the most recognized is CRP, amember of the pentraxin family that attaches to the plasma membraneof damaged cells causing cell death through activation of thecomplement cascade (46). A large volume of epidemiologic dataconnect CRP to coronary events, atherosclerotic disease, andprogression to type 2 diabetes (47,48). Clearly, CRP is oneof the strongest markers of metabolic risk and, in addition,may participate directly in the arterial cell wall mechanismsleading to atherosclerotic lesions and cardiac events (49).Because CRP production by the liver is governed by circulatingIL-6 and because, in industrialized countries, the single mostimportant determinant of serum IL-6 concentration is whole-bodyadiposity, it is likely, therefore, that this adipose tissuecytokine contributes significantly to the chronic systemic inflammatorydisorder associated with the metabolic syndrome. Although increasedCRP is the most recognized marker of IL-6 action, numerous otherIL-6-dependent factors may contribute to cardiovascular risk.Increases of fibrinogen, another acute-phase reactant, are mediatedby IL-6, as are increases in both platelet number and plateletactivity, all of which would contribute to the risk of clotformation (50). Moreover, endothelial cells and vascular smoothmuscle cells are targets of IL-6 action, resulting in increasedexpression of adhesion molecules and activation of local renin-angiotensinpathways, both modifications that favor vascular wall inflammationand damage (51).
In the CNS, IL-6 is a powerful catabolic agent that leads todecreased food intake and increased energy expenditure, basedon numerous studies involving the administration of IL-6 intothe cerebral ventricles (52). The expression and release ofIL-6 by neurons and glial cells seems to be essential for theeffects of this cytokine on energy balance, but it remains unclearto what extent central IL-6 production is controlled by circulatingIL-6 in the serum, although transport mechanisms seem to existto deliver IL-6 across the blood-brain barrier (52). Importantly,mice with a genetic deletion of IL-6 develop adult-onset obesity,suggesting that this cytokine is involved in the chronic physiologicregulation of energy balance and that decreased IL-6 signalingis associated with weight gain (53). Therefore, if IL-6 secretionby adipose tissue contributes to energy homeostasis throughan endocrine action on the CNS, then one could invoke a stateof obesity-induced IL-6 resistance, much as described for theeffects of obesity on leptin and insulin signaling. This suppositionalso suggests the possibility that increased adipose-tissueIL-6 secretion associated with obesity may be a regulatory mechanismattempting to correct excess body weight and achieve negativeenergy balance, as hypothesized for obesity-related increasesin leptin. The systemic inflammation resulting from IL-6 effectson liver and endothelium therefore could be an unintended consequenceof appropriately elevated IL-6 levels in the face of obesityand central IL-6 resistance.
The endocrine cytokine IL-6, therefore, is a likely mediatorof proinflammatory signaling from adipose tissue; however, strategiesdesigned to block IL-6 action remain to be evaluated as treatmentsof the metabolic syndrome. Importantly, limiting IL-6 effectson liver and endothelium may well impair the normal host responseto acute infection, whereas preventing IL-6 secretion from adiposetissue could potentially worsen obesity if peripheral IL-6 secretionprovides negative feedback to hypothalamic areas that governenergy balance.
The role of TNF- in the systemic inflammatory response triggeredby obesity has been studied extensively (54). Within adiposetissue, macrophages account for nearly all TNF- production (23),and both TNF- mRNA content and TNF- production increase in adiposetissue of obese individuals (55). Circulating TNF- concentration,in turn, also rises with increasing obesity and correlates withinsulin resistance (56). However, a study measuring arteriovenousdifferences showed no net secretion of TNF- from subcutaneousadipose tissue depots (42), and although in vitro studies haveshown that visceral adipose tissue produces more TNF- than subcutaneousfat (57), net secretion of TNF- from visceral fat into the circulationhas not yet been documented. Therefore, it remains unclear whetherTNF- secretion from adipose tissue directly accounts for theelevated serum TNF- concentration seen in obesity. In vivo studieshave complicated the interpretation of the role of circulatingTNF-, as two rodent studies using chimeric TNF- receptor (58)or overexpression of a soluble TNF- receptor fragment (59) bothresulted in significant improvement of insulin resistance inobese rats, whereas other studies using anti-TNF- antibodieshad no effect on insulin action in obese rats (60) or in obeseindividuals with type 2 diabetes (61). Nonetheless, TNF- clearlymay have an important role as a paracrine factor in the inflammatoryresponse triggered by obesity independent of circulating concentrationof the cytokine. Within adipose tissue, TNF- causes adipocyteinsulin resistance through serine phosphorylation (inactivation)of both the insulin receptor (IR) and insulin receptor substrate1 (IRS-1), both of which result in diminished activation ofphosphoinositol-3-kinase, the essential second messenger signalthat governs most of insulin’s metabolic effects (Figure 1)(62). The intracellular pathways activated by the TNF- receptorthat interact with insulin signaling remain to be establishedbut are thought to involve NF-B and/or JNK signaling (63,64).Impairment of activation of IR and IRS-1 has also been shownto occur in skeletal muscle (65), where it is proposed thatTNF- derived from macrophages within the fat depots that liebetween myocytes may result in muscle insulin resistance viaa paracrine mechanism (23). Surprising, this mechanism of insulinresistance does not occur in hepatocytes, even though the liverwould presumably be the prime target for TNF- released by visceralfat (66). Nonetheless, one in vivo study in rodents did showan improvement in hepatic insulin sensitivity when TNF- wasneutralized, suggesting that this cytokine may also have animpact on critical insulin-dependent pathways in the liver (59).
Figure 1. Schematic overview of the potential interaction between the second messenger pathways activated by insulin and by TNF- signaling.
A second mechanism whereby TNF- may contribute to insulin resistanceis through elevations in circulating FFA levels caused by theinduction of lipolysis and stimulation of hepatic lipogenesis(67). However, most of the effects of TNF- on lipid metabolismhave been studied under conditions of acute inflammation orwith relatively high-dose intravenous TNF- administration (68),casting doubt on the relevance of this mechanism to the pathophysiologyof the metabolic syndrome given the more modest elevations inTNF- seen in obesity.
More recently, a third potential mechanism whereby TNF- influencesinsulin resistance has been identified. Adiponectin secretionby adipocytes is potently reduced by TNF- signaling (69), andthis hormone seems to be a crucial mediator of insulin sensitivity,potentially explaining how paracrine effects of TNF- withinfat could cause systemic insulin resistance.
However, predictions regarding the significance of TNF- in themetabolic syndrome have been tempered significantly by the factthat mice with genetic deletions of either TNF- or the TNF-receptors demonstrate only modest protection from weight gain,hyperglycemia, and insulin resistance when obese (70,71). Therefore,although TNF- is a macrophage-derived inflammatory factor thatcontributes to insulin resistance in adipose tissue and musclevia paracrine and potentially endocrine mechanisms, other inflammatorymolecules may be able to compensate for the absence of TNF-signaling; thus, the viability of antagonists of TNF- signalingin the treatment of the metabolic syndrome remains unclear.
Intracellular Pathways that Control Inflammatory Signaling
Although inflammation can clearly impair IR and IRS signaling,until recently, the intracellular mechanism whereby cytokinessuch as TNF- prevent activation of these molecules has remainedunknown. Experiments using in vitro models of insulin resistancehave demonstrated that serine/threonine kinases can phosphorylateboth IR and IRS molecules such that activation by tyrosine phosphorylationis prevented (72). Although cytokines are known to activatea number of intracellular serine/threonine kinases, considerableattention has now focused on the inhibitor B kinase (IKK) complexas a mediator of insulin resistance (Figure 1). This enzymecomplex is best known for a vital role in triggering the NF-Bpathway, a crucial second messenger system for inflammatorycytokine signaling (73). When activated, IL-1 and TNF- receptorsrecruit kinases that activate the IKK complex. IKK2, the keycatalytic subunit of the IKK complex, phosphorylates inhibitorB, causing this cytoplasmic chaperone molecule to be degradedand allows the transcription factor NF-B to translocate intothe nucleus and activate inflammatory target genes (74). Invitro studies have shown that the activity of the IKK complexcan be inhibited by high-dose salicylate administration (75).Moreover, high-dose aspirin was already described as a treatmentof diabetes in the late 1800s (76) and dramatically decreaseshyperglycemia and glycosuria in patients with diabetes (77).The astute juxtaposition of these two pieces of informationled to a number of recent studies demonstrating conclusivelya role for the NF-B pathway in causing insulin resistance. High-doseaspirin administration, unlike other nonsteroidal anti-inflammatorycompounds, reversed insulin resistance and normalized the activationof the insulin receptor and downstream insulin signaling moleculesin obese rodents in vivo and in TNF--treated adipocytes in vitro(78). That mutant mice lacking one copy of the IKK2 gene (Ikk2+/–)had improved insulin sensitivity on both low-fat and high-fatdiets and that this heterozygous mutation bred into leptin-deficientob/ob mice was able to reduce hyperglycemia and improve glucosetolerance in these obese animals established that the IKK complexis a critical serine/threonine kinase that, when activated,results in insulin resistance by diminishing insulin-stimulatedIR and IRS-1 activation. However, the strength of this conclusionwas questioned recently by a genetic mouse model specificallylacking IKK2 activity only in muscle that did not develop insulinresistance even on a high-fat diet (79). Therefore, the IKKcomplex may be one of multiple cytokine-activated serine/threoninekinases that can cause insulin resistance, and recent evidencepoints to JNK as another TNF--activated kinase that may be involvedin diminishing normal IR and IRS-1 function (63,80). As multipleproinflammatory cytokines may have similar effects on insulinsignaling, the shared, cytokine-induced second messenger pathwaysmay be excellent therapeutic targets for the treatment of metabolicsyndrome and type 2 diabetes. However, the individual role ofthese cytokine-induced pathways in skeletal muscle, adiposetissue, liver, and the CNS remains to be determined, and theissue of redundancy within signaling pathways will need to beovercome. Moreover, the potential immunosuppressive effectsof compounds that globally dampen inflammatory signaling mustremain a significant concern in the effort to design drugs toblock the deleterious effects of chronic inflammation in obesity.
Other Adipose Tissue-Derived Inflammatory Molecules
Numerous other inflammatory mediators are produced and potentiallysecreted into the circulation by adipose tissue (Table 2). Amongthese, adiponectin (81), resistin (20), acylation-stimulatingprotein (82), and components of the renin-angiotensin system(83) may be the most important in contributing to chronic inflammation,insulin resistance, and cardiovascular disease risk.
Chronic inflammation is a common feature of the metabolic syndrome,and inflammatory signals may originate within visceral adiposetissue as this fat depot expands in response to chronic positiveenergy balance. Both adipocytes and macrophages within fat secretenumerous hormones and cytokines that may contribute to the characteristicpathophysiologic changes seen in the metabolic syndrome, andlocal inflammation within adipose tissue may be the sentinelevent that causes systemic insulin resistance and systemic inflammation,two of the cardinal features of the metabolic syndrome. Theinciting event that causes adipose tissue to become inflamedas it expands remains unknown but will likely have a significantgenetic component potentially accounting for some of the variancein metabolic risk between equivalently obese individuals. Thecontribution of individual cytokines in causing the pathophysiologicfeatures of the metabolic syndrome remains controversial; however;that the metabolic alterations triggered by acute inflammationmimic the metabolic syndrome in many ways suggests that circulatingcytokines, whether they are derived from adipose tissue or peripheralblood immune cells, may have similar metabolic effects on muscle,liver, and endothelium while potentially having differentialeffects on immune function. In addition, adipose tissue-derivedcytokines, such as IL-6 and leptin, may also participate directlyin endothelial cell activation and inflammation in the vascularbed, both changes that could contribute to the progression ofatherosclerosis. Recognition of the interaction between adipocytesand macrophages within fat exposes a new paradigm whereby adipocyte-derivedfactors modulate local immune responses and macrophage-derivedcytokines alter adipocyte differentiation and metabolic responses.As future studies continue to provide new information regardinglinks between inflammation and metabolism, the potential toidentify new therapeutic options for the treatment of the metabolicsyndrome remains high, encouraging the global effort to reducethe morbidity associated with this highly prevalent disease.
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Top
Abstract
Introduction
, are highlighted specifically. 
, as well as numerous other factors that prime the immune system or participate directly in the defense against pathogenic organisms. The question of whether adipose tissue plays a significant role in controlling immune function in humans has yet to be answered conclusively; however, that adipose tissue can elaborate acute inflammatory signals suggests that dysregulation of the inflammatory capability of fat could play a role in triggering or perpetuating the chronic inflammation characteristic of the metabolic syndrome. Although acute and chronic inflammation are dissimilar in many ways, the metabolic perturbations seen during acute infection share many common features with the known characteristics of the metabolic syndrome. Most important, insulin resistance and hyperglycemia are common to both conditions, as are hypertriglyceridemia, impaired lipolysis, and increases in nonesterified fatty acids. Leptin, IL-6, TNF-
B and/or JNK signaling (63,64). Impairment of activation of IR and IRS-1 has also been shown to occur in skeletal muscle (65), where it is proposed that TNF-
