inflammation, stress and diabetes

8/2/2019 Inflammation, stress and diabetes

1/9

ReviewInflammation, stress, and diabetes

Kathryn E. Wellen and G6khan S. HotamisligilDepa rtment o f Gene ti cs & Comp le x D is ea s es , H a rv a rd S c ho o l o f P u bl ic H e a lt h, B o st on , M a s sa c hu s et ts , USA .

Over the last decade, an abundance of evidence has emerged demonstrating a close link between metabolism andimmunity. It is now clear that obesity is associated with a state of chronic low-level inflammation. In this article,we discuss the molecular and cellular underpinnings of obesity-induced inflammation and the signaling pathwaysat the intersection of metabolism and inflammation that contribute to diabetes. We also consider mechanismsthrough which the inflammatory response may be initiated and discuss the reasons for the inflammatory responsein obesity. Weput forth for consideration some hypotheses regarding important unanswered questions in the fieldand suggest a model for the integration of inflammatory and metabolic pathways in metabolic disease.Inflammation, stress, and diabetesSurvival of multicellular organisms depends on the ability tofight infection and heal damage and the ability to store energyfor times oflow nutrient availability or high energy need. Meta-bolic and immune systems are therefore among the most basicrequirements across the animal kingdom, and many nutrientand pathogen-sensing systems have been highly conserved fromorganisms such as Caenorhabditis elegans and Drosophila to mam-mals. Perhaps not surprisingly, metabolic and immune pathwayshave also evolved to be closely linked and interdependent. Manyhormones, cytokines, signaling proteins, transcription factors,and bioactive lipids can function in both metabolic and immuneroles. In addition to using some of the same cellular machinery,metabolic and immune systems also regulate each other. Thenormal inflammatory response relies upon metabolic support,and energy redistribution, particularly the mobilization ofstoredlipid, plays an important role in fighting infection during theacute-phase response (1).The basic inflammatory response thusfavors a catabolic state and suppresses anabolic pathways, such asthe highly conserved and powerful insulin signaling pathway.The integration ofmetabolism and immunity, which under nor-mal conditions isbeneficial for the maintenance of good health,can become deleterious under conditions ofmetabolic challenge,as exemplified by the immunosuppression characteristic ofmal-nourished or starving individuals (1-3). Famine has been apromi-nent hazard to human health throughout history, and for thou-sands of years the link between infection and poor nutrition hasbeen well recognized. Today this threat is aswidespread as ever,and there are approximately 1billion undernourished individu-alsworldwide (3).In the past century, however, the pendulum hasalso swung in the opposite direction, and now asmany ifnot morepeople are overweight or obese (4).With the advent of this chronicmetabolic overload, anewset ofproblems and complications at theintersection ofmetabolism and immunity has emerged, includingthe obesity-linked inflammatory diseases diabetes, fatty liver dis-ease, airwayinflammation, and atherosclerosis (5).There is now awealth of evidence indicating close ties betweenmetabolic and immune systems. Among the many reasons toNonstandard abbreviations used: AP-l) activator prorein-L, DAGJ diacylglycerol;FABP) fatty acid-binding protein; IKE)inhibitor ofNF-KB; IKKJ inhibitor ofNF-KBkinase; IRS) insulin receptor substrate; JIPIJ JNK-interacting protcin-L; LXRJ liver Xreceptor; TLR Toll-like receptor; TZD thiazolidinedione.Conflict of interest: The authors havedeclared that no conflict of interest exists.Citation for this article:] Clin.lnvest.115:1111-1119 (2005).doi:1O.1172/]CI200525102.

maintain a healthy weight is the emerging paradigm that meta-bolic imbalance leads to immune imbalance, with starvation andimmunosuppression on one end of the spectrum and obesityand inflammatory diseases on the other end (Figure 1). In thisarticle, wewill discuss the molecular and cellular links betweenmetabolism and inflammation, particularly in the context ofobesity and diabetes. Common inflammatory mediators, stressresponses, and signaling pathways will be highlighted. Finally,wewill consider the origin of and the reasons for the inflamma-tory response in obesity.Obesity is characterized by inflammationFactors at the crossroads of inflammation and metabolic disease. Alittlemore than a decade ago, the first molecular link between inflam-mation and obesity - TNF-a - was identified when it was dis-covered that this inflammatory cytokine is overexpressed in theadipose tissues of rodent models of obesity (6, 7). As is the casein mice, TNF-a is overproduced in the adipose aswell as muscletissues of obese humans (8-10). Administration of recombinantTNF-a to cultured cellsor towhole animals impairs insulin action,and obesemice lacking functional TNF-a orTNF receptors haveimproved insulin sensitivity compared with wild-typecounterparts(6,11). Thus, particularly in experimental models, it is clear thatoverproduction ofTNF-a in adipose tissue isan important featureof obesity and contributes significantly to insulin resistance.It rapidly became clear, however, that obesity is characterized

bya broad inflammatory response and that many inflammatorymediators exhibit patterns of expression and/or impact insulinaction in a manner similar to that ofTNF-a during obesity, inanimals ranging from mice and cats to humans (12-14). Tran-scriptional profiling studies have revealedthat inflammatory andstress-response genes are among the most abundantly regulatedgenesets in adipose tissue ofobese animals (15 -17). Alist ofmanyof these genes, which have been identified through a variety ofapproaches, is provided in Table 1.In addition to inflammatory cytokines regulating metabol-

ic homeostasis, molecules that are typical of adipocytes, withwell-established metabolic functions, can regulate the immuneresponse. Leptin is one such hormone that plays important rolesin both adaptive and innate immunity, and both mice and humanslacking leptin function exhibit impaired immunity (18-20).Indeed, reduced leptin levelsmayberesponsible, at least in part, forimmunosuppression associated with starvation, asleptin adminis-tration has been shown to reversethe immunosuppression ofmicestarved for 48 hours (21). Adiponectin, resistin, and visfatin are

TheJournal ofClinical Investigation http://www.jci.org Volume115 Number5 May2005 1111
http://www.jci.org/http://www.jci.org/


2/9

review

Immunosuppression,susceptibility to

infectionIMalnutritJonNormal immune

functionI Irnrnunoactivation,suoceptibJlity toinflammatory diseaseIOvernutrition

Figure 1Metabolism and immunity are closely linked.Both overnutrition and undernutrition haveimplications for immune function. Starvationand malnutrition can suppress immune func-tion and increase susceptibility to infections.Obesity is associated with a state of aber-rant immune activity and increasing risk forassociated inflammatory diseases, includingatherosclerosis, diabetes, airway inflamma-tion, and fatty liver disease. Thus, optimalnutritional and metabolic homeostasis is animportant part of appropriate immune func-tion and good health.

also examples ofmolecules with immunological activity that areproduced in adipocytes (22-26).Finally, lipids themselves also participate in the coordinateregulation of inflammation and metabolism. Elevated plasmalipid levels are characteristic of obesity, infection, and otherinflammatory states. Hyperlipidemia in obesity is responsible inpart for inducing peripheral tissue insulin resistance and dyslip-idemia and contributes to the development of atherosclerosis.It is interesting to note that metabolic changes characteristic ofthe acute-phase response are also proatherogenic; thus, alteredlipid metabolism that is beneficial in the short term in fightingagainst infection is harmful if maintained chronically (1). Thecritical importance of bioactive lipids is also evident in theirregulation of lipid-targeted signaling pathways through fattyacid-binding proteins (FABPs)and nuclear receptors (see"Regu-lation of inflammatory pathways," below).

Macrophages and the link between inflammation and metabolism. Thehigh level of coordination of inflammatory and metabolic path-ways is highlighted by the overlapping biology and function ofmacrophages and adipocytes in obesity (Figure2).Geneexpressionis highly similar; macrophages express many, if not the majorityof"adipocyte" gene products such as the adipocyre/rnacrophageFABPaP2 (also known as FABP4)and PPARy,while adipocytescan express many "macrophage" proteins such as TNF-a,IL-6, and MMPs (6,27-29). Functional capability of these 2 celltypes also overlaps. Macrophages can take up and store lipid tobecome atherosclerotic foam cells.Preadipocytes under some con-ditions can exhibit phagocytic and antimicrobial properties andappear to even be able to differentiate into macrophages in theright environment, which suggests a potential immune role forpreadipocytes (30,31).Furthermore, macrophages and adipocytescolocalizein adipose tissue in obesity.The recent finding that obe-sity is characterized bymacrophage accumulation inwhite adiposetissue has added another dimension to our understanding of thedevelopment of adipose tissue inflammation in obesity (16, 17).Macrophages in adipose tissue are likelyto contribute to the pro-duction ofinflammatory mediators either alone orin concert withadipocytes, which suggests a potentially important influence of1112

macrophages in promoting insulin resistance. However,no directevidencehas been offered to establish this connection thus far.In terms of the immune response, integration between

macrophages and adipocytes makes sense, given that both celltypes participate in the innate immune response: macrophagesin their role as immune cells by killing pathogens and secret-ing inflammatory cytokines and chemokines; and adipocytes byreleasing lipids that maymodulate the inflammatory state or par-ticipate in neutralization of pathogens. While it is not yet knownwhether macrophages aredrawn to adipose tissue in other inflam-matory conditions, it is conceivable that macrophage accumula-tion in adipose tissue is a feature not onlyof obesity, but ofotherinflammatory states aswell.Inflammatory pathways to insulin resistanceAs discussed above, it is now apparent that obesity is associatedwith a state of chronic, low-grade inflammation, particularly inwhite adipose tissue.Howdo inflammatory cytokines and/or fattyacids mediate insulin resistance? How do the stresses of obesitymanifest inside of cells?In recent years, much has been learnedabout the intracellular signaling pathways activated byinflamma-tory and stress responses and how these pathways intersect withand inhibit insulin signaling.Insulin affects cells through binding to its receptor on the sur-face of insulin-responsive cells. The stimulated insulin receptor

phosphorylates itself and severalsubstrates, including members ofthe insulin receptor substrate (IRS)family, thus initiating down-stream signaling events (32,33).The inhibition of signaling down-stream of the insulin receptor is a primary mechanism throughwhich inflammatory signalingleadsto insulin resistance.Exposureof cells to TNF-a or elevated levels of free fatty acids stimulatesinhibitory phosphorylation of serine residues ofIRS-1 (34-36).This phosphorylation reduces both tyrosine phosphorylation ofIRS-1 in response to insulin and the ability ofIRS-1 to associatewith the insulin receptor and thereby inhibits downstream signal-ing and insulin action (35,37, 38).Recently it has become clear that inflammatory signaling path-ways can also become activated bymetabolic stresses originating

TheJournal of Clinical Investigation http://www.jci.org Volume115 Number5 May2005


3/9

Table 1F ac to rs th at m e dia te th e in te rs ec tio n o f m eta bo lis m a nd im m un ity

review

FactorsTNF-aIL-6

Me t abo l ic r e gu l at io nr in o be sity (S 1, S 2) Ar in o be sity (S 6, S 7)

Lept in r i n o b es ity ( S 12 )

Adiponect in t i n o b es ity ( S 15 )

Visfat inResist in

r i n o b es ity ( S 20 )V a ri ab le i n o b e si ty ( S2 2 , S 2 3)

IL-1 r b y h y pe rg ly cem ia ( S 2S )

IL -1RaIL-SIL-10

r i n o b es ity ( S 31 )r i n o b es ity ( S 32 )r i n o bes it y; t in m e ta bo lic s yn dr om e ( S3 5)

IL-1SMCP -1

r in o be sity ( S3 7, S 3S )r i n o b es ity ( S 41 )

M IFM -CSF

r i n o b es ity ( S 43 )

TGF-[3 r in o be sity ( S4 5, S 46 )

S o lu b le TN FRC- reac ti ve p ro te in

r i n o bes it y ( S5 2-S5 4)r in o be sity ( S5 5, S 56 )

Haptog lobin r i n o b es ity ( S 60 )

EffectsP romo te s in s ul in r es is ta n ce ( S 1, S 3 )

P r omo te s i n su l in r e si st a nc e ;c en tr a l a n ti -o be s it y a c ti o n (SS -S1 1 )M u lti pl e e ff ec ts o n immun e fu n cti on ;

s upp re s s es appe ti te ;p rom o te s F A o x id a ti on ( S 12 -S 1 4)

Ant i in f lammatory;p r omo te s i n su l in s ensi ti vi ty ;

s ti m ula te s F A o x id a tio n ( S1 5, S 1 6)E a rly B c ell g ro w th fa cto r; in su lin m im e tic ( S2 0, S 2 1)

I nduced in endo t oxem ia /i n fl ammat ion ;p r omo te s i n su l in r e si st a nc e ;

r eg u la te s f as tin g b lo o d g lu c os e le v el ( S2 3- S 26 )Proinf lammatory;

r e gu l at e s i n su l in s e c re t io n ;i nv o lv e d i n c e nt ra ll ep tin a c ti on ( S2 9 , S 3 0)

A n ti in fl amma to ry ; o p p os e s l ep tin a c ti on ( S 29 )P r oa the rog en ic ( S3 3, S3 4 )Ant i in f lammatory;

p rom o te s i ns u li n s e ns iti vi ty ( S 36 )P r oa the rog en ic ( S3 9, S4 0 )

Proatherogenic ;p rom o te s in s uli n r es is ta n ce ( S 34 , S 4 1, S 4 2)

I n hi b it s mac r ophag e m i g ra t io nMonocy t e /mac rophage d i ff e ren t ia t ion ;

s ti m ula te s a d ip o se g row th ( S 44 )I n hi b it s ad ip o c y te d i ff e re n ti at io n and

ad ip o s e t is s ue dev e lo pmen t;r e gu la t es a t he r o sc le r os is ( S47 -S49 )

Proinf lammatoryP ro in fl ammato r y ; a t he rogen i c ;

r is k fa c to r f or d ia b et es ( S 55 , S 5 7- S5 9)Proinf lammatory

M o us e m o de lL OF ( S 4) , GOF ( S 5)

L OF ( S 10 ), GOF ( S 11 )LOF (S1 2 )

L OF ( S 17 ), GOF ( S 1S , S 1 9)

LOF (S2 0 )L OF ( S 24 ), GOF ( S 25 , S 2 7)

LOF (S3 0 )

LOF (S3 3 )

L OF ( S 40 ) GOF ( S 39 )LOF (S4 2 )

GOF (S4 4 )L OF ( S 50 , S 5 1) , GOF ( S 49 )

GOF (S5 7 )

t, increase; ~, decrease; FA, fat ty acid; GOF, gain-of-function; IL-1Ra, IL-1 receptor a; LOF, loss-of-function; MCP-1, monocyte chemotact ic prote in-1;MIF, macrophage migration inhib itory factor;TNFR, TNF receptcr.cSee Supplemental References; supplemental material avai lable online with this art ic le;doi:10.1172/JCI200525102DSl

from inside the cell aswell asbyextracellular signaling molecules.It has been demonstrated that obesity overloads the functionalcapacity of the ERand that this ERstress leads to the activation ofinflammatory signaling pathways and thus contributes to insulinresistance (39-41). Additionally, increased glucosemetabolism canlead to a rise in mitochondrial production ofROS. ROS produc-tion is elevated in obesity, which causes enhanced activation ofinflammatory pathways (42, 43).Severalserine/threonine kinases are activated by inflammatory

or stressful stimuli and contribute to inhibition of insulin signal-ing, includingJNK, inhibitor ofNF-KB kinase (IKK),and PKC-8(44). Again, the activation of these kinases in obesity highlightsthe overlap ofmetabolic and immune pathways; these are the samekinases, particularly IKKandJNK, that are activated in the innateimmune response byToll-likereceptor (TLR)signaling in responseto LPS,peptidoglycan, double-stranded RNA,and other microbialproducts (45).Hence it is likelythat components ofTLR signalingpathways will also exhibit strong metabolic activities.

JNK. The 3 members of the JNK group of serine/threoninekinases, JNK-1, -2, and -3, belong to the MAPK family and

regulate multiple activities in development and cell function,in large part through their ability to control transcription byphosphorylating activator protein-1 (AP-1)proteins, includingc-Jun andJunB (46).JNK has recently emerged asa central meta-bolic regulator, playing an important role in the developmentof insulin resistance in obesity (47). In response to stimuli suchas ERstress, cytokines, and fatty acids, JNK is activated, where-upon it associates with and phosphorylates IRS-Ion Ser307,impairing insulin action (36, 39, 48). In obesity, JNK activityis elevated in liver, muscle, and fat tissues, and loss of JNK1prevents the development of insulin resistance and diabetes inboth genetic and dietary mouse models of obesity (47). Modula-tion of hepatic JNK1 in adult animals also produces systemiceffects on glucose metabolism, which underscores the impor-tance of this pathway in the liver (49). The contribution of theJNK pathway in adipose, muscle, or other tissues to systemicinsulin resistance is currently unclear. In addition, a mutationin JNK-interacting protein-1 (jlP1), a protein that binds JNKand regulates its activity, has been identified in diabetic humans(50). The phenotype of the jlP'l Ioss-of-funcr iou model is very



4/9

reviewAdipocyte

Macrophage

FABP" r ' rna"Nuclear hormone receptors:L X R ' r A I > ;InflammatoryresponseCytokines: TNF-a, IL-6

to lipid infusion, high-fat diet, or geneticobesity (59, 60). Moreover, inhibition ofIKK~ in human diabetics by high-doseaspirin treatment also improves insulinsignaling, although at this dose, it is notclearwhether other kinases are also affect-ed (61). Recent studies have also begun totease out the importance of IKK in indi-vidual tissues or cell types to the devel-opment of insulin resistance. Activationof IKK in liver and myeloid cells appearsto contribute to obesity-induced insulinresistance, though this pathway may notbe asimportant in muscle (62-64).

Other pathways. In addition to serine/threonine kinase cascades, other path-wayscontribute to inflammation-inducedinsulin resistance. For example, at least 3members of the SOCS family, SOCS1, -3,and -6, have been implicated in cytokine-mediated inhibition of insulin signaling(65-67). These molecules appear to inhibitinsulin signaling either byinterfering withIRS-1and IRS-2tyrosine phosphorylationor by targeting IRS-1 and IRS-2 for pro-teosomal degradation (65, 6S).SOCS3hasalsobeen demonstrated to regulate centralleptin action, and both whole body reduc-tion in SOCS3 expression (SOCS3+/-) andneural SOCS3 disruption result in resis-tance to high-fat diet-induced obesity andinsulin resistance (69, 70).Inflammatory cytokine stimulation canalso lead to induction of iNOS. Overpro-duction of nitric oxide also appears to

contribute to impairment of both muscle cellinsulin action and~ cell function in obesity (71,72). Deletion of iNOS preventsimpairment of insulin signaling in muscle caused by a high-fatdiet (72). Thus, induction of SOCS proteins and iNOS repre-sent 2 additional and potentially important mechanisms thatcontribute to cytokine-mediated insulin resistance. It is likelythat additional mechanisms linking inflammation with insulinresistance remain to be uncovered.

Metabolicresponse

Figure 2Lipids and inflammatory mediators: integration of metabolic and immune responses in adipocytesand macrophages through shared mechanisms. Under normal conditions, adipocytes storelipids and regulate metabolic homeostasis, and macrophages function in the inflammatoryresponse, although each cell type has the capacity to perform both functions. In obesity, adi-pose tissue becomes inflamed, both via infiltration of adipose tissue by macrophages and as aresult of adipocytes themselves becoming producers of inf lammatory cytokines. Inf lammation ofadipose tissue is a crucial step inthe development of peripheral insulin resistance. In addit ion, inproatherosclerotic conditions such as obesity and dyslipidemia, macrophages accumulate l ipidto become foam cells. Adipocytes and macrophages share common features such as expres-sion of cytokines, FABPs, nuclear hormone receptors, and many other factors. As evidenced bygenetic loss-of-function models, adipocyte/macrophage FABPs modulate both l ipid accumula-tion in adipocytes and cholesterol accumulation in macrophages, as well as the developmentof insulin resistance and atherosclerosis. PPARy and LXR pathways oppose inflammation andpromote cholesterol eff lux from macrophages and lipid storage in adipocytes.

similar to that of JNK1 deficiency in mice, with reduced JNKactivity and increased insulin sensitivity (51). Interestingly, theJNK2 isoform plays a significant nonredundant role in athero-sclerosis (52), though apparently not in type 2 diabetes. Recentstudies in mice demonstrate that JNK inhibition in establisheddiabetes or atherosclerosis might be a viable therapeutic avenuefor these diseases in humans (52,53).

PKC andIKK. Two other inflammatory kinases that playa largerole in counteracting insulin action, particularly in response tolipid metabolites, are IKK and PKC-8. Lipid infusion has beendemonstrated to lead to a rise in levelsof intracellular fatty acidmetabolites, such as diacylglycerol (DAG) and fatty acyl CoAs.This rise is correlated with activation of PKC-8 and increasedSer307 phosphorylation ofIRS-1 (54). PKC-8may impair insu-lin action by activation of another serine/threonine kinase,IKK~, orJNK (55). Other PKCisoforms have also been reportedto be activated by lipids and may also participate in inhibitionof insulin signaling (56).IKK~can impact on insulin signaling through at least 2 path-

ways. First, it can directly phosphorylate IRS-Ion serine resi-dues (34,57). Second, it can phosphorylate inhibitor ofNF-KB(IKB),thus activating NF-KB,a transcription factor that, amongother targets, stimulates production ofmultiple inflammatorymediators, including TNF-a and IL-6 (5S). Mice heterozygousfor IKK~ are partially protected against insulin resistance due1 1 1 4

Regulation of inflammatory pathwaysLipidsand lipid targets.The roleoflipids inmetabolic disease is com-plex.Asdiscussed above,hyperlipidemia leads to increased uptakeof fatty acids bymuscle cells and production of fatty acidmetab-olites that stimulate inflammatory cascades and inhibit insulinsignaling (54). On the other hand, intracellular lipids can alsobe antiinflammatory. Ligands of the liver X receptor (LXR)andPPARfamilies of nuclear hormone receptors are oxysterols andfatty acids, respectively,and activation of these transcription fac-tors inhibits inflammatory gene expression in macrophages andadipocytes, in large part through suppression ofNF-KB (73-79).LXRfunction is also regulated by innate immune pathways.Signaling from TLRsinhibits LXRactivity inmacrophages, caus-ing enhanced cholesterol accumulation and accounting, at leastin part, for the proatherogenic effects of infection (SO).Indeed,lack of MyDSS, a critical mediator of TLR signaling, reduces

TheJournal ofClinical Investigation http://www.jci.org Volume115 Number5 May2005


5/9

review( .. ER stress ........----------1

Obesity (nutrients) ~ Infection (pathogens)L . . . . --tI.. Activation of signaling cascades: ........ )JNKand IKK

~

Figure 3Nutrient and pathogen sensing or responsesystems have important overlapping features,and their modulation by obesity or infectioncan lead to overlapping physiological out-comes. For example, the chronic inflammationof obesity leads to elevated plasma lipid lev-els and the development of insul in resistance,eventually resulting in fatty liver disease, ath-erosclerosis, and diabetes. Infection typical lyleads to a more transient and robust inf lamma-tory response and short-term hyperlipidemiathat aids in the resolution of the infection. Insome circumstances of chronic infection, how-ever, insulin resistance, diabetes, and athero-sclerosis can result.

~ ~ - - - - - - - - Inflammation I IInsulin resistance ........----------- ...... Hyperlipidemia

~ + ~ ~Diabetesatherosclerosis in apoli> mice (81). Interestingly, despite theinhibitory effects ofTLR signaling on LXRcholesterol metabo-lism, LXRappears to be necessary for the complete response ofmacrophages to infection. In the absence ofLXR, macrophagesundergo accelerated apoprosis and are thus unable to appropri-ately respond to infection (82). Unliganded PPARo also seemsto have proinflammatory functions, mediated at least in partthrough its association with the transcriptional repressor Bcelllymphoma 6 (BeL-6) (83).The activity of these lipid ligands is influenced by cytosolicFABPs.Animals lacking the adipocyte/rnacrophage FABPsap2and mall are strongly protected against type 2 diabetes and ath-erosclerosis, a phenotype reminiscent of that of thiazolidinedi-one-treated (TZD-treated) mice and humans (27, 84, 85). Onemechanism for this phenotype ispotentially related to the avail-ability of endogenous ligands for these receptors that stimulatestorage oflipids in adipocytes and suppress inflammatory path-ways in macrophages (86). In general, it appears that locationin the body, the composition of the surrounding cellular envi-ronment, and coupling to target signaling pathways are criticalfor determining whether lipids promote or suppress inflam-mation and insulin resistance. Accumulation of cholesterol inmacrophages promotes atherosclerosis and of lipid in muscleand liver promotes insulin resistance, while, as seen in TZD-treated and FABP-deficient mice, iflipids are forced to remainin adipose tissue, insulin resistance in the context of obesity canbe reduced (85). Thus, lipids and their targets clearly play bothmetabolic and inflammatory roles; however, the functions thatthey assume are dependent onmultiple factors.

Pharmacological manipulation of inflammation. In corroborationof genetic evidence in mice that loss of inflammatory mediatorsor signaling molecules prevents insulin resistance (11, 47, 59),pharmacological targeting of inflammatory pathways alsoimproves insulin action. Effective treatment has been demon-strated both with inhibitors of inflammatory kinases and withagonists of relevant transcription factors. As discussed above,salicylates promote insulin signaling by inhibiting inflamma-tory kinase cascades within the cell. Through inhibition ofIKK and possibly other kinases, salicylates are able to improveglucose metabolism in both obese mice and diabetic humans(53,55,74). Targeting oONK using a synthetic inhibitor and/oran inhibitory peptide has been demonstrated to improve insulin

Atherosclerosis

action in obesemice and reduce atherosclerosis in the apoE-defi-cient rodent model (52, 53). These results directly demonstratethe therapeutic potential oONK inhibitors in diabetes.Synthetic ligands have been produced to all 3 PPARisoforms

as well as LXR-a, though only PPARyand PPARa ligands havebeen approved for clinical treatment (87,88). TZDs, high-affinityligands ofPPARy,which aregiven clinicallyas insulin-sensitizingagents, likely improve insulin action through multiple mecha-nisms, including both activating lipid metabolism and reducingproduction ofinflammatoty mediators such asTNFu (85,89-93).SyntheticPPARaligands, fibrates, areused to treat hyperlipidemia.These drugs appear to work predominantly through stimulationof fatty acid oxidation, though they also have antiinflammatoryactions that contribute to their effects (87, 94).LXRligands havebeendemonstrated to improve glucose metabolism in experimen-tal animals (88), and it remains to beseenwhether suppression ofinflammation contributes to this action.In targeting inflammation to treat insulin resistance and diabe-tes, it is possible that seeking inhibitors for individual inflamma-toty mediators may not be amaximally effectivestrategy, asotherredundant components maybesufficient to continue to propagateinflammatory pathways.For example,targeting individual inflam-matoty cytokinesmaynot behighly effective,whereastargeting theinflammatory kinasesJNKand IKKgenerates a robust antidiabeticaction becausethesefactors integrate signals frommultiple inflam-matory mediators. On the other hand, if amore central process ormediator canbe identified, thismayprovide an evenmore attractivetarget. TheERstress pathway could potentially beone such centralprocess, in that this pathway is able to activatebothJNK and IKK;thus, inhibiting the ERstress response through addition of chap-erones or other mechanisms couldpotentially disableboth of thesearms of the inflammatory response and rescueinsulin action (39).It has recentlybeen demonstrated that miceinwhich the chaperoneORP150 is transgenically or adenovirally overexpressed exhibitedreduced ERstress and improved insulin tolerance compared withcontrols, whereas reduction of the expression of this molecule inliverresults in increased ERstress and insulin resistance (40,41).Origin of inflammation in obesityWhilewe are now aware ofmany of the inflammatory factors thatmediate insulin resistance and have some understanding of theintracellular pathways involved, there is still much that remains



6/9

reviewInflammatory~ - ~~ -- cytokines and ...... - - ...lipids IR-

I---llRS-1 12 ----Insulin actions/ I ~~K~ . . . . . . . o s FABP ~ ,t - ' - [ N - - - , F I = = - - K B - - ' ~ _ _ ' [ ~ A _ P _ . I _ l , - - - - , - c_ ' n _ . f _ l a _ m _ m _ a _ I O _ r y " - - , , g . _ e n _ ~ _ sU p i d l c h o l e s l e r o lFA - - - - - - - ,. _ _ c P _ F '_ ! A R l _ R . .- L - - - - - - - - " - r _ L _ X R _ _ , _ l _ . C_ m _ e - - - , t a _ c _ b _ D _ l I s _ m _ _ _ , , _ Q e _ n - - - , e s

IrHyperlipidemia,hyperglycemia L_,:;--_----I~

""" " ""

\\

Nucleus\I\

Figure 4Model of overlapping metabolic and inflammatory signaling and sensing pathways in adipocytes or macrophages. Inflammatory pathways canbe initiated by extracellular mediators such as cytokines and lipids or by intracellular stresses such as ER stress or excess ROS productionby mitochondria. Signals from all of these mediators converge on inflammatory signaling pathways, including the kinases JNK and IKK. Thesepathways lead to the production of addit ional inf lammatory mediators through transcriptional regulat ion as well as to the direct inhibit ion of insul insignaling. Other pathways such as those mediated through the SOCS proteins and iNOS are also involved in inflammation-mediated inhibition ofinsulin action. Opposing the inflammatory pathways are transcription factors from the PPAR and LXR families, which promote nutrient transportand metabolism and antagonize inflammatory activity. More proximal regulation is provided by FABPs, which likely sequester ligands of thesetranscription factors, thus promoting a more inf lammatory environment. The absence of FABPs is antiinf lammatory. The cel l must str ike a balancebetween metabolism and inflammation. In conditions of overnutrition, this becomes a particular challenge, as the very processes required forresponse to nutrients and nutrient utilization, such as mitochondrial oxidative metabolism and increasing protein synthesis in the ER, can inducethe inf lammatory response. IR, insul in receptor.

poorly understood. Crucial questions that are currently openregard the initiation of the inflammatory response. Is inflamma-tion the primary event linking obesity with insulin resistance, ordoes the inflammatory response begin only after the onset of resis-tance to insulin? How and why does the body initiate an inflam-matory response to obesity?Does obesity per seinduce an inflam-matory response, or is inflammation initiated as asecondary eventbyhyperlipidemia or hyperglycemia?In reviewing the facts, it is fairly clear that obesity promotesstates of both chronic low-grade inflammation and insulin resis-tance. However, evenin the absence of obesity, infusion of animalswith inflammatory cytokines or lipids can cause insulin resistance(54).Additionally, humans with some other chronic inflammatoryconditions are at increased risk for diabetes; for example, aboutone-third of patients with chronic hepatitis C develop type 2 dia-betes, and elevatedTNF-a levelsare implicated in this link (95,96).Rheumatoid arthritis also predisposes patients to diabetes andparticularly cardiovascular disease, and some evidence indicates alink between inflammatory lung diseases and risk of cardiovascu-lar disease and diabetes (97-99). Finally, removal of inflammatorymediators or pathway components, such asTNF-a,]NK, and IKK,protects against insulin resistance in obese mouse models, and1116

treatment of humans with drugs that target these pathways, suchassalicylates, improves insulin sensitivity (6,11,47,59,61). Thus,the available evidence strongly suggests that type 2 diabetes is aninflammatory disease and that inflammation is a primary causeof obesity-linked insulin resistance, hyperglycemia, and hyperlip-idemia rather than merely a consequence (Figure 3).But how does the inflammatory response begin? Though this

question cannot currently be answered, we can suggest some rea-sonable speculations based on the available data. It seems likelythat the inflammatory response is initiated in the adipocytesthemselves, as they are the first cells affected bythe developmentof obesity, or potentially in neighboring cells that may be affect-ed by adipose growth. How might expanding adipocytes triggeran inflammatory response?One mechanism that, based on newly emerging data, appears

to be of central importance is the activation of inflamma-tory pathways by ER stress. Obesity generates conditions thatincrease the demand on the ER (39-41). This is particularly thecase for adipose tissue, which undergoes severe changes in tissuearchitecture, increases in protein and lipid synthesis, and per-turbations in intracellular nutrient and energy fluxes. In bothcultured cells and whole animals, ER stress leads to activation

TheJournal of Clinical Investigation http://www.jci.org Volume 115 Number 5 May 2005


7/9

of JNK and thus contributes to insulin resistance (39). Inter-estingly, ERstress also activates IKK and thus may represent acommon mechanism for the activation of these 2 important sig-naling pathways (100).A second mechanism that may be relevant in the initiationof inflammation in obesity is oxidative stress. Due to increaseddelivery of glucose to adipose tissue, endothelial cells in the fatpad may take up increasing amounts of glucose through theirconstitutive glucose transporters. Increased glucose uptake byendothelial cells in hyperglycemic conditions causes excesspro-duction ofROS inmitochondria, which inflicts oxidativedamageand activates inflammatory signaling cascadesinside endothelialcells (101).Endothelial injury in the adipose tissue might attractinflammatory cells such asmacrophages to this site and furtherexacerbate the local inflammation. HyperglycemiaalsostimulatesROS production in adipocytes, which leads to increased produc-tion ofproinflammatory cytokines (42).Why inflammation?Perhaps one of the most difficult questions to answeriswhy obe-sity elicits an inflammatory response. Why, if the ability to storeexcess energy has been preserved through the course of evolu-tion, does the body react in amanner that isharmful to itself?Wehypothesize that this reaction is tied to the interdependency ofmetabolic and immune pathways.Could obesity-induced inflammation simply be a side effect of

this interaction that was never selected against since chronic obe-sity and its associated disorders have been so rare over time forpeople in their reproductive years?Perhaps the stresses ofobesityare similar enough to the stresses of an infection that the bodyreacts to obesity asit would to an infection. For example, in bothinfection and obesity, intracellular stress pathways such as theJNK and IKK-NF-KBpathways are activated. Could these path-ways be activated by similar mechanisms in both conditions?One mechanism that appears to be critical for initiation of thisresponse in both situations is ERstress. During viral infection,stress pathways are activated by an excess of viral proteins inthe ER(102). Similarly, the demands of obesity also result in anoverloaded ERand activation of these pathways (39). Anotherscenario might be related to the capturing of components of theinsulin-signaling pathway bymicroorganisms. Some pathogensactivate host intracellular signaling cascades, including the PI3K-Akt pathway, which is also critical for insulin signaling (102).Perhaps in a situation inwhich this pathway becomes overstimu-lated byan increased need to take up glucose, the cell begins tointerpret the signal asan indication ofinfection and responds byresisting the anabolic insulin signal and instead activating cata-bolic and inflammatory pathways.On the other hand, perhaps the inflammatory response to obe-

sity is not simply an undesirable byproduct, but rather a homeo-static mechanism to prevent the organism from reaching a pointat which excessfat accumulation impairs mobility or otherwisediminishes fitness. Lipid storage and accumulation of fat weightrequire anabolic processes, exemplified byinsulin action, whereasinflammation stimulates catabolism, including lipolysis fromadipocytes. It is conceivable that mechanisms such as the acti-vation of catabolism via inflammation (and hence resistance toanabolic signals) maybe an attempt to keep bodyweight withinacceptable bounds. While there is no available experimental evi-dence that addresses the role oflow-grade inflammation in such

review

homeostasis, some support for this idea can be seen in findingsthat experimentally induced local inflammation or insulin resis-tance in adipose tissue, such as that in adipose-specific insulinreceptor knockout mice and adipose-specific TNF transgenicmice, ismetabolically favorable, resulting in a leanphenotype andsystemic insulin sensitivity(103,104).ConclusionsOur understanding of the characteristics of inflammation inobesity and the mechanisms bywhich this inflammation con-tributes to insulin resistance has been increasing rapidly overthe last decade, such that we can now suggest a synthesizedmodel (Figure 4). While it is clear that inhibition of insulinreceptor signaling pathways is a central mechanism throughwhich inflammatory and stress responses mediate insulin resis-tance, it is likely that other relevant pathways, molecules, andalternative mechanisms involved in this interaction have yet tobe uncovered. Of particular interest is the role of alterations inmitochondrial function in diabetes. Whilewedid not cover thistopic in this article, the reader is referred to an excellent recentreviewfor more information (105).Another important question iswhether genetic differences canpredispose some individuals to inflammation-mediated insulinresistance. Several studies have reported associations betweendiabetes and polymorphisms in the promoters ofTNF-a and IL-6(106-109). The most well-accepted polymorphism associatedwith type 2 diabetes is found in the gene encoding PPARy(110).Asit is a transcription factor with some antiinflammatory activ-ities, such as suppressing the production ofTNF-a, one couldimagine howaltered activity ofPPARycould affect susceptibilityto inflammation in obesity. Similarly, genetic variations in theFABP,JNK, IKK, or ER stress pathways or any other loci thatmodulate the extent of inflammation and consequently insu-lin resistance could define the risk of individuals for developingmetabolic complication of obesity.Finally, in addition to diabetes and cardiovascular disease,

inflammation is also known to be important for linking obesityto airwayinflammation and asthma, fatty liverdisease, and possi-blycancerand other pathologies. Understanding themechanismsleading from obesity to inflammation will haveimportant impli-cations for the design ofnovel therapies to reduce the morbidityand mortality of obesity through the prevention of its associatedchronic inflammatory disorders.AcknowledgmentsWearegrateful to the members of the Hotamisligillaboratory fortheir contributions. Research in the Hotamisligillaboratory hasbeen supported by the NIH, the American Diabetes Association,and the Pewand Sandler Foundations. Weregret the omission ofmany important references by our colleagues in the field due tospace limitations.Note: References S1-S60 are available online with this article;doi:10.1172/JCI200525102DSl.Address correspondence to: Gokhan S. Hotamisligil, Depart-ment of Genetics and Complex Diseases, Harvard School ofPublic Health, 665 Huntington Avenue, Boston, Massachusetts02115,USA.Phone: (617)432-1950;Fax: (617)432-1941; E-mail:[email protected].

TheJournal of Clinical Investigation http://www.jci.org Volume115 Number5 May2005 1117
mailto:[email protected]://www.jci.org/http://www.jci.org/mailto:[email protected].


8/9

review1.Khovidhunkit, W.)et al. 2004. Effects of infectionand inflammation on lipid and lipoprotein metab-olism: mechanisms and consequences to the host[review].]. Lipid Res. 45:1169-1196.

2.Chandra) R.K. 1996. Nutrition) immunity andinfection: from basic knowledge of dietary manip-ulation of immune responses to practical applica-tion of ameliorating suffering and improving sur-vival.Proc.Natl. Acad. Sci. U S.A. 93:14304-14307.

3.Blackburn, G.L.2001. Pasteur's Quadrant and mal-nutrition. Nature. 409:397-401.

4. Cummings) D.E.) and Schwartz) M.W. 2003. Genet-ics and pathophysiology of human obesity. Annu.Rev. Med. 54:453-471.

5.Hotamisligil, G.S.2004. Inflammation, TNFalpha,and insulin resistance. In Diabetes mellitus: afunda-mental and clinicaltext.D.T.S.LeRoith and J.M.Olef-sky)editors. 3rd edition. Lippincott) Williams andWilkins. NewYork, NewYork, USA 953-962.

6.Hotamisligil, G.S.) Shargill, N.S.) and Spiegelman)B.M. 1993. Adipose expression of tumor necrosisfactor-alpha: direct role in obesity-linked insulinresistance. Science. 259:87-91.

7.Sethi, J.K, and Hotamisligil, G.S. 1999. The roleofTNF alpha in adipocyte metabolism. Semin. CellDev. Bioi. 10:19-29.

8.Hotamisligil, G.S.) et al. 1995. Increased adiposetissue expression of tumor necrosis factor-alpha inhuman obesity and insulin resistance.]. Clin.Invest.95:2409-2415.

9.Kern) P.A.)et al. 1995. The expression of tumornecrosis factor in human adipose tissue. Regula-tion by obesity) weight loss) and relationship tolipoprotein lipase.]. Clin.Invest. 95:2111-2119.

10.Saghizadeh, M., et al. 1996. The expression ofTNFalpha byhuman muscle. Relationship to insulinresistance.]. Clin.Invest. 97:1111-1116.

11.Uysal, K.T.)et al. 1997. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 389:610-614.

12.Pickup) J.C. 2004. Inflammation and activatedinnate immunity in the pathogenesis oftype 2 dia-betes. DiabetesCare. 27:813-823.

13. Dando na, P., Aljada, A, and Bandyopadhyay, A2004. Inflammation: the link between insulinresistance) obesity and diabetes. Trends Immunol.25:4-7.

14.Miller) e) et al. 1998. Tumor necrosis factor-alphalevels in adipose tissue of lean and obese cats.].Nutr. 128(Suppl. 12):2751S-2752S.

15.Soukas, A.)et al. 2000. Leptin-specific patterns ofgene expression in white adipose tissue. GenesDev.14:963-980.

16.Weisberg) S.P.) et al. 2003. Obesity is associatedwith macrophage accumulation in adipose tis-sue.]. Clin. Invest. 112:1796-1808. doi:10.1172/]CI200319246.

17.Xu)H.)etal. 2003.Chronic inflammation infat playsa crucial role in the development of obesity-relatedinsulin resistance.]. Clin. Invest. 112:1821-1830.doi:10.1172/]CI200319451.

18.Fernandes) G.)et al. 1978. Immune response in themutant diabetic C57BL/Ks-dt+ mouse. Discrepan-cies between in vitro and in vivo immunologicalassays.]. Clin.Invest. 61:243-250.

19.Parooqi, 1.5.)et al.2002. Beneficial effects ofleptinon obesity)T cellhyporesponsiveness) and neuroen-docrine/metabolic dysfunction of human congeni-talleptin deficiency.]. Clin. Invest. 110:1093-1103.doi:10.1172/]CI200215693.

20. Chandra, R.K 1980. Cell-mediated immunity ingenetically obese C57BL/6] ob/ob] mice. Am.].Clin.Nutr.33:13-16.

21.Lord, G.M., et al. 1998. Leptin modulates the T-cellimmune response and reversesstarvation-inducedimmunosuppression. Nature. 394:897-901.

22. Berg, AH., Combs, T.P., and Scherer, P.E. 2002.ACRP30/adiponectin: an adipokine regulating

1118

glucose and lipid metabolism. Trends Endocrinol.Metab.13:84-89.

23. Ouchi, N.) et al. 2003. Obesity) adiponectin andvascular inflammatory disease. CurroOpin. Lipidol.14:561-566.

24. Srcppan, eM.) and Lazar)M.A.2004. The currentbiology of resistin.]. Intern. Med. 255:439-447.

25. Lehrke) M.) et al. 2004. An inflammatory cascadeleading to hyperresistinemia in humans. PLoSMed.1:e45. doi:10.1371/journal.pmed.0010045.

26.Pukuhara, A.)et al. 2005. Visfatin: a protein secret-ed byvisceral fat that mimics the effects ofinsulin.Scieuce.307:426-430.

27.Makowski, L., et al. 2001. Lack of macrophagefatty-acid-binding protein aP2 protects mice defi-cient in apolipoprotein E against atherosclerosis.Nat. Med. 7:699-705.

28. Tontonoz, P.)et al. 1998. PPARgamma promotesmonocyte/macrophage differentiation and uptakeof oxidized LDL. Cell.93:241-252.

29. Boulo umie, A.) et al. 2001. Adipocyte producesmatrix metalloproteinases 2 and 9:involvement inadipose differentiation. Diabetes. 50:2080-2086.

30. Cousin) B.)et al. 1999. A role for preadipocytes asmacrophage-like cells.FASEB]. 13:305-312.

31.Charriere, G.)et al. 2003. Preadipocyte conversionto macrophage. Evidence of plasticity.]. Bioi. Chem.278:9850-9855.

32.White, M.F. 1997.The insulin signalling system andthe IRSproteins. Diabetologia. 40(Suppl. 2):S2-S17.

33. Saltiel, AR., and Pessin, J.E. 2002. Insulin signal-ing pathways in time and space. Trends Cell Bioi.12:65-71.

34.Yin) M.J.)Yamamoto) v. , and Gaynor) R.B. 1998.The anti-inflammatory agents aspirin and salicy-late inhibit the activity ofI(kappa)B kinase-beta.Nature. 396:77-80.

35.Hotamisligil, G.S.,et al. 1996. IRS-I-mediated inhi-bition of insulin receptor tyrosine kinase activityinTNF-alpha- and obesity-induced insulin resistance.Scieuce.271:665-668.

36. Aguirre, V.,et al. 2000. The c-]un NH(2)-termi-nal kinase promotes insulin resistance duringassociation with insulin receptor substrate-1and phosphorylation of Ser(307).]. Bioi. Chem.275:9047-9054.

37. Aguirre, V.,et al. 2002. Phosphorylation of Ser307in insulin receptor substrate-1 blocks interactionswith the insulin receptor and inhibits insulinaction.]. Bioi. Chern.277:1531-1537.

38.Paz) K.)et al. 1997. A molecular basis for insu-lin resistance. Elevated serine/threoninephosphorylation ofIRS-1 and IRS-2 inhibits theirbinding to the juxtamembrane region of the insu-lin receptor and impairs their ability to undergoinsulin-induced tyrosine phosphorylation.]. Biol.Chem.272:29911-29918.

39. Ozcan, U.) et al. 2004. Endoplasmic reticulumstress links obesity) insulin action) and type 2 dia-betes. Science. 306:457-461.40. Nakatani) y.) et al.2005. Involvement of endoplas-mic reticulum stress in insulin resistance and dia-betes.]. Bioi. Chem. 280:847-851.

41.Ozawa)K.)et al.2005. The endoplasmic reticulumchaperone improves insulin resistance in type 2diabetes. Diabetes. 54:657-663.

42.Lin, Y. , et al. 2005. The hyperglycemia-inducedinflammatory response in adipocytes: the role ofreactive oxygenspecies.].Bioi.Chern.280:4617-4626.

43.Furukawa) S.) et al. 2004. Increased oxidativestress in obesity and its impact on metabolic syn-drome.]. Clin.Invest.114:1752-1761. doi:10.1172/]CI200421625.

44. Zick, Y.2003. Role ofSer/Thr kinases in the uncou-pling of insulin signaling. Int.]. Obes.Relat. Metab.Disord. 27(Suppl. 3):S56-S60.

45.Medzhitov, R. 2001. Toll-like receptors and innateimmunity. Nat. Rev. Immunol. 1:135-145.

46. Davis, R.J. 2000. Signal transduction by the ]NKgroup ofMAP kinases. Cell.103:239-252.

47.Hirosumi j ] ., et al. 2002. A central role for JNK inobesity and insulin resistance.Nature. 420:333-336.

48.Gao)Z.)et al.2004. Inhibition of insulin sensitivityby free fatty acids requires activation of multipleserine kinases in 3T3-L1adipocytes.Mo!.Endocrinol.18:2024-2034.49. Nakatani, Y. , et al. 2004. Modulation of the]NKpathway in liver affects insulin resistance status.]. Bioi. Chem. 279:45803-45809.

50.Waeber, G.,etal. 2000. The geneMAPK81P1, encod-ing islet-brain-L, is a candidate for type 2 diabetes.Nat. Genet. 24:291-295.

51.]aeschke, A, Czech, M.P., and Davis, R.J. 2004. Anessential role ofthe]IP1 scaffold protein for]NK acti-vation in adipose tissue. GenesDev. 18:1976-1980.

52.Ricci)R.)et al.2004. Requirement ofJNK2 for scav-enger receptor A-mediated foam cell formation inatherogenesis. Scieuce. 306:1558-1561.

53. Kaneto, H.) et al. 2004. Possible novel therapyfor diabetes with cell-permeable ]NK-inhibitorypeptide. Nat. Med. 10:1128-1132.

54.Yu,C,,et al. 2002. Mechanism bywhich fatty acidsinhibit insulin activation of insulin receptor sub-strare-I (IRS-I)-associated phosphatidylinositol3-kinase activity in muscle. J. Bioi. Chem.277:50230-50236.

55.Perseghin, G.)Petersen)K.)and Shulman) G.!.2003.Cellular mechanism of insulin resistance: potentiallinks with inflammation. Int.]' Obes.Relat. Metab.Disord. 27(Suppl. 3):S6-S11.

56. Schmitz-Peiffer) C. 2002. Protein kinase C andlipid-induced insulin resistance in skeletal muscle.Ann. N. Y . Acad. Sci.967:146-157.

57. Gao, Z., et al. 2002. Serine phosphorylation ofinsulin receptor substrate 1 by inhibitor kappa Bkinase complex.]. Bioi. Chem. 277:48115-48121.

58. Shoelson, S.E.)Lee)].)and Yuan)M. 2003. Inflamma-tion and the IKK beta/I kappa B/NF-kappa B axisin obesity- and diet-induced insulin resistance. Int.]. Obes.Relat. Metab. Disord.27(Suppl. 3):S49-S52.

59. Yuan, M., et al. 2001. Reversal of obesity- and diet-induced insulin resistance with salicylatesor target-ed disruption ofIkkbeta. Science. 293:1673-1677.

60.Kim)J.K.) et al. 2001. Prevention of fat-inducedinsulin resistance by salicylate. ]. CZin. Invest.108:437-446. doi:10.1172/]CI200111559.

61. Hundal, R.S., et al. 2002. Mechanism by whichhigh-dose aspirin improves glucose metabolismin type 2 diabetes.]. Clin. Invest. 109:1321-1326.doi:10.1172/]CI200214955.

62.Cai,D.) et al.2005. Localand systemic insulin resis-tance resulting from hepatic activation ofIKK-betaand NF-kappaB.Nat. Med. 11:183-190.

63. Arkan, M.e., et al. 2005. IKK-beta links inflam-mation to obesity-induced insulin resistance. Nat.Med.11:191-198.

64. Rohl, M., et al. 2004. Conditional disruption ofIkappaB kinase 2 fails to prevent obesity-inducedinsulin resistance.]. CZin.Invest. 113:474-481.doi:10.1172/]CI200418712.

65.Ru i,L.,et al.2002. SOCS-1 and SOCS-3 block insu-lin signaling byubiquitin-mediated degradation ofIRS1 and IRS2.]. Bioi. Chem. 277:42394-42398.

66.Mooney, R.A, et al. 2001. Suppressors of cytokinesignaling-1 and -6 associate with and inhibitthe insulin receptor. A potential mechanism forcytokine-mediated insulin resistance.]. Biol. Chem.276:25889-25893.

67. Emanuelli, B., et al. 2001. SOCS-3 inhibits insulinsignaling and isup-regulated in response to tumornecrosis factor-alpha in the adipose tissue of obesemice.]. Bioi. Chem. 276:47944-47949.

68. Ueki, K, Kondo, T., and Kahn, CR. 2004. Suppres-sor of cytokine signaling 1 (SOCS-1) and SOCS-3cause insulin resistance through inhibition of tyro-sine phosphorylation of insulin receptor substrate

The Journal ofClinical Investigation http://www.jci.org Volume115 Number5 May2005


9/9

proteins by discrete mechanisms. Mol. Cell Bioi.24:5434-5446.

69.Mori, H.)et al. 2004. Socs3 deficiency in the brainelevates leptin sensitivity and confers resistance todiet-induced obesity.Nat. Med. 10:739-743.

70. Howard) J.K.) et al. 2004. Enhanced leptin sensi-tivity and attenuation of diet-induced obesity inmice with haploinsufficiency of Socs3. Nat. Med.10:734-738.

71. Shimabukuro) M.) et al. 1997. Role of nitric oxidein obesity-induced beta cell disease. J. Clin. Invest.100:290-295.

72. Perreault) M.) and Marette) A.2001. Targeted dis-ruption of inducible nitric oxide synthase protectsagainst obesity-linked insulin resistance inmuscle.Nat.Med.7:1138-1143.

73.Seo, J.B.) et al. 2004. Activated liver X receptorsstimulate adipocyte differentiation through induc-tion of peroxisome proliferator-activated receptorgamma expression. Mol. Cell.Bioi. 24:3430-3444.

74.Moller, D.E., and Berger,].P. 2003. RoleofPPARs inthe regulation of obesity-related insulin sensitivityand inflammation. Int. J. Obes.Relat. Metab. Disord.27(Suppl. 3):S17-S21.

75.Joseph, S.B., et al. 2003. Reciprocal regulation ofinflammation and lipid metabolism by liver Xreceptors. Nat. Med. 9:213-219.

76.Jiang, c., Ting, AT., and Seed, B. 1998. PPAR-gamma agonists inhibit production of monocyteinflammatory cytokines. Nature. 391:82-86.

77. Chawla, A, et al. 2001. PPAR-gamma dependentand independent effects on macrophage-geneexpression in lipid metabolism and inflammation.Nat. Med. 7:48-52.

78.Chawla,A, etal. 2001. APPARgamma-LXR-ABCA1pathway in macrophages is involved in cholesterolefflux and atherogenesis. Mol. Cell.7:161-171.

79. Dayncs, R.A.)and Jones) D.C. 2002. Emerging rolesofPPARs in inflammation and immunity. Nat. Rev.Immunol.2:748-759.

80. Castrillo, A, et al. 2003. Crosstalk between LXRand toll-like receptor signaling mediates bacterialand viral antagonism of cholesterol metabolism.Mol. Cell. 12:805-816.

81.Bjorkbacka, H.)et al.2004.Reduced atherosclerosisin MyD88-null mice links elevated serum choles-terollevels to activation of innate immunity signal-ing pathways. Nat. Med. 10:416-421.

82.Joseph, S.B.,et al.2004. LXR-dependent geneexpres-sion is important for macrophage survival and theinnate immune response. Cell.119:299-309.

83. Lee)C.H.) et al. 2003. Transcriptional repressionof atherogenic inflammation: modulation by

PPARdelta. Science.302:453-457.84.Maeda, K., et al. 2005.Adipocyte/macrcphage fattyacid binding proteins control integrated metabolicresponses in obesity and diabetes. CellMetabolism.1:107-119.

85.Spiegelman, B.M. 1998. PPAR-gamma: adipogenicregulator and thiazolidinedione receptor. Diabetes.47:507-514.86.Makowski, 1.., and Hotamisligil, G.S. 2004. Fattyacid binding proteins - the evolutionary cross-roads of inflammatory and metabolic responses.]. Nutr. 134:2464S-2468S.

87.Lee)C.H.) Olson) P.)and Evans) R.M. 2003. Mini-review: lipid metabolism) metabolic diseases)and peroxisome proliferator-activated receptors.Endocrinology. 144:2201-2207.

88. Laffitte) B.A.)et al. 2003. Activation of liver Xreceptor improves glucose tolerance throughcoordinate regulation of glucose metabolism inliver and adipose tissue. Proc.Nat!' Acad. Sci.U.S.A.100:5419-5424.

89.Wellen)K.E.)et al.2004. Interaction of tumor necro-sis factor-alpha- and thiazolidinedione-regulatedpathways in obesity. Endocrinology. 145:2214-2220.

90.Peraldi, P., Xu, M., and Spiegelman, B.M. 1997.Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling.]. Clin.Invest. 100:1863-1869.

91.Ruan, H., Pownall, H.J., and Lodish, H.F. 2003.Troglitazone antagonizes tumor necrosis fac-tor-alpha-induced reprogramming of adipocyregene expression by inhibiting the transcriptionalregulatory functions ofNF-kappaB.]. Bioi. Chem.278:28181-28192.

92.Miles, P.D., et al. 1997. TNF-alpha-induced insu-lin resistance in vivo and its prevention bytrogli-tazone. Diabetes. 46:1678-1683.

93.Lehmann.Llvl., et al. 1995. Anantidiabetic thiazoli-dinedione isahigh affinity ligandfor peroxisome pro-liferator-activated receptor gamma (PPARgamma).]. Bioi. Chem. 270:12953-12956.

94.Steels, B.) et al. 1998. Activation of human aor-tic smooth-muscle cells is inhibited by PPARal-pha but not by PPARgamma activators. Nature.393:790-793.

95.Knobler, H.)et al.2003.Tumor necrosis factor-alpha-induced insulin resistance may mediate the hepati-tis Cvirus-diabetes association. Am. J. Gastroenterol.98:2751-2756.

96.Bahtiyar, G.) et al. 2004. Association of diabetesand hepatitis C infection: epidemiologic evidenceand pathophysiologic insights. CurroDiab. Rep.4:194-198.

review97.Iribarren, c., Tolsrykh, LV.,and Eisner, M.D. 2004.Are patients with asthma at increased risk of coro-naty heart disease? Int.]. Epidemiol. 33:743-748.

98.Raria, J.S.)et al. 2004. Chronic obstructive pulmo-nary disease) asthma) and risk of type 2 diabetes inwomen. DiabetesCare. 27:2478-2484.

99. Sattar, N., et al. 2003. Explaining how "high-grade" systemic inflammation accelerates vas-cular risk in rheumatoid arthritis. Circulation.108:2957-2963.

100.Hung, ].H., et al. 2004. Endoplasmic reticulumstress stimulates the expression ofcyclooxygenase-2through activation of NF-kappaB and pp38mitogen-activated protein kinase. J. Bio!. Chem.279:46384-46392.

Lul.Brownlee, M. 2001. Biochemistry and molecu-lar cell biology of diabetic complications. Nature.414:813-820.

102.Hatada) E.N.) Krappmann, D.)and Scheidereit, C.2000. NF-kappaB and the innate immune response.Curr Opin. Immunol. 12:52-58.

Lu.s.Bluher, M.) et al. 2002. Adipose tissue selectiveinsulin receptor knockout protects against obesityand obesity-related glucose intolerance. Dev. Cell.3:25-38.

104.Xu) H.) et al. 2002. Exclusive action of transmem-brane TNF alpha in adipose tissue leads to reducedadipose mass and local but not systemic insulinresistance. Endocrinology. 143:1502-1511.

105.Lowell, B.B., and Shulman, G.L 2005. Mitochon-drial dysfunction and type 2 diabetes. Science.307:384-387.

106.Vozarova, B., et al. 2003. The interleukin-6 (-174)G/C promoter polymorphism is associated withtype-2 diabetes mellitus in Native Americans andCaucasians. Hum. Genet. 112:409-413.

Luz.Dalziel, B.)et al. 2002. Association of the TNF-alpha -308 G/A promoter polymorphism withinsulin resistance in obesity. Obes.Res. 10:401-407.

108.Costa) A.)et al. 2003. Lower rate of tumor necrosisfactor-alpha -863Aallele and higher concentrationof tumor necrosis factor-alpha receptor 2 in first-degree relatives of subjects with type 2 diabetes.Metabolism. 52:1068-1071.

109.Furuta) M.) et al. 2002. Relationship of the tumornecrosis factor-alpha -308 A/G promoter polymor-phism with insulin sensitivity and abdominal fatdistribution inJapanese patients with type 2 diabe-tes mellitus. DiabetesRes. Clin. Pract. 56:141-145.

110.Florez, j.c., Hirschhorn, J., and Altshuler, D. 2003.The inherited basis of diabetes mellitus: implica-tions for the genetic analysis of complex traits.Annu. Rev. GenomicsHum. Genet.4:257-291.

TheJournal of Clinical Investigation http://www.jci.org Volume115 Number5 May2005 1119

inflammation, stress and diabetes

Documents