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Inflammatory links between obesity andmetabolic disease
Carey N. Lumeng, Alan R. Saltiel
J Clin Invest. 2011;121(6):2111-2117. https://doi.org/10.1172/JCI57132.
The obesity epidemic has forced us to evaluate the role of inflammation in the healthcomplications of obesity. This has led to a convergence of the fields of immunology andnutrient physiology and the understanding that they are inextricably linked. The reframing ofobesity as an inflammatory condition has had a wide impact on our conceptualization ofobesity-associated diseases. In this Review, we highlight the cellular and molecularmechanisms at play in the generation of obesity-induced inflammation. We also emphasizehow defining the immune regulation in metabolic tissues has broadened the understandingof the diversity of inflammatory responses.
Review Series
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Review series
TheJournalofClinicalInvestigationâ â â http://www.jci.orgâ â â Volumeâ121â â â Numberâ6â â â Juneâ2011â 2111
Inflammatory links between obesity and metabolic disease
Carey N. Lumeng1,2 and Alan R. Saltiel2,3,4
1Department of Pediatrics and Communicable Diseases, 2Department of Molecular and Integrative Physiology, and 3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA. 4Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
Theobesityepidemichasforcedustoevaluatetheroleofinflammationinthehealthcomplicationsofobesity.Thishasledtoaconvergenceofthefieldsofimmunologyandnutrientphysiologyandtheunderstandingthattheyareinextricablylinked.Thereframingofobesityasaninflammatoryconditionhashadawideimpactonourconcep-tualizationofobesity-associateddiseases.InthisReview,wehighlightthecellularandmolecularmechanismsatplayinthegenerationofobesity-inducedinflammation.Wealsoemphasizehowdefiningtheimmuneregulationinmetabolictissueshasbroadenedtheunderstandingofthediversityofinflammatoryresponses.
IntroductionTheâburdenâofâobesityâonâhealthâextendsâacrossâmultipleâorganâsystemsâandâdiseases.âWhileâitsâimpactâonâtissuesâinvolvedâinânutrientâregulationâisâmanifestâinâtheâdevelopmentâofâinsulinâresistanceâandâtypeâ2âdiabetes,âthereâareâalsoâunexpectedâcon-nectionsâbetweenâobesityâandâtheâriskâofâcancerâandâpulmonaryâdiseases.âOverâtheâpastâdecade,âtheâsearchâforâaâpotentialâunifyingâmechanismâbehindâtheâpathogenesisâofâobesity-associatedâdis-easesâhasârevealedâaâcloseârelationshipâbetweenânutrientâexcessâandâderangementsâinâtheâcellularâandâmolecularâmediatorsâofâimmunityâandâinflammation.âThisâhasâgivenâbirthâtoâtheâconceptâofââmetainflammationââ(1)âtoâdescribeâtheâchronicâlow-gradeâinflammatoryâresponseâtoâobesity.âWeâpresentâhereâaâbroadâover-viewâofâtheâlinksâbetweenâobesityâandâimmuneâresponsesâwithâaâfocusâonâmetabolicâdiseaseâandâargueâthatâtheâintersectionâbetweenâtheâpathwaysâthatâcontrolânutrientâmetabolismâandâinflammatoryâresponsesâmayâbeâbroadlyâapplicableâtoâourâunder-standingâofâinflammationâandâtheâimmuneâsystem.
The nature of obesity-induced inflammationInflammationâisâaâcoordinatedâresponseâtoâharmfulâstimuli,âwithâtheâgoalâofâreturningâtheâsystemâbackâtoâaânormalâbaseline.âTheâinflammatoryâresponseâtriggeredâbyâobesityâinvolvesâmanyâcom-ponentsâofâtheâclassicalâinflammatoryâresponseâtoâpathogensâandâincludesâsystemicâincreasesâinâcirculatingâinflammatoryâcytokinesâandâacuteâphaseâproteinsâ(e.g.,âC-reactiveâprotein),ârecruitmentâofâleukocytesâtoâinflamedâtissues,âactivationâofâtissueâleukocytes,âandâgenerationâofâreparativeâtissueâresponsesâ(e.g.,âfibrosis;âref.â2).ââHowever,â theânatureâofâobesity-inducedâmetainflammationâ isâuniqueâcomparedâwithâotherâinflammatoryâparadigmsâ(e.g.,âinfec-tion,âautoimmuneâdisease)âinâseveralâkeyâaspects.âTheâchronicânatureâofâobesityâproducesâaâtonicâlow-gradeâactivationâofâtheâinnateâimmuneâsystemâthatâaffectsâsteady-stateâmeasuresâofâmeta-bolicâhomeostasisâoverâtime.âChildhoodâobesityâmayâplaceâindi-vidualsâatâriskâforâlifelongâmetainflammation,âsinceâinflammatoryâmarkersâareâelevatedâinâobeseâchildrenâasâyoungâasâ3âyearsâoldâ(3).âSuperimposedâonâthisâchronicâinflammationâareârecurrentâacuteâepisodesâofânutrition-relatedâimmuneâactivationâinducedâbyânutri-entâavailabilityâ(fastingâorâhigh-fatâmeals)â(4â6).
Inâaddition,âtheâmulti-organâinvolvementâofâobesity-inducedâinflammationâisâuniqueâandâpresentsâaâchallengeâtoâresearchersâattemptingâtoâteaseâoutâdiseaseâmechanismsâinâcomplexâmeta-bolicâsystemsâ(ref.â7âandâFigureâ1).âItâisâclearâthatâinflammationâparticipatesâinâtheâlinkâbetweenâobesityâandâdisease.âNon-biasedâassessmentsâofâgeneâexpressionânetworksâinâadiposeâtissueâidentifyâaârobustâpatternâofâoverexpressedâinflammatoryâgenesâassociatedâwithâobesityâandâmetabolicâdiseaseâandâenrichedâforâmacrophageâgenesâ(8,â9).âMultipleâinflammatoryâinputsâcontributeâtoâmeta-bolicâdysfunction,âincludingâincreasesâinâcirculatingâcytokinesâ(10),âdecreasesâinâprotectiveâfactorsâ(e.g.,âadiponectin;âref.â11),âandâcommunicationâbetweenâinflammatoryâandâmetabolicâcells.âForâexample,âdirectâandâparacrineâsignalsâfromâM1âclassicallyâacti-vatedâmacrophagesâcanâimpairâinsulinâsignalingâandâadipogenesisâinâadipocytes,âwhileâunstimulatedâorâM2âalternativelyâactivatedâmacrophagesâfailâtoâgenerateâtheseâeffectsâ(12).âSimilarâeffectsâonâadipocyteâinflammationâandâglucoseâtransportâareâgeneratedâbyâsignalsâfromâactivatedâconventionalâTâcellsâsuchâasâIFN-Îłâ(13).âInâparallel,âdysregulatedâmacrophage-myocyteâandâmacrophage-hepatocyteâsignalingâcanâinfluenceâinsulinâsensitivityâ(14,â15).âWhileâtransientâinflammatoryâstatesâsuchâasâsepsisâcanâhaveâmulti-organâeffects,âfewâotherâchronicâinflammatoryâdiseasesâareâchar-acterizedâbyâtheâfeaturesâofâpancreatic,âliver,âadipose,âheart,âbrain,âandâmuscleâinflammationâasâisâseenâinâobesity.
Immunity and the maintenance of metabolic homeostasis.âInâsomeâcases,âadaptiveâimmuneâresponsesâmayâbeâbeneficialâandâhelpâpreserveâmetabolicâhomeostasis.âAllâmetabolicâtissuesâcontainâresidentâpopulationsâofâleukocytesâpresentâevenâinâleanâhealthyâanimals,âindicatingâthatâtheâimmuneâsystemâisâpoisedâtoârespondâtoânutrient-derivedâsignalsâ(16,â17).âForâexample,âtheâextentâofâadiposeâtissueâmacrophageâ(ATM)âinfiltrationâisâdynamicallyâalteredâwithâlipidâfluxâinâadipocytesâinâleanâandâobeseâstates,âandâmayâserveâtoâsuppressâlipolyticâsignalsâ(4).âATMsâareârecruitedâtoâadiposeâtissueâwhenâchemokineâorâlipidâreleaseâ(lipolysis)âisâtriggeredâandâmayâfunctionâtoâpromoteâlipidâstorageâbyâsuppress-ingâlipolysis.âTheseâeventsâcouldâbeâclassifiedâasâanâinflammatoryâresponse,âasâitâinvolvesâtheâacuteârecruitmentâofâleukocytesâtoâfat,âbutâitâlacksâmanyâofâtheâcardinalâsignsâofâclassicâinflammationâ(dolor,ârubor,âcalor,âandâtumor).
Reconcilingâtheseâobservationsârequiresâaâmoreâexpansiveâviewâofâ whatâ immunologicâ activationâ meansâ beyondâ theâ classicalâproinflammatoryâparadigm.âTheâdiversityâofâATMâfunctionâsup-
Conflictofinterest:âTheâauthorsâhaveâdeclaredâthatânoâconflictâofâinterestâexists.
Citationforthisarticle:âJ Clin Invest.â2011;121(6):2111â2117.âdoi:10.1172/JCI57132.
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2112 TheJournalofClinicalInvestigationâ â â http://www.jci.orgâ â â Volumeâ121â â â Numberâ6â â â Juneâ2011
portsâthisâbroadâview,âasâdoesâtheâobservationâthatâleukocytesâadoptâaâwideârangeâofâactivationâstatesâdependentâuponâtheâlocalâstimuliâ(18).âUponâstimulationâbyâLPSâandâIFN-Îł,âmacrophagesâassumeâaâclassicalâproinflammatoryâactivationâstateâ(M1)âthatâgeneratesâbac-tericidalâorâTh1âresponsesâtypicallyâassociatedâwithâobesity.âInâcon-trast,âTh2âcytokinesâsuchâasâIL-4âandâIL-13âgenerateâanâalternativeâ
macrophageâactivationâstateâ(M2)âthatâpro-motesâfibroticâresponsesâandâattenuationâofâclassicalâNF-ÎșBâdependentâactivationâpath-ways.âWhileâATMsâlikelyâassumeâaânum-berâofâstatesâalongâtheâM1/M2âspectrumâdependingâonâfatâdepotâlocationâandânutri-tionalâstatusâ(19,â20),âincreasingâadiposityâresultsâinâaâshiftâinâtheâinflammatoryâprofileâofâATMsâasâaâwholeâfromâanâM2âstateâtoâoneâinâwhichâclassicalâM1âproinflammatoryâsig-nalsâpredominateâ(21â23).
Uniqueâ molecularâ linksâ betweenâ theâM1/M2âpolarizationâaxisâandâmetabolismâsuggestâthatâtheâhomeostaticâregulationâofânutrientâutilizationâandâtheâ immuneâsystemâareâcoupledâtogether.âTheâM2âacti-vationâstateâisâintrinsicallyâlinkedâtoâtheâactivityâofâPPARÎŽâandâPPARÎł,âwell-knownâregulatorsâofâlipidâmetabolismâandâmito-chondrialâactivityâ(24).âPpard-âandâPparg-knockoutâmiceâfailâtoâgenerateâanâM2âacti-vationâstateâandâareâmoreâsusceptibleâtoâtheâM1-skewedâinflammationâthatâaccom-paniesâdiet-inducedâobesityâ(DIO)âinâtheâliverâandâadiposeâtissueâ(17,â25,â26).âPhysi-ologicâenhancementâofâtheâM2âpathwaysâ(e.g.,âeosinophilârecruitmentâinâparasiticâinfection)âalsoâappearsâ toâbeâcapableâofâreducingâmetainflammationâandâimprov-ingâinsulinâsensitivityâ(27).
Inâfat,âtheâM2âstateâofâresidentâATMsâisâmaintainedâbyâcytokineâproductionâ(e.g.,âIL-4)âfromâuniqueânaturalâhelperâlympho-cytesâandâeosinophils;âtheârecruitmentâofâtheseâcellsâtoâfatâisâsuppressedâinâtheâobeseâenvironmentâ(27,â28).âThisâdemonstratesâthatâ maintainingâ metabolicâ homeosta-sisârequiresâaâbalancedâimmuneâresponseâandâanâintegratedânetworkâofâmultipleâcellâtypes.âAdiposeâtissueâalsoâcontainsâpotentâtolerogenicâ CD4+â Tregsâ thatâ areâ down-regulatedâbyâobesity,âaâpotentialâinitiatingâeventâinâmetainflammationâ(13,â29).âLike-wise,â thereâ appearâ toâ beâ innateâ systemsâbyâwhichânutrientâsignalsâareâutilizedâtoâself-limitâinflammation.âForâexample,âtheâobesity-inducedâincreaseâinâexpressionâofâGPR120,âanâomega-3âfattyâacidâ(FA)ârecep-torâonâmacrophagesâcapableâofâattenuatingâM1âmacrophageâactivationâandâincreasingâM2âgeneâexpression,âlimitsâinflammation;âitâisâpossibleâthatâthisâmechanismâmightâbeâexploitedâinâfutureâdrugâdevelopmentâ(30).
Tissue specific proinflammatory changes with obesityTheâdiscoveryâofâATMâactivationâwithâobesityâsparkedâaâwaveâofâinterestâintoâhowâimmuneâresponsesâintersectâwithâobesityâ(31,â32).ââWeâknowânowâthatâtheâdynamicâregulationâofâinflammatoryâcellsâwithâobesityâisânotâlimitedâtoâfatâandâthatâinflammatoryâandâmeta-bolicâsignalsâconvergeâinâaâmyriadâofâcontexts.âThisâprovidesânewâ
Figure 1Cellular mediators of inflammation and immunity in obesity. The multisystem effects of obesity are linked to an imbalance in homeostatic and proinflammatory immune responses. Obesity triggers inflammatory pathways in the brain and adipose tissue that dysregulate physiological responses that maintain insulin and leptin sensitivity. Over time, ectopic lipid accumulation in muscle, liver, and blood vessels activates tissue leukocytes, contributes to organ-specific disease, and exacerbates systemic insulin resistance. Cellular- and cytokine-mediated inflam-mation in pancreatic islets accelerates the progression toward diabetes. FFA, free FA; INS, insulin; KC, Kupffer cell; Tconv, conventional CD4+ T cells.
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opportunitiesâtoâunderstandâtheâpathogenesisâofâmanyâorgan-spe-cificâdiseasesâassociatedâwithâobesityâ(Figureâ1).
Pancreatic islets.âRelevantâtoâtypeâ2âdiabetesâisâtheâdemonstrationâthatâinflammationâinâpancreaticâisletsâcanâreduceâinsulinâsecretionâandâtriggerâÎČâcellâapoptosisâleadingâtoâdecreasedâisletâmass,âcriticalâeventsâinâtheâprogressionâtoâdiabetesâ(33,â34).âTheâmediatorsâofâtheseâeffectsâareâmultifactorialâandâlikelyâinvolveâcytokinesâpro-ducedâbyâÎČâcellsâthemselvesâ(35).âAsâinâadiposeâtissue,âmacrophagesâaccumulateâinâisletsâwithâDIOâandâmayâbeâaâsignificantâsourceâofâproinflammatoryâcytokinesâthatâblockâÎČâcellâfunctionâ(36).âThisâpointâisâoftenâignoredâinâstudiesâthatâmanipulateâmacrophagesâbyâCre-mediatedârecombinationâorâBMâtransplantationâandâmayâbeâanâunderappreciatedâmechanismâforâprotectionâfromâdiabetesâinâmanyâanimalâmodels.
Adipose tissue.âAdiposeâtissueâinsulinâresistanceâandâdysfunctionalâlipidâstorageâinâadipocytesâareâsentinelâeventsâinâtheâprogressionâtowardâmetabolicâdysregulationâwithâobesity.âForcedâexpansionâofâadiposeâtissueâbyâtransgenicâoverexpressionâofâtheâadipokineâadiponectinâpreventsâmetabolicâdiseaseâdespiteâmassiveâobesityâ(37).âImpairedâlipogenic/adipogenicâcapacityâisâassociatedâwithâincreasedâvisceralâfatâinâobeseâadolescentsâ(38),âandâsmallerâomen-talâadipocytesâisâaâfeatureâofâmetabolicallyâhealthyâobeseâadultsâ(39).âTheseâfindingsâsupportâtheâmodelâthatâlipidââspilloverââfromâfatâpromotesâmetabolicâdiseaseâbyâfosteringâectopicâlipidâdepo-sition.âSinceâanâestimatedâexcessâofâ20â30âmillionâmacrophagesâaccumulateâwithâeachâkilogramâofâexcessâfatâinâhumans,âoneâcouldâargueâthatâincreasedâadiposeâtissueâmassâisâdeâfactoâaâstateâofâincreasedâinflammatoryâmassâ(40).
InputsâintoâthisâinflammatoryâresponseâincludeâERâstress,âadi-poseâtissueâhypoxia,âandâadipocyteâdeathâ(41â43).âSinceâchangesâinâATMânumberâandâgeneâexpressionâprofileâoccurâcoincidentâwithâtheâdevelopmentâofâinsulinâresistanceâ(41,â44),âitâisâpossibleâthatâATMsâareâmerelyâeffectorsâofâaâcoordinatedâinflammatoryâresponseâthatâincludesâtheâaccumulationâofâCD8+âTâcells,âTh1-polarizedâCD4+âTâcells,âandâtheâlossâofâTregsâ(29,â44).âNKâcells,âNKTâcells,âandâmastâcellsâareâalsoâimplicatedâinâmetainflammationâ(40,â45,â46).âOverall,âourâchallengeâinâunderstandingâadiposeâtissueâinflammationâwillâbeâtoâidentifyâtheâtemporalâandâspatialâinter-actionsâbetweenâleukocytesâinâfatâinâtheâcontextâofâinflammatoryâinitiationâasâwellâasâtheirâresolution.
Inflammation in liver and muscle.âNonalcoholicâfattyâliverâdiseaseâ(NAFLD)âisâaâstrongâriskâfactorâforâinsulinâresistance,ânonalco-holicâsteatohepatitis,âandâdyslipidemia,âindependentâofâvisceralâadiposityâ(47).âManyâofâtheâsignalingâpathwaysâinvolvedâinâbothâinflammationâandâmetabolismâareâelevatedâinâsteatoticâliverâ(e.g.,âJNK,âTLR4,âERâstress).âSimilarâtoâtheâeffectsâofâobesityâonâadiposeâtissue,âNAFLDâisâassociatedâwithâanâincreaseâinâM1/Th1âcytokinesâandâquantitativeâincreasesâinâimmuneâcellsâ(48â50).âInâaddition,âmodulationâofâPPARÎŽ-dependentâM2âpolarizationâpathwaysâpro-tectsâmiceâfromâNAFLDâ(17,â26).âTheseâeffectsâmayâbeâmediatedâviaâKupfferâcellsâresidentâinâtheâliver,âorâbyâuniqueâcellâpopulationsârecruitedâtoâtheâliverâwithâobesityâ(51).
Thereâisâalsoâevidenceâofâincreasedâinflammatoryâcytokineâpro-ductionâandâincreasedâinflammationâinâskeletalâmuscleâinâobesityâ(52).âMyocytesâhaveâtheâcapacityâtoârespondâtoâinflammatoryâsig-nalsâviaâpatternârecognitionâreceptorsâ(PRRs)âsuchâasâTLR4âwithâdirectâmetabolicâeffectsâ(53).âMuscleâinflammationâmayâbeâlinkedâtoâinfiltratingâmacrophagesâthatâareâ inducedâinâobeseâmuscleâandâhaveâpropertiesâofâM1âactivationâ(23,â54).âThisâtopicâisâcom-plicatedâbyâtheâfactâthatâleukocyteâtraffickingâofâmonocytesâandâ
macrophagesâisâintrinsicallyâlinkedâtoâmuscleâinjuryâandârepairâ(55),âincreasingâtheâchallengeâofâde-convolutingâtheâacuteâandâchronicâinflammatoryâchangesâinâmuscleâwithâDIO.
Hypothalamic inflammation and obesity.â Humanâ genomeâ wideâassociationâstudiesâhaveâidentifiedâlociânearâorâwithinânumerousâneuronalâgenesâthatâaffectâBMI,âsuggestingâthatâvariationâinâtheâcentralâcontrolâofâmetabolismâplaysâaâprominentâroleâinâgeneticâobesityâriskâ(56).âLipidâinfusionâandâaâhigh-fatâdietâ(HFD)âacti-vateâhypothalamicâinflammatoryâsignalingâpathways,âresultingâinâincreasedâfoodâintakeâandânutrientâstorageâ(57).âWithâDIO,âmetabolitesâsuchâasâdiacylglycerolsâandâceramidesâaccumulateâinâtheâhypothalamusâandâinduceâleptinâandâinsulinâresistanceâinâtheâCNSâ(58,â59).âPartâofâthisâeffectâisâmediatedâbyâsaturatedâFAs,âwhichâactivateâneuronalâJNKâandâNF-ÎșBâsignalingâpathwaysâwithâdirectâeffectsâonâleptinâandâinsulinâsignalingâ(60).âDisruptionâofâsignalingâthroughâTLR4/MyD88,âIKKÎČ/NF-ÎșB,âandâERâstressâpathwaysâinâneuronsâprotectsâmiceâfromâDIOâandâitsâdownstreamâmetabolicâeffectsâ(60â62).
Theâeffectsâofâbrainâinflammationâonâtheâmetabolicâfunctionâofâperipheralâtissuesâareâbroad.âIndependentâofâobesity,âhypotha-lamicâinflammationâcanâimpairâinsulinâreleaseâfromâÎČâcells,âimpairâperipheralâinsulinâaction,âandâpotentiateâhypertensionâ(63â65).âManyâofâtheseâeffectsâareâgeneratedâbyâsignalsâfromâtheâsympathet-icânervousâsystem,âwhichâisâalsoâcapableâofâinducingâinflammatoryâchangesâinâadiposeâtissueâinâresponseâtoâneuronalâinjuryâ(66).âAâfutureâchallengeâisâtoâunderstandâhowâinflammatoryâsignalsâinâtheâbrainâgenerateâresponsesâthatâinâsomeâcasesâgenerateânegativeâenergyâbalanceâ(anorexia),âwhileâinâotherâcasesâgeneratesâpositiveâenergyâbalanceâ(weightâgain)â(67).
Theâdynamicâinterplayâbetweenâhypothalamicâinflammationâandâ obesityâ suggestâ additionalâ targetsâ forâ antiinflammatoryâtherapiesâinâobesity.âAâkeyâextensionâofâtheseâobservationsâisâtheâpotentialâthatâantiinflammatoryâpathwaysâmayâcounteractâtheseâCNSâinflammatoryâeventsâandâimproveâleptinâsensitivity.âRecentâevidenceâsuggestsâthatâIL-6âandâIL-10âareâinvolvedâinâtheâexercise-inducedâsuppressionâofâhyperphagiaâandâsuppressâIKKÎČ/NF-ÎșBâandâERâstressâinâtheâbrainâ(68).âTheâIKKÎČ/NF-ÎșBâinhibitorâsodiumâsalicylateâisâalsoâcapableâofâpreventingâtheâaccumulationâofâcerami-desâinâtheâhypothalamusâwithâlipidâinfusionâ(58).
Development.âAnotherâintriguingâpossibleâlinkâbetweenâinflam-mationâandâtheâriskâforâobesityâinvolvesâeventsâinâearlyâembryonicâdevelopment.âEpidemiologicâandâanimalâmodelsâhaveâdemonstrat-edâaâstrongâassociationâbetweenâtheâprenatalâandâperinatalâenvi-ronmentâandâobesity-associatedâdiseasesâ(69).âTheâriskâforâobesityâandâmetabolicâdisordersâfollowsâaâU-shapedâdistributionâbasedâonâbirthâweight,âwithâincreasedâriskâinâlow-âandâhigh-birth-weightâinfantsâ(70,â71).âSinceâpregnancyârepresentsâaâphysiologicâinflam-matoryâstateâinvolvingâtheâinnateâandâacquiredâimmuneâsystem,âinflammatoryâmechanismsâmayâcontributeâtoâtheâinâuteroâpro-grammingâofânutrientâmetabolismâ(72).âMaternalâobesityâisâassoci-atedâwithâendotoxemiaâandâATMâaccumulationâthatâmayâaffectâtheâdevelopingâfetusâ(73).âPlacentalâinflammationâisâaâcharacteristicâofâmaternalâobesity,âaâriskâfactorâforâobesityâinâoffspring,âandâinvolvesâinflammatoryâmacrophageâinfiltrationâthatâcanâalterâtheâmater-nal-fetalâcirculationâ(74).âInflammatoryâdisturbancesâinâtheâpla-centaâmayâalterâtheânutrientâsetâpointsâestablishedâearlyâinâlifeâandâpredisposeâtoâanâacceleratedâpatternâofâcatch-upâgrowthâthatâcon-tributesâtoâtheâriskâforâlaterâobesity,âespeciallyâinâlow-birth-weightâinfantsâ(75,â76).âTheâconceptâthatâinflammatoryânetworksâcanâinfluenceâtheâpredilectionâtowardâobesityâisâsupportedâbyâtheâfind-
review series
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ingsâthatâvariationâinâobesityâsusceptibilityâbetweenâmouseâstrainsâisâintrinsicallyâlinkedâtoâtheâinflammatoryânetworksâandâleukocyteâcompositionâofâadiposeâtissueâestablishedâpriorâtoâHFDâexposureâ(77).âOverall,âthereâisâmuchâtoâbeâlearnedâaboutâhowâmaternalâandâpaternalâfactorsâcontributeâtoâtheâepigeneticâprogrammingâofâmetabolismâgenesâthatâcontributeâtoâlong-termâeffectsâonâadultâbodyâweightâ(78,â79).âItâwillâbeâinterestingâtoâseeâwhetherâinflam-matoryâresponseâgenesâareâcoordinatelyâalteredâwithâmetabolicâgeneânetworksâbasedâonâtheâinâuteroâenvironment.
How does inflammation cause metabolic dysfunction?Manyâmolecularâsignalingâpathwaysâhaveâbeenâdescribedâatâtheâinterfaceâbetweenâinflammationâandâmetabolismâ(e.g.,â insulinâreceptorâsignalingâinâmacrophages;âref.â80).âHereâweâwillâhighlightâseveralâprominentâpathwaysâthatâareâcoordinatelyâregulatedâduringâobesityâthatâtranslateâaâmetabolicâchallengeâintoâanâinflammatoryâresponseâandâcontributeâtoâobesity-associatedâdiseaseâ(Figureâ2).
PRRs as metabolic sensors.âPRRsâareâcomponentsâofâtheâ innateâimmuneâ systemâ wellâ knownâ forâ theirâ abilityâ toâ senseâ foreignâmoleculesâ(pathogen-associatedâmolecularâpatterns)âandâinitiateâaâdefenseâresponse.âHowever,âtheâabilityâofâPRRsâtoâsenseâendog-enousâligandsâinducedâinâtheâobeseâstateâisânowâunderstoodâtoâbeâaâ
triggerâinâobesity-associatedâinflammation.âOfâtheseâPRRs,âTLR4âhasâreceivedâtheâmostâattention,âasâthisâreceptorâcanâbeâactivatedâbyâfreeâFAsâtoâgenerateâproinflammatoryâsignalsâandâactivateâNF-ÎșBâ(81).âTLR4-defi-cientâmiceâareâprotectedâfromâtheâinflam-matoryâactivationâinducedâbyâobesityâandâdemonstrateâprotectionâfromâinsulinâresis-tanceâinducedâbyâlipidâinfusionâ(82).âPartâofâthisâeffectâisâmediatedâbyâleukocytesâ(83),âbutâthereâisâclearâevidenceâthatâdirectâeffectsâofâTLR4âactivationâinânon-hematopoieticâcellsâcontributeâtoâtheâmetabolicâphenotypeâ(53).âAdiposeâtissueâexpressesânearlyâallâTLRâfamilyâmembers,âandâTLR2-knockoutâmiceâareâprotectedâfromâhigh-fatâDIOâandâinsulinâresistance,âsuggestingâaâbroadâroleâforâTLRsâinâobesityâandâitsâassociatedâmorbiditiesââ(84,â85).âBesidesâFAs,âTLRsâalsoâsenseâandâregulateâgutâmicrobesâinâaâwayâthatâcontrib-utesâtoâmetabolism,âasâTlr5â/ââmiceâdemon-strateâobesityâandâinsulinâresistanceârelatedâtoâalterationsâinâtheâgutâmicrobiomeâ(86).
TheâNod-likeâreceptorâ(NLR)âfamilyâofâPRRsâalsoâsenseâobesity-inducedâsignalsâinâmultipleâcontexts.âNLRsâareâactivatedâbyâdangerâsignalsâfromâstressedâorâdyingâcellsâandâmobilizeâleukocytesâtowardâtheseâstimuliâtoâconstrainâtissueâdamageâ(87,â88).âInâmacrophages,âNLRâactivationâstimulatesâtheâ cryptopyrin/NLRP3â inflammasomeâtoâinduceâIL-1ÎČâandâIL-18âproductionâviaâcaspase-1.âTheseâpathwaysâcontributeâtoâpancreaticâÎČâcellâdeathâwithâchronicâhyper-glycemiaâandâaffectâdiabetesâprogressionâ(89).âCaspase-1âandâIL-1ÎČâareâalsoâinducedâinâadiposeâtissueâwithâDIO,âandâNlrp3-âandâCasp1-deficientâ miceâ demonstrateâ resis-
tanceâtoâDIO-inducedâinflammationâ(90).âTheâmechanismâofâthisâprotectiveâeffectâmayâbeâdrivenâbyâalterationsâinâtheâM1âactiva-tionâofâATMs,âasâNlrp3-knockoutâmiceâshowâdecreasedâM1âandâincreasedâM2âgeneâexpressionâwithoutâquantitativeâchangesâinâATMs.âIfâPRRsâcanâbroadlyâactâasâdualâsensorsâofâpathogenicâandâendogenousâsignalsârelevantâtoâobesity,âtheâpotentialâpathwaysâcontributingâtoâmetainflammationâmayâbeâvast.
IKKÎČ and NF-ÎșB.âTheâintracellularâsignalsâdownstreamâofâTLRâactivationâoccurâviaâmultipleâpathways,âwhichâmayâbeâdependentâon,âorâindependentâof,âtheâadaptorâproteinâMyD88.âWhileâMyD88-dependentâsignalingâcontributesâtoâhypothalamicâinflammationâwithâobesityâ(61),âitsâroleâinâotherâmetabolicâtissuesâisâunclear,âasâMyd88â/ââmiceâareâmoreâsusceptibleâtoâinsulinâresistanceâwithâDIOâ(91).âActivationâofâIÎșBâkinase-ÎČâ(IKKÎČ)âoccursâdownstreamâofâMyD88âandâplaysâcriticalârolesâinâinflammationâinâtheâliver,âmyeloidâcells,âandâtheâhypothalamusâinâtheâobeseâstateâ(92,â93).âThisâwideârangeâofâactionâlikelyâexplainsâtheâinsulin-sensitizingâeffectâofâsalicylate,âanâIKKÎČâinhibitorâthatâisâcurrentlyâinâclinicalâtrialsâforâtypeâ2âdiabetesâtherapyâ(94,â95).
TheâultimateâendpointâforâTLR/IKKÎČâsignalsâisâNF-ÎșBâdepen-dentâactivationâofâinflammatoryâgeneâtranscriptionâ(96).âInâvivoâimagingâofâNF-ÎșBâactivationâidentifiedâadiposeâtissueâandâATMsâ
Figure 2Molecular pathways at the interface between obesity and inflammation. Multiple signaling path-ways participate in translating obesity-derived nutrient and inflammatory signals into a cellular response relevant in disease. These include proinflammatory (red) and antiinflammatory (blue) signals from the cell surface that integrate through many common intracellular pathways to generate the coordinated increase in inflammatory genes while repressing genes important in maintaining proper nutrient metabolism. PKR, RNA-dependent protein kinase.
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asâtheâmajorâsitesâofâNF-ÎșBâinductionâwithâDIOâ(97).âOneâNF-ÎșBâsensitiveâgeneâinducedâbyâHFDâisâtheâproteinâkinaseâIkke,âwhichâappearsâtoâplayâaâroleâinâmaintainingâbodyâweightâandâinsulinâresis-tanceâbyâsuppressingâthermogenesisâ(97).âTheâtemporalâcontrolâofâNF-ÎșBâactivationâisâalsoâimportant,âandâthereâareâunresolvedâissuesâdifferentiatingâtheâmetabolicâeffectsâofâacuteâandâchronicâNF-ÎșBâactivation.âForâexample,âacuteâexerciseâinâleanâadultsâstimu-latesâmuscleâNF-ÎșBâactivityâcorrelatingâwithâtheâtransientâreleaseâofâproinflammatoryâcytokinesâsuchâasâIL-6â(98).
Ceramides and intracellular lipids in inflammation and metabolism.âTheâdownstreamâeffectsâofâTLR4âactivationâareânotâlimitedâtoâtheâactivationâofâNF-ÎșB.âAâkeyâcommonâdenominatorâbetweenâmetabolismâandâinflammationâmayâlieâinâtheâbalanceâbetweenâintracellularâlipidâspeciesâsuchâasâceramidesâandâsphingolipidsâ(99,â100).âInhibitionâofâceramideâproductionâblocksâtheâabilityâofâsaturatedâFAsâtoâinduceâinsulinâresistanceâ(101).âTheâinductionâofâceramideâsynthesisâbyâLPSâandâsaturatedâFAâisâdependentâuponâTLR4âinâmanyâmetabolicâtissues,âincludingâtheâhypothalamusâandâmuscle,âwhereâceramideâproductionâcanâinhibitâinsulinâsignalingâthroughâAktâ(58).âTLR4-mediatedâceramideâproductionâinâmeta-bolicâtissuesâisâdependentâonâIKKÎČ,âasâsalicylatesâdecreaseâceramideâlevelsâinâtheâliver,âmuscle,âandâhypothalamus.
Theâadipokineâadiponectinâhasâlongâbeenârecognizedâtoâhaveâpositiveâbenefitsâonâmultipleâcellâtypesâtoâpromoteâinsulinâsensitiv-ityâandâdeactivateâproinflammatoryâpathways.âCeramideâregulationâmayâbeâaâcommonâdenominatorâofâtheseâeffects,âasâadiponectinâstimulatesâceramidaseâactivityâandâmodulatesâtheâbalanceâbetweenâceramidesâandâsphingosine-1-phosphateâ(102).âTheâinfluenceâofâadiponectinâonâceramideâcontentâinâcellsâappearsâtoâbeâimportantâforâmultipleâtissues,âasâitâguardsâagainstâapoptosisâofâcardiomyo-cytesâandâÎČâcellsâ(102).âAdiponectinâreceptorâassociatedâcerami-daseâactivityâmayânotâbeâtheâonlyâmechanismâatâplay.âAwazawaâetâal.âfoundâthatâinsulinâsensitivityâwasâimprovedâwithâadiponectinâinfu-sionâinâhepatocytesâviaâIRS2âinduction;âhowever,âthisâwasânotâcellâautonomousâ(103).âSurprisingly,âinductionâofâIL-6âbyâadiponectinâinâmacrophagesâgeneratedâthisâinsulin-sensitizingâeffect;âthisâwasâlargelyâindependentâofâadiponectinâreceptorsâR1âandâR2.
JNK and ER stress.âInâadditionâtoâNF-ÎșB,âobesityâalsoâactivatesâJNKâinâinsulin-responsiveâtissues,âprobablyâthroughâupstreamâpathwaysâsharedâbyâIKK/NF-ÎșBâinâresponseâtoâstressâsignalsâsuchâasâFAs,âinsulin,âhyperglycemia,âandâinflammatoryâcytokinesâ(104).âTheâdifferentialâcontributionâofâJNKâinâhematopoieticâandânonhe-matopoieticâcellsâinâobesityâisâwellâdescribedâcomparedâwithâotherâinflammatoryâsignalingâcomponents.âWhileâbothâJNK1âandâJNK2âisoformsâcontributeâtoâmetabolicâregulation,âJNK1âhasâaâmoreâprominentâroleâinâtheâprotectionâfromâDIOâ(105,â106).âTheâeffectsâofâJNK1âinânonhematopoieticâcellsâcontrolâbodyâweightâandâenergyâexpenditure.âAsâwithâtheâIKKÎČâpathway,âJNK1âalsoâregulatesâhypo-thalamicâsignals;âinactivationâofâJNK1âinâtheâhypothalamusâpro-tectsâmiceâfromâDIOâandârecapitulatesâtheâreducedâbodyâweightâphenotypeâseenâinâtheâwholeâbodyâofâJNK1-deficientâanimalsâ(107).âJNK1âinactivationâinâhematopoieticâcellsâdoesânotâalterâadiposityâbutâisâsufficientâtoâattenuateâobesity-inducedâinflammationâwithâbeneficialâeffectsâonâmetabolismâ(108,â109).
ERâstressâandâtheâdownstreamâactivationâofâtheâmolecularâpath-waysâgoverningâtheâunfoldedâproteinâresponseâappearâtoâbeâcloselyâtiedâtoâbothâJNK1âandâIKK/NF-ÎșBâactivationâpathwaysâinâmultipleâmetabolicâtissuesâ(e.g.,âhypothalamusâandâadiposeâtissue)â(110).âWidespreadâactivationâofâERâstressâsignalingâcomponentsâandâcas-cadesâ(ATF6,âPERK,âIRE-1)âisâseenâinâobesity,âandâpharmacologicâ
inhibitionâofâERâstressâcanâreverseâmetabolicâdysfunctionâ(43,â111).âTheâdouble-strandedâRNA-dependentâproteinâkinaseârepresentsâaâPRRâthatâsitsâatâtheâinterfaceâbetweenâERâstressâandânutrientsâtoâtranslateâtheseâsignalsâintoâanâinflammatoryâresponseâthroughâJNKâ(112).âFurtherâworkâisâneededâtoâestablishâhowâwidespreadâERâstressâisâinâotherâacuteâandâchronicâstressâsituationsâandâhowâitsâmechanismâoverlapsâwithâitsâroleâinâtheâpathogenesisâofâathero-sclerosisâandâfoamâcellâbiologyâ(113).
Antiinflammatory therapies for metabolic diseaseTheâobservationsâaboveâdemonstrateâpotentialânewâapproachesâtowardâtheâdevelopmentâofâdrugsâthatâtargetâinflammationâtoâbreakâtheâlinksâbetweenâobesityâandâdisease.âSalsalate,âaâprodrugâofâsalicy-late,âcanâattenuateâIKKÎČ/NF-ÎșBâactivityâandâhasâbeenâshownâtoâimproveâglycemicâcontrolâinâpatientsâwithâtypeâ2âdiabetesâ(95,â114).âPreclinicalâstudiesâhaveâalsoâdemonstratedâaâmetabolicâbenefitârelat-edâtoâtheâantiinflammatoryâeffectsâofâtargetingâERâstressâ(111)âandâPPARÎłâ(115).âBlockadeâofâinflammatoryâcytokineâsignalsâinâmetabol-icâdiseaseâalsoâshowsâpromise,âasâIL-1âreceptorâantagonistsâ(anakinra)âimproveâglycemiaâandâÎČâcellâfunctionâandâdecreaseâsystemicâinflam-matoryâmarkersâ(116).âInâaggregate,âTNF-αâblockadeâwithâetanerceptâhasânotâdemonstratedâsignificantâimprovementsâinâinsulinâsensitiv-ity,âbutâbeneficialâeffectsâofâTNF-αâblockadeâonâfastingâglucoseâandâcirculatingâinflammatoryâcytokinesâhaveâbeenâobserved,âsuggestingâapplicationâinâotherâobesity-relatedâmorbiditiesâ(117,â118).
ConclusionTheâunexpectedâoverlapâbetweenâinflammatoryâandâmetabolicâsen-sorsâandâtheirâdownstreamâtissueâresponsesâindicatesâthatâinflamma-tionâplaysâaâcrucialâroleâinâtheâmanyâcomplicationsâofâobesity.âHow-ever,âthereâremainâmanyâcontradictionsâthatâhaveâyetâtoâbeâsortedâout,âsuchâasâhowâhypothalamicâinflammationâcausesâbothâobesityâandâanorexia,âtheâroleâofâtheâinnateâimmuneâsystemâinâmaintainingâobe-sity,âandâtheâteleologicalâreasonsâforâobesity-dependentâinflamma-tion,âamongâothers.âWeâfeelâthatâansweringâtheseâquestionsârequiresâapproachesâthatâallowâaâhigher-resolutionâviewâofâtheâdifferentâcel-lularâmediatorsâ(e.g.,âmacrophages,âadipocytes,âandâlymphocytes)âinâfatâthatâcontributeâtoâdiseaseâphenotypes.âAâsecondâchallengeâwillâbeâtoâestablishâtheâdifferencesâandâsimilaritiesâbetweenâacuteâinflamma-toryâsignalsâandâchronicâactivationâofâtheseâpathwaysâinâdiseasesâsuchâasâobesity.âThisâtemporalâquestionâisâalsoâaâcriticalâoneâforâimmunol-ogists,âwhoâareâemployingâsystemsâbiologyâapproachesâtoâteaseâoutâtheâdynamicânetworkâeffectsâofâtransientâversusâpersistentâstimuliâ(119).âTheseâeffortsâprovideâopportunitiesâtoâcontinueâtoâreviseâourâunderstandingâofâtheânatureâofâmetainflammationâinâtheâhopeâofâmodifyingâitâtoâpreventâandâtreatâdisease.
AcknowledgmentsTheâObesityâReviewâSeriesâisâsupportedâinâpartâbyâunrestrictedâedu-cationalâgrantsâfromâMerckâ&âCo.âandâtheâLifeâSciencesâInstituteâofâtheâUniversityâofâMichigan.âThisâworkâwasâsupportedâbyâNIHâNationalâInstituteâofâDiabetesâandâDigestiveâandâKidneyâDiseasesâgrantsâtoâC.N.âLumengâ(R01DK090262,âK08DK078851)âandâA.R.âSaltielâ(R01DK060591).
Addressâcorrespondenceâto:âCareyâLumeng,âUniversityâofâMichi-ganâMedicalâSchool,âDepartmentâofâPediatricsâandâCommunica-bleâDiseases,â4520BâMSRBâI,â1150âWâMedicalâCenterâDrive,âAnnâArbor,âMichiganâ48109-5652,âUSA.âPhone:â734.936.4200;âFax:â734.763.9512;âE-mail:â[email protected].
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