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Omega-3FattyAcidsReduceAdiposeTissueMacrophagesinHumanSubjectsWithInsulinResistanceMichaelSpencer,1BrianS.Finlin,1ResatUnal,1BeibeiZhu,1AndrewJ.Morris,2LindseyR.Shipp,1JonahLee,3R.GraceWalton,1AkosuaAdu,1RodErfani,3MarilynCampbell,3RobertE.McGeheeJr.,4CharlotteA.Peterson,3andPhilipA.Kern1Fishoils(FOs)haveanti-inflammatoryeffectsandlowerserumtriglycerides.Thisstudyexaminedadiposeandmuscleinflam-matorymarkersaftertreatmentofhumanswithFOsandmeasuredtheeffectsofv-3fattyacidsonadipocytesandmacro-phagesinvitro.Insulin-resistant,nondiabeticsubjectsweretreatedwithOmega-3-AcidEthylEsters(4g/day)orplacebofor12weeks.Plasmamacrophagechemoattractantprotein1(MCP-1)levelswerereducedbyFO,butthelevelsofothercytokineswereunchanged.Theadipose(butnotmuscle)ofFO-treatedsubjectsdemonstratedadecreaseinmacrophages,adecreaseinMCP-1,andanincreaseincapillaries,andsubjectswiththemostmacro-phagesdemonstratedthegreatestresponsetotreatment.Adiposeandmusclev-3fattyacidcontentincreasedaftertreatment;how-ever,therewasnochangeininsulinsensitivityoradiponectin.Invitro,M1-polarizedmacrophagesexpressedhighlevelsofMCP-1.Theadditionofv-3fattyacidsreducedMCP-1expressionwithnoeffectonTNF-a.Inaddition,v-3fattyacidssuppressedtheupregulationofadipocyteMCP-1thatoccurredwhenadipocyteswerecoculturedwithmacrophages.Thus,FOreducedadiposemacrophages,increasedcapillaries,andreducedMCP-1expres-sionininsulin-resistanthumansandinmacrophagesandadipo-cytesinvitro;however,therewasnomeasureableeffectoninsulinsensitivity.Diabetes62:1709–1717,2013Thedevelopmentoftype2diabetesrepresentsacomplexseriesofeventsthatbeginswiththedevelopmentofinsulinresistance.Thechangesinadiposetissuethataccompanyobesity,themetabolicsyndrome,andinsulinresistanceincludein-creasedadiposetissuemacrophages,circulatinginflam-matorymarkerssuchastumornecrosisfactor-a(TNF-a)andinterleukin(IL)-6(1–3),andthedevelopmentofachronicinflammatorystate.Inadditiontotheinfiltrationofmacrophages,otherchangesoccurintheadiposetissueofobese,insulin-resistantsubjects,includinganincreaseinextracellularmatrix(ECM)components,suchascolla-genVI,thrombospondin,andcollagenVandadecreaseinelastin(4–7).Alongwithadipocyteexpansion,changesintheadiposevasculaturehavebeendescribed,includingadecreaseincapillariesandanincreaseinlargerbloodvessels(7,8),leadingtothehypothesisthatadipocytene-crosisandinflammationdevelopasaresultofadipocyteexpansionintoarelativelyhypoxic,nonelasticECM(9).Fishoils(FOs)arerichsourcesofv-3polyunsaturatedfattyacids(v-3PUFAs),andthereisalargeamountofliteratureonthepotentialbenefitsofFOsonloweringserumtriglycerides,cardiovascularprotection,andim-munemodulation.Thereisconsiderableevidencesup-portingtheanti-inflammatoryeffectsofv-3PUFAs(10),andFOsmaybeanadjunctinthetreatmentofrheumatoidarthritis,inflammatoryboweldisease,andasthma(11,12).Althoughthemechanismofthiseffectiscomplex,partoftheanti-inflammatoryactioninvolvesaninhibitionoftheproductionofeicosanoidsfromarachadonicacid(13).Inaddition,anumberofstudieshavedemonstratedthatFOshaveaperoxisomeproliferator–activatedreceptorg(PPARg)–likeeffect(14).PPARgagonistdrugs,suchasthethiazolidinediones,improveinsulinsensitivityandhaveanti-inflammatoryproperties.Previousstudieshavedem-onstratedthiazolidinedione-mediatedreductionsinplasmainflammatorymarkersandadiposetissuemacrophagesandanincreaseinbloodadiponectin(15–18).Altho...