ReviewObesity and Atherosclerosis: Mechanistic InsightsFina Lovren, PhD,aHwee Teoh, PhD,a,band Subodh Verma, MD, PhD, FRCSCaaDivision of Cardiac Surgery, Keenan Research Centre for Biomedical Science, St Michaels Hospital, University of Toronto, Toronto, Ontario, CanadabDivision of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science, St Michaels Hospital, University of Toronto, Toronto, Ontario, CanadaABSTRACTObesityisamultifactorial chronicdiseasecharacterizedbyanaccu-mulationof visceral andsubcutaneousfat, whichleadstoapredis-position toward cardiometabolic diseases. A plethora of mechanisms,including abnormalities in lipid metabolism, insulin resistance,inammation, endothelial dysfunction, adipokine imbalance, andinammasomeactivationhavebeensuggestedtounderlietherela-tionship between obesity and atherosclerosis. More recent data pointtoward an emerging role of impaired autophagy and altered gutmicrobiomehomeostasisaspotentiallycontributingfactors. Thisre-view provides an overview of this area.R

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ELob esit eestune maladiechronique multifactoriellecaract eris eeparune accumulation de graisse visc erale et de graisse sous-cutan ee, quientraneunepr edispositionaux maladies cardiom etaboliques. Unepl ethoredem ecanismes, dont lesanomaliesdum ecanismedesli-pides, linsulinor esistance, linammation, ladysfonctionendoth elial,led es equilibredesadipocytokinesetlactivationdelinammasomeontet e sugg er es pouretayer le lien entre lob esit e et lath eroscl erose.Desdonn eesplusr ecentessugg eraient commerle emergent lad ecience de lautophagie et lalt eration de lhom eostasie dumicrobiome intestinal dtre des facteurs potentiellement contributifs.La pr esente revue donne un aperu de ce domaine de recherche.Obesityis a major risk factor for atherosclerotic vasculardis-ease and cardiometabolic syndrome. Various mechanisms havebeensuggestedtolinkobesitytoatherosclerosis. Thesearedetailed in Table 1 and are reviewed herein.AdipokineImbalanceThe visceral adipose tissue is a source of numerousadipokines, most of which are deemed to be proinammatory.Increasing evidence suggests that an imbalance betweenproinammatory vs anti-inammatory adipokines (such asadiponectin) might be responsible for the development ofinsulin resistance and endothelial dysfunction and athero-sclerosis in patients with obesity (Fig. 1).Adiponectinisthemostabundantanti-inammatoryandvasculoprotective adipokine secreted by adipose tissues.Numerous studies have to date demonstrated that plasma levelsofadiponectinarelowerinpatientswithobesityand/ordia-betes. Adiponectinimprovesinsulinsensitivitybyincreasingenergy expenditure and fatty acid oxidation through thephosphorylation of 5-adenosine-monophosphate-activatedprotein kinase, and via an increase in the expression of perox-isome proliferator-activatedreceptor-atarget genes suchasCD36, acyl-coenzyme oxidase, anduncouplingprotein2.2The adiponectin receptors, AdipoR1 and AdipoR2, areresponsible for mediating the metabolic actions of adiponectin.Adiponectinexerts its vasculoprotectiveeffects throughamultitude of pathways. In vitro, adiponectin induces nitric oxide(NO) productionin human aortic endothelial cells via activationof the 5-adenosine-monophosphate-activated proteinkinasepathway and enhancement of endothelial NOsynthase (eNOS)activity.3Adiponectin additionally suppresses proliferation andsuperoxide generation, andalsoenhances eNOSactivityinendothelial cells treated with oxidized low-density lipoprotein.4Adiponectin has also been demonstrated to attenuate theadhesionof monocytes toendothelial cells, primarily via amechanism that involves inhibition of tumour necrosis factor(TNF)-a- and interleukin (IL)-8-induced synthesis of intercel-lular adhesionmolecule 1(ICAM1), vascular cell adhesionmolecule 1 (VCAM1), and E-selectin.5Adiponectin suppressesthe expression of class Amacrophage scavenger receptors andconsequently reduces foam cell formation and decreases secre-tion of proinammatory cytokines.6Notably, foam cellformationis further reducedbyadiponectin-induceddown-regulationofacyl-coenzymeA:cholesterol acyltransferase-1inmacrophages, the enzyme that catalyzes the formation ofcholesteryl esters.7Accordingly, adiponectin limits the initiationof atherosclerotic plaque formation. Recent data point towardtheabilityof adiponectintoprimemonocytedifferentiationtowardtheanti-inammatoryM2macrophagelineage,8andCanadian Journal of Cardiology 31 (2015) 177e183Received for publication November 18, 2014. Accepted November 25, 2014.Correspondingauthor: DrSubodh Verma,Division ofCardiacSurgery,KeenanResearchCentreforBiomedical Science, StMichaelsHospital, 30BondSt, Toronto, OntarioM5B1W8, Canada. Tel.: 1-416-864-5997;fax: 1-416-864-5991.E-mail: vermasu@smh.caSee page 181 for disclosure information.http://dx.doi.org/10.1016/j.cjca.2014.11.0310828-282X/ 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.that in states of adiponectin deciency (such as obesity),monocytes might beprimarilydriventowardtheproathero-sclerotic M1lineage. Physiological concentrations of adipo-nectin signicantly suppress the proliferation and migration ofhuman aortic smooth muscle cells induced by platelet-derivedgrowth factor BB in vitro9by directly binding platelet-derivedgrowth factor-BB and inhibiting growth factor-stimulatedextracellular signal-regulatedkinase signalling. These resultssuggest that adiponectinmight also prevent vascular remodellingin atherosclerosis. In other studies, adiponectin has been shownto selectively increase the expression of tissue inhibitor ofmetalloproteinase-1 in human monocyte-derived macro-phages,10suggestingthat it might favour plaque stabilization.Via improving vascular function, adiponectin has been recentlyimplicated in protection against sepsis induced multiorgandysfunction.11Invivostudies inmice have conrmedtheantiatherogenic properties of adiponectin. Adiponectin-decientmice,comparedwithwildtypecontrols,showneo-intimal thickening and increased proliferation of vascularsmooth muscle cells after mechanical injury to arteries.12Adenovirus-mediateddelivery of adiponectininthese miceconsiderably attenuated the extent of neointimal proliferation.12Furthermore, treatment of apolipoprotein E-decient mice(ApoE/)withadiponectin-expressingadenovirusesreducedatherosclerotic lesion formation compared with control mice.13Takentogether, thebalanceofpublishedinformationwouldstrongly associate low adiponectin levels in obesity as a causaland/or permissive basis of atherosclerotic risk.Resistin is a proinammatory adipokine that is released inexcess amounts in individuals with visceral adiposity. Resistinprofoundly upregulates the expression of TNF-a and IL-6 inhuman peripheral blood mononuclear cells.14Human resistinhas been reported to stimulate the synthesis of proin-ammatory cytokines such as TNF-a, IL-1, IL-6, andIL-12invariouscell types throughanuclear factor-kB-dependentpathway.15Apositivecorrelationbetweenresistinlevelsandvascular inammation has been demonstrated in obesehumans.16As further evidence of its proinammatory prole,resistin upregulates the expression of adhesion moleculesVCAM1andICAM1, andinduceschemokine(C-Cmotif)ligand 2 and endothelin (ET)-1 release in human endothelialcells.17Indeed, we demonstratedthat resistindirectly trig-gered endothelial cell activation by promoting ET-1 release, inpart by inducing ET-1promoter activity via the activatorprotein-1site. Furthermore, resistinupregulatedtheexpres-sion of adhesion molecules and chemokines and down-regulatedtumor necrosis factor receptor-associatedfactor-3,aninhibitor of CD40ligandsignallinginendothelial cells.Therefore, increasedresistinlevels might be another factorthat contributes to obesity-induced atherosclerosis.17The adipokine, leptin, has a main function to control foodintakeandenergyexpenditure.18Levelsof circulatingleptinuctuate; theyareincreasedwithoverfeedinganddecreasedwithstarvation.Micewithamutationinthegeneencodingleptin(ob/ob mice) or the gene encodingthe leptinreceptor(db/db mice) have obese phenotypes,19and also exhibitincreased atherosclerosis.20Leptin is considered to be aproinammatory cytokineandis structurallysimilarto otherproinammatory cytokines such as IL-6, IL-12, and theTable 1. Suggested mechanisms of obesity-induced atherosclerosisEndothelial dysfunctionAdipokine imbalanceVascular inammationMacrophage NLRP3 inammasome activationAltered gut microbiomeLoss of autophagicuxOxidative stressFigure 1. Anti- and proinammatory adipokines. AT, angiotensin II; CRP, C-reactive protein; EC, endothelial cell; ET-1, endothelin-1; ICAM, intercellularadhesion molecule; IL, interleukin; MCP-1, monocyte chemoattractant protein 1; MMP, matrix metalloproteinase; NO, nitric oxide; oxLDL, oxidized low-density lipoproteins; PAI-1, plasminogen activator inhibitor-1; SMC, smooth muscle cell; TNF, tumour necrosis factor; VCAM, vascular cell adhesionmolecule. Reproduced from Lau et al.1with permission from American Physiological Society. Copyright 2014, The American Physiological Society.178 Canadian Journal of CardiologyVolume 31 2015granulocyte colony stimulating factor.18Leptin modulates theT-cell immune response, stimulates the proliferationof T-helper cells, and increases production of proinammatorycytokines byregulatingdifferent immune cells.21Increasedproductionofleptin,therefore,modulatescaloricintakeandatherosclerotic susceptibility.ImpairedAutophagyAccumulating data suggest that loss of autophagy might bean important determinant of atherosclerosis, particularly withaging.22-25One theory that is rapidly gaining popularity is thatloss of autophagy might be a central mechanismthrough whichcardiometabolic diseases arise. An intact autophagic machineryis essential in limiting lipid uptake by macrophages. Autophagy-relatedprotein7(ATG7) is a critical autophagygene andmacrophage specic ATG7-decient mice exhibit increasedsusceptibility toward atherosclerosis25via an increase inmacrophage low-density lipoprotein uptake and foam cell for-mation. Autophagic uxiscompromisedinobesityandthemetabolic syndrome. Ina recent seminal paper, mice withglobal haploinsufciencyof ATG7(Atg7/mice) didnotshowmetabolicabnormalities but developeddiabetes whencrossed with ob/ob mice. Atg7/-ob/ob mice showaggravatedinsulin resistance with increased lipid content and inamma-tory changes, suggesting that autophagy haploinsufciencyimpairstheadaptiveresponsetometabolicstress.26Further-more, intracellular lipid content and insulin resistance after lipidloading are increased as a result of autophagy insufciency, andthere is increased inammasome activation in Atg7/-ob/obmice.26These results suggest that systemic autophagy insuf-ciencycouldbeafactor intheprogressionfromobesitytodiabetes, and associated inammation and atherosclerosis.OxidativeStress Links Obesity toAtherosclerosisObesity is strongly associated with an increase in systemicoxidative stress. The extent of fat accumulation in obesehumans closely correlates with the markers of oxidativestress.27Similarly, the oxidative stress is augmented in plasmaand adipose tissue fromobese mice.27Increased oxidantproduction, through quenching NO, has been linked toincreased atherosclerosis susceptibility.Oxidative stress results fromanimbalance betweentheproductionoffreeradicalsandantioxidantsystems. Increaseinreactiveoxygenspecies(ROS)productionbytheadiposetissueinobesityisaccompaniedwithanincreaseinnicotin-amide adenine dinucleotide phosphate (NADPH) oxidaseexpressionsuggestingthataugmentedNADPHoxidasecon-tributes to increased ROS production in adipose tissue.27Impairedexpressionofantioxidativeenzymes,suchas super-oxidedismutase, glutathioneperoxidase, andcatalaseinadi-pose tissue lead to increased ROS production.27Furthermore,in cultured adipocytes, it has been shown that increased levelsof fattyacidsincreaseoxidativestressandaugmentthepro-ductionof proinammatorycytokines. Inobesemice, treat-ment with NADPH oxidase inhibitor reduced ROSproductioninadipose tissueandstrikinglyaugmentedadi-ponectin production, attenuated proinammatory cytokinerelease, and improved insulin-sensitivity and hepatic steatosis.Gut MicrobiomeasaLinkBetweenObesityandAtherosclerosis?The resident gut microbiota have crucial roles in hostfunctioning, andsubsequently inhealthanddisease. Mostbacterial speciesinthehumanandmousegutbelongtothephyla Bacteroidetes and Firmicutes and to a lesser extentbacterial phyla, suchas Actinobacteria, Proteobacteria, andVerrucomicrobia, andmethanogenic archaea, mainlyMeth-anobrevibacter smithii.28The gut microbiota possess a varietyof functional properties and affect host physiology within andoutside the gut.Someoftheessential functionsofthegutmicrobiotaarenormal development and homeostasis of the immune systeminthe gut, modulationof epithelial cell proliferation, pro-tectionagainstpathogenicbacteria,andmodulationofvillusarchitecture and angiogenesis within the intestine.29Studies inhumans and mice have shown that altered gut microbiota areassociatedwithseveral diseases, includingobesity, diabetes,inammation, and atherosclerosis.Therst report of gut microbial difference between obeseand lean phenotypeswas reported in leptin-decient (ob/ob)mice.30This study showed differences in gut microbialcomposition with fewer phylumBacteroidetes and morephylumFirmicutes inobeseob/obmicethanintheir leanlittermates. Becausebothgroupsof micewerefedthesamediet, theresults suggestedthat obesitycouldbeduetothedifference in gut microbial composition. Similarly, a decreaseinBacteroidetes proportionwithanincrease inFirmicutesproportion was found in obese human twins.31Furthermore, the transfer of microbiota, harvestedfromnot only obese mice32but also fromlean or obese in-dividuals,31into germ-free mice reproduces the correspondingphenotype demonstrating that the obese phenotype wastransferred by the microbiota.33It has also been reported thatobese children already have different gut microbiota comparedwith lean children.34However, some conictingndings havebeen observed recently, showing no association35or anopposite association with an increase in Bacteroidetes in obeseindividuals.36Obesegutmicrobiotahavebeendemonstratedtoinducechronic low-grade inammation in the host gut.37,38A high-fatdietinratsledtochangesinthecompositionofthegutmicrobiotaandactivationoftoll-likereceptor4signallinginthe gut epithelia and might aggravategastrointestinal inam-mation associated with the obese phenotype.37Inarecentseminal reportbyKarlssonet al.,39shotgunsequencing of the gut metagenome was performed todemonstratethat thegenus Collinsellawas enrichedinpa-tientswithsymptomaticatherosclerosis, denedasstenoticatherosclerotic plaques in the carotid artery leading tocerebrovascularevents,whereasRoseburiaandEubacteriumwere enriched in healthy control subjects. Furthercharacterization of the functional capacity of the meta-genomes revealed that patient gut metagenomes wereenriched in genes encoding peptidoglycan synthesis anddepleted in phytoene dehydrogenase; patients also hadreducedserumlevelsof b-carotene. These ndingssuggestthat the gut metagenome is associated with the inammatorystatus of the host andpatients withsymptomatic athero-sclerosis harbour characteristic changes in the gutmetagenome.39Lovren et al. 179Obesity and Atherosclerosis: Mechanistic InsightsEndothelial DysfunctionAnimal andhumanstudies have demonstratedimpairedendothelial function in obesity.40Several mechanisms lead todiminished NO production and availability in obesity. Theseinclude decreased expression of eNOS,41,42or increasedinactivationof eNOS(secondarytoincreasedproductionofROS). Plasma levels of asymmetric dimethylarginine areincreased in obese patients43and in obese subjects withmetabolic syndrome. Asymmetric dimethylarginine serves as astoichiometricinhibitorof eNOSandmightbeyetanothermechanism through which obesity reduces the bioavailabilityof NO.In addition to NO, alterations in endothelium-derivedprostacyclinandthromboxanehavealsobeenimplicatedinobesity. Obesity increases prostanoid-dependent vasocon-striction and vascular thromboxane receptor gene expres-sion.44These changes are likely to promote the developmentof vascular disease, hypertension, andthrombosis associatedwithobesity. Animpairedcyclooxygenasepathway, withanincrease inthe release of the thromboxane A2 metabolitethromboxane B2, has been reported in microvessels fromobese spontaneous hypertensive rats.45Likewise in obeseZucker rats, the release of prostacyclinis attenuated46andactivity of prostacyclin and eNOS in arterial endothelial cellswas decreasedbecause of oxidation of fatty acids.47The endotheliumis the source of the potent vasocon-strictor peptide ET-1. ET-1 augments the vascular actions ofother vasoactive peptides such as angiotensin-II, norepineph-rine, and serotonin, participates actively in leukocyte andplateletactivation, andfacilitatesaprothromboticandproa-therogenic phenotype. Obesityis associatedwithenhancedET-1-mediated vascular tone. In obesity, increased ET-1-mediated vasoconstriction contributes to diminishedendothelium-dependent vasodilation.48Increased ET-1plasmalevels havebeenfoundinnormotensiveandhyper-tensive obese subjects.49Additionally, in experimental obesity,there is an increase in gene and protein expression of ET-1 inthecardiovascularsystem.44ET-1-mediatedvasoconstrictionmight therefore promote hypertension, atherosclerosis, andthrombosis, conditions frequently observed in obese patients.Obesity-inducedvascular dysfunctionis observedinthemacrovascular andmicrovascular beds. Inhumans, reducedendothelium-dependent vasodilation to methacholine wasdemonstrated in the leg microcirculation of obese patients.50Similarly, a progressive decline inendothelial functionwasdescribedintheforearmmicrocirculationofoverweightandobesepatients.51Inthesamestudy,intra-arterial infusionofascorbicacidimprovedacetylcholineresponses, suggestingarole of oxidative stress in obesity-related endothelial dysfunc-tion.51Furthermore, small resistancearteriesfromobesepa-tients are characterized by a signicantly impairedendothelium-dependent relaxationcomparedwithleancon-trol subjects.52,53Thesedatademonstratethatsmall arteriesfrom obese patients are characterized by a marked endothelialdysfunction as result of decreased NO availability.Ithasbeen established thatendothelialcellactivationis acrucial early step in inammation. However, the role ofoverweight and obesity, and, inparticular, the associationbetween specic fat depots and endothelial activation, has notbeenfullydetermined.Ithasbeenshownthatthereleaseoffreefattyacidbyadiposetissuedirectlyinducedendothelialdysfunction.54Subjects withupperbodyobesityhavehigherlevels of free fatty acid than subjects with obesity in the lowerextremities,55thus suggesting that visceral fat has a moreprominent effect on endothelial dysfunction than fat stored inother sites of the body. Furthermore, infusion of free fatty acidatconcentrationssimilartothoseobservedinobesesubjectsincreased plasma ICAM1 and VCAM1 levels in healthy sub-jects, thus indicating a direct effect of free fatty acid on endo-thelial cell activation.56Similar ndings have already beenreported in animal models of obesity in which surgical removalof visceral fat resulted in decreased concentrations of free fattyacid in rat plasma,57,58suggesting that visceral adiposity playsan important role in the regulation of free fatty acid levels. Theremoval of abdominal fat in humans by liposuction leads to adecrease inconcentrations of free fatty acid.59Conversely,removalofonlysubcutaneousfatfailsto showanyimprove-mentininammationordecreaseinfreefattyacidconcen-trations60linking visceral fat and free fatty acid levels.Children and adolescents with obesity-related hypertensionhaveaheightenedsystemicinammatoryresponsewithevi-dence of endothelial activation relative to normotensive obesesubjects.61Recently, it has been shown that adiposity isassociatedwithhigherlevelsofinsulinresistance, E-selectin,andVCAM1eveninhealthy normal-weight childrenat ayoung age of 2-3 years, and such associations are evident eveninchildrenwithrelatively lowlevels of adiposity.62Thesestudies thereforestronglyarguethat overweight andobesityare associated with endothelial activation and it is possible thatadiposityin the visceralregionmightbe a stronger predictorof endothelial activation than overall adiposity.InammasomeActivationinObesity andAtherosclerosisInammationmightbeoneofthemostimportantcom-monthreadstolinkobesitywithatherosclerosis.63Accumu-lating data now suggest that the nucleotide-bindingoligomerization domain-like receptor family pyrin domaincontaining 3(NLRP3) inammasome,largely within macro-phages, might be stimulatedby various cardiovascular riskfactors, includingcrystalline cholesterol. NLRP3inamma-someactivationisresponsiblefortheeventual conversionofpro-IL-1b into IL-1b. During obesity, circulating levels of freefatty acids are increased and lipids such as ceramide andpalmitate activate the cells of the innate immune system andtrigger inammasome activation.64Lipopolysaccharide-primed macrophages stimulated with ceramide displayNLRP3-dependent caspase-1activationandleadtoproduc-tion of IL-1b at relatively low levels.65More recently, anotherlipid, thesaturatedfattyacidpalmitate, has beenshowntoactivate the NLRP3 inammasome.66Palmitate is one of themost abundant free fatty acids in plasma and is highlyincreasedinobesity. Several studies demonstratedthat theNLRP3 inammasome in obesity is an important mechanismthat participates in the development of insulin resistance.65-67Likewise,theNLRP3inammasomehasbeendemonstratedto be essential in the development of atherosclerosis,68makingit a very attractive common mechanism (and potential target)of cardiometabolic risk.Obesity-induced inammation has been linked to theactivation ofadipose tissuemacrophages,T cells,andB cells180 Canadian Journal of CardiologyVolume 31 2015within fat deposits.69The mechanisms that regulate theactivationof these immune cells inadipose tissue are stilllargely unknown, however, a recent study found that obesityitselfinducedtheassemblyoftheNLRP3inammasomeinadipose tissue macrophages.65Moreover, inammasome-mediatedcaspase-1activationinadiposetissueandliverhasbeenshowntoimpairinsulinsignallingandglucosehomeo-stasis.67In free-feeding mice given a normal chowdiet,increased expression of NLRP3 and IL-1b in visceral adiposetissuehasbeenfoundtocorrelatedirectlywithbodyweightandadiposity. DirectinvolvementofNLRP3inobesityhasbeen also conrmed in NLRP3 gene-decient mice fed a highfat diet. Inthese mice, caspase-1activationandpro-IL-1bexpressioninadipose tissue, andloss of serumIL-18pro-ductionwereprofoundlyreducedcomparedwiththeirwildtype counterparts. Moreover, NLRP3- and caspase-1-decientmicearemoreprotectedfromhigh-fat diet-inducedinsulinresistance. Similar observations were reported in humans.Weight loss inobese diabetic patients is associatedwithadecrease inNLRP3andIL-1bexpressioninsubcutaneousadipose tissue.65,67ConclusionsObesity leads to increased cardiovascular risk throughvariousmechanisms.Althoughitisimpossibletodissectouttheuniquemechanisticcontributionofobesity(vstheasso-ciatedfeatures of the metabolic syndrome) towardathero-thrombotic risk, several important themes have emerged.Theserelatetoalterationsinadipokines, inammation, andinammasome activation, gut microbiota, oxidative stress, andendothelialdysfunction.Themostcompellingcontemporarymechanismthatmighthelptieall ofthesefacetstogetherisinammation, and signalling via the NLRP3 inammasome.DisclosuresThe authors have no conicts of interest to disclose.References1. Lau DC, Dhillon B, Yan H, Szmitko PE, Verma S. Adipokines:molecular links between obesity and atheroslcerosis. Am J Physiol HeartCirc Physiol 2005;288:H2031-41.2. Yamauchi T, Kadowaki T. 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