The Role of Immune System in Obesity

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Hindawi Publishing CorporationJournal o Obesity Volume , Article ID , pageshttp://dx.doi.org/.//

Review ArticleThe Role of the Immune System in Obesity andInsulin Resistance

Payal S. Patel,1 Eric D. Buras,1 and Ashok Balasubramanyam1,2

DiabetesResearch Center, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, X , USA Endocrine Service, Ben aub General Hospital, Houston, X , USA

Correspondence should be addressed to Payal S. Patel; [email protected]

Received November ; Accepted February

Academic Editor: Nicola Abate

Copyright © Payal S. Patel et al. Tis is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Te innate immune system provides organisms with rapid and well-coordinated protection rom oreign pathogens. However,under certain conditions o metabolic dysunction, components o the innate immune system may be activated in the absence o external pathogens, leading to pathologic consequences. Indeed, there appears to be an intimate relationship between metabolicdiseases and immune dysunction; or example, macrophages are prime players in the initiation o a chronic inammatory state inobesity which leads to insulin resistance. In response to increases in ree atty acid release rom obese adipose depots, M-polarizedmacrophages inltrate adipose tissues. Tese M macrophages trigger inammatory signaling and stress responses within cellsthat signal through JNK or IKK pathways, leading to insulin resistance. I overnutrition persists, mechanisms that counteract

inammation (such as M macrophages and PPAR signaling) are suppressed, and the inammation becomes chronic. Althoughmacrophages are a principal constituent o obese adipose tissue inammation, other components o the immune system such aslymphocytes and mast cells also contribute to the inammatory cascade. Tus it is not merely an increased mass o adipose tissuethat directly leads to attenuation o insulin action, but rather adipose tissue inammation activated by the immune system in obeseindividuals that leads to insulin resistance.

1. Introduction

Te obesity epidemic in the USA continues to expand atan alarming rate, with a % increase in prevalence since []. Te Centers or Disease Control and Prevention(CDC) reports that more than one-third o USA adults andover one-sixth o children and adolescents are obese. Te

requencies o other metabolic disorders have increased pari passu, including dyslipidemia, nonalcoholic steatohepatitis,and type diabetes. Dysunctional adipose tissue is central toall these conditions. Adipose tissue is increasingly recognizedas a complex endocrine organ and not merely a depot orstorage o at. Adipose tissue in obese persons developsan inammatory milieu which ultimately leads to insulinresistance. Although many components o the immune sys-tem have been ound to play a role in either promoting orattenuating adipose tissue inammation, macrophages arekey players. Tis paper discusses the various stimuli andnetworks that lead to insulin resistance, with a primary ocuson the role o macrophages in adipose tissue inammation.

2. Macrophage Accumulation in Visceral Adipose Tissue in Obesity

Adipose tissue comprises not only adipocytes but also aheterogenous constellation o adipocyte precursors, nerveterminals, blood vessels, and leukocytes collectively termed

the “stromal vascular compartment” (SVC). In , pioneer-ing studies by Xu et al. [] and Weisberg et al. [] demon-strated that obesity is associated with signicant increasesin macrophage number within the SVC o visceral adiposetissue (VA). Weisberg et al. discovered the increase inmacrophage number through gene expression proling o VA rom multiple obese mouse models and lean controls.

Tey ound that levels o roughly genes directly cor-related with body mass, and o the most signicantly correlated genes, % were macrophage-related []. Detailed

analysis o SVC viaow cytometry revealed that macrophagesmake up approximately % o SVC cells rom obese rodents,compared to only % o SVC cells in lean litter mates [].


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o understand the role o macrophages in adipose tissueinsulin resistance, it is important to distinguish visceral atrom subcutaneous at. Visceral at is ound in associationwith internal organs such as omentum, mesentery, and per-inephric adipose tissue []. Visceral adiposity is predictive o hepatic steatosis, cardiovascular disease, and type diabetes,

whereas an increase in the mass o subcutaneous at appearsto pose little or no risk o these conditions []. Visceral andsubcutaneous at also differ in immune cell composition,particularly macrophages [–]. Similar to mouse models,increased macrophage accumulation has been demonstratedin the adipose tissue o obese humans and those with type diabetes, with signicantly moremacrophages residing in vis-ceral omental at depot compared to subcutaneous inguinaldepot in these subjects [, ]. Additionally, while macrophagecontent increases in both visceral and subcutaneous at depotollowing a high-at diet (HFD) eeding, the increase isseveralold greater in VA []. Overall these ndings indicatethat increased macrophage accumulation in VA may be akey pathologic eature o obesity and thereby o associatedconditions such as type diabetes, cardiovascular disease,and atty liver.

3. Lipolysis, Resulting in an Increaseof Free Fatty Acids, Promotes AdiposeTissue Macrophage Accumulation

What is the underlyingactor thatpromotesthe accumulationo adipose tissue macrophages (AMs)? Kosteli et al. pro-posed that this phenomenon may be driven by alterations inadipose metabolic unction and substrate uxes, specically increased concentrations o ree atty acids (FFAs) []. Tey suggested that obesity causes an increase in basal lipolysis,and the resultant increase in local extracellular ree atty acid concentrations could provide a chemotactic stimulusor entry and accumulation o macrophages. Basal lipolysisis chronically elevated in adipose tissue o obese comparedwith lean persons and in intra-abdominal compared withsubcutaneous adipose tissue []. Consistent with thishypoth-esis, visceral adipose tissue depots contain more AMs thanabdominal subcutaneous depots []. Many details o thisprocess remain to be claried. Basal lipolysis could release anumber o potentialsignaling molecules that could play a rolein macrophage chemotaxis, or example, arachidonic acidproducts []. An additional intriguing eature is that lipolysis

also increases during weight loss, and AMs recruited inresponse to weight loss have a more anti-inammatory phenotype (see below) than those in the adipose tissueo stably obese animals []. Tese differences suggest thatadditional actors are required or the entering macrophagesto take on a proinammatory phenotype.

4. Recruitment of Macrophages in Adipose Tissue

Recruitment o macrophages into adipose tissue is anearly event in obesity-induced adipose depot inammation.

However, it is only one o several early events—overnutritionalso causes adipocytes to release chemokines, such asmonocyte chemoattractant protein- (MCP-), providing achemotactic gradient that attracts monocytes into adiposetissue []; these presumably can transorm into tissue resi-dent macrophages, that is, AMs. A variety o chemokines

released rom AMs can then recruit additional mono-cytes/macrophages, promoting a eed-orward process [].For instance, MCP-, secreted primarily by macrophages andendothelial cells, is also secreted by adipocytes []. TeMCP- ligand has high affinity or C-C moti receptor (CCR) on macrophages, and signals generated by this path-way stimulate macrophage migration into inamed or dam-aged tissues [, ]. CCR(−/−) mice display reduced AMcontent, reduced proinammatory cytokines, and improvedsystemic insulin sensitivity relative to body weight-matchedwild-type (W) controls []. Tere were some conound-ing phenotypic changes in the CCR(−/−) mice; howeverOh et al. showed that transplanting monocytes rom theCCR(−/−) mice into W mice or W monocytes into MCP-(−/−) mice also resulted in decreased AM accumulation[]. Similar effects were observed when obese wild-typemice were treated with a CCR antagonist or a short term[]. Conversely, transgenic mice overexpressing MCP- inadipocytes exhibited increased AM levels, hepatic steatosis,and insulin resistance [].

Another critical mediator o AM accumulation is integrin, which permits macrophage adhesion to endothe-lial cells and their subsequent transmigration through theendothelial barrier. Mice carrying a loss-o-unction integrin point mutation had reduced monocyte inltra-tion into VWA and were protected rom obesity-inducedinsulin resistance []. Cbl-associated protein (CAP), aknown regulator o glucose transport (GLU) in adipocytes,also promotes macrophage mobility []. When the CAPgene is deleted rom macrophages in vivo, the knock-out(KO) mice show a decrease in AM content with reducedtissue inammatory markers and cytokine concentrations[]. Te chemokine LB is a potent chemoattractant orneutrophils—it is mainly produced by leukocytes, but is alsoexpressed by adipocytes, and it augments MCP- expressionin human monocytes, thus contributing to AM inltration[]. Recent studies by Spite et al. have shown that micelacking the gene encoding the LB receptor, BL, mani-ested decreased inammation in adipose tissue and liver andwere protected rom systemic glucose and insulin intolerance

compared to W littermates []. In keeping with these nd-ings, deletion o other monocyte chemokine receptorssuch asCCR also mitigates AM accumulation in HFD-ed mice.CCR and its ligands were robustly upregulated in VWAo HFD-induced and genetically induced obese mice [].However, CCR(−/−) mice were protected rom insulin resis-tance, glucose intolerance, and hepatic steatosis induced by HFD eeding []. aken together, these ndings indicate thatmultiple chemoattractants draw macrophages, monocytes,and neutrophils into adipose tissue. An intriguing, unstud-ied possibility is whether these multiple chemoattractant-receptor pairs recruit different populations o macrophagesor immune cells into adipose tissues.


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Treg

TH2

IL-4

IL-10

IL-13

Eosinophils

IL-4

Lean adipose

F4/80

CD11b

IL-10

M2 macrophage polarization

CLS

TH1

Obese adipose

CD8+T cells

IFN-

B cells

Ig’s

M1 macrophage polarization

Mast

cells

F4/80

CD11b

CD11c

TNF

TNF

IL-1

F : Role o the immune system in lean versus obese adipose tissue. In lean adipose tissue, -helper type ( H2) cells produceanti-inammatory cytokines such as interleukin (IL)-, , and which promote alternatively activated M macrophage polarization. Mpolarization is also induced by regulatory cells (regs) and eosinophils via IL-. M macrophages secrete other anti-inammatory signalssuchas IL-which maintaininsulin sensitivity withinlean adipose tissue. Conversely, H1 typecytokinessuch as intereron (IFN)- stimulateM macrophage polarization in obese adipose tissue. Other immune cells are also increased in obese adipose tissue which contribute to

insulin resistance including mast cells, B cells, and immunoglobulins (Igs). CD(+) cells promote AM accumulation and proinammatory gene expression and are also increased as well. Macrophages are not homogenously distributed throughout obese adipose tissue but ratheraggregated around dead adipocytes orming crown-like structures (CLS). M macrophages are proinammatory, secreting cytokines such asNF- and IL-. Macrophages are bone-marrow-derived myeloid cells hence both M and M macrophages express themyeloid cell suracemarkers F/ and CDb. However, only the M population expresses the marker CDc.

5. Heterogeneity of AdiposeTissue Macrophages

AMs that reside in lean adipose tissue differ rom thosein obese adipose tissue. Classically activated macrophages(CAMs), termed M, are generally stimulated by -helper-

-type cytokines such as IFN- or bacterial by-products.M macrophages are proinammatory, secreting cytokinessuch as NF- and IL-, and have high phagocytic andbactericidal potential []. M cells are generally recruitedrom the circulation in a CCR-dependent manner, so it islikely that their accumulation in adipose tissues is possibly due to increased entry rom the circulation. In contrast, -helper--type cytokines such as interleukins (IL)-, , and promote alternatively activated macrophages termed M.M macrophages have antiparasitic unctions, secrete anti-inammatory cytokines such as IL-, and unction in tissuerepair and remodeling []. M cells are thought to be derivedrom replication o AM resident macrophages—hence it is

possible, but unproven, that their increase in adipose tissue isdue to accelerated local multiplication (Figure ).

issue macrophages respond to alterations in the localenvironment by changing their polarization status. Obesity not only promotes inltration and migration o macrophages,but also induces a shif in macrophage balance towards the

M phenotype []. In act, obesity shifs the adipose M: Mratio rom : in normal mice to . : []. Tis shif is evi-dent in the expression level o CDc on AMs. Macrophagesare bone-marrow-derived myeloid cells; hence both M andM macrophages express the myeloid cell surace markersF/ andCDb. However, only the M population expressesthe marker CDc, whereas M macrophages are CDc(−)[, ]. M, CDc(+) recruited macrophages account orthe majority o the increase in AMs observed in obeseadipose tissue, where >% o recruited monocytes becomeCDc(+) AMs [, ]. Also, M correlates with insulinresistance as demonstrated by Patsouris et al. []. Teseinvestigators deleted CDc(+) macrophages in mice using


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a genetic system in which the primate diphtheria toxinreceptor (DR) gene is driven by the CDc promoter;the intention was to make CDc(+) cells expressing DR on their surace undergo apoptotic death when the animalwas exposed to diphtheria toxin. In mice ed HFD or weeks, diphtheria toxin exposure ablated about hal o all

AMs, while also reducing myeloid cell content in the liverand skeletal muscle. Remarkably, only – hours aferdiphtheria toxin administration, glucose tolerance tests com-pletely normalized in these mice, associated with improvedinsulin sensitivity in both liver and skeletal muscle []. Tisstudy illustrated that CDc(+) macrophagepopulations (M)are responsible or insulin resistance in obese animals anddemonstrated that their continued presence is required tomaintain this state.

AM M polarization status is not necessarily perma-nent; it can revert to M predominance under certaincircumstances. For instance, switching mice rom a HFDto a chow diet [] or treating obese mice with thiazo-

lidinediones (ZDs) [] changed AM polarization romM to M and subsequently improved insulin sensitivity.Although switching HFD to chow eeding reversed adiposetissue inammatory cytokine levels, it did not change thequantity o CDc(+) cells until weeks afer the dietchange, indicating that the macrophage phenotype may bedynamic []. Furthermore, Shaul et al. demonstrated thatnot all CDc(+) cells reect the typical M phenotype asdened in vitro and in conditions o acute inammation[]. However, to summarize current understanding o acomplex and emerging paradigm o adipose inammation,M predominant AMs are typically seen in normal, leansubjects while a transormation to the M state propagates theinammatory state associated with obesity.

6. Adipocyte Death and Crown-Like Structures

Macrophage accumulation in VA occurs in the context o continuous tissue remodeling that is pathologically acceler-ated in the obese state. Adipocytes increase and decrease insize in order to accommodate changes in lipid load duringminor uctuations in weight. With excessive weight gain,extreme increases in adipocyte size are accompanied by anelevated requency o adipocyte death and macrophage accu-mulation []. Te accelerated adipocyte death rate couldpartly be explained by hypoperusion causing an inadequate

supply o oxygen in the ace o expanding adipose tissue. Tisphenomenon o poorly oxygenated adipose tissue was rstobserved in mice but has also been shown in obese humans[]. Hypoxia activates the transcription actor hypoxia-inducible actor- (HIF-), which induces expression o

various target genes; deletion o HIF- in adipocytes par-tially protects mice rom HFD-induced obesity and insulinresistance compared with similarly ed wild-type controls[, ]. Strissel et al. tracked the adipocyte death rate inobese, HFD mice by assessing VA histology periodically or weeks and ound that the proportion o dead adipocytesincreased rom % during the courseothestudy[]. Te adipocyte death rate wasassociated with

parallel increases in weight, numbers o AMs (expressingCDc), NF and MCP- levels, and insulin resistance [].

Macrophages are not homogeneously distributedthroughout VA but rather aggregated around dead adi-pocytes as shown in Figure . Dead adipocytes lack uni-locular lipid droplets and thereore do not stain or perilipin

[]. Clusters o F/-staining macrophages surroundingperilipin (−) adipocytes are termed “crown-like structures”(CLS) []. Individual CLS contain up to macrophages andthe majority o AMs are localized to CLS []. While it israre to see CLS in chow-ed mice, there is greater than -oldincrease in CLS number in HFD-ed mice []. Ingenetic andHFD models o rodent obesity, CLS are more numerous in

visceral compared to subcutaneous depots, and CLS numbercorrelates directly with insulin resistance [, , ]. Te sameholds true in obese humans, in whom CLS are signicantly enriched in omental compared to inguinal adipose tissue [].Furthermore, the number o omental depot CLS correlateswith local levels o inammatory mediators, insulin resist-ance, and systemic vascular endothelial dysunction, inhumans [, ]. aken together, CLS are pathological lesionsin VA o obese subjects, and they are highly correlated withadipose inammation and insulin resistance.

7. Inflammatory Signaling and StressResponses Causing Insulin Resistance

Obesity-associated insulin resistance (IR) is consistently associated with elevated levels o proinammatory cytokinessuch as NF, IL-, and IL-, and neutralization o NFimproves insulin sensitivity in obese rodents []. Bothadipocytes and the M subset o AMs are a major source o

these cytokines. Tese cytokines activate inammatory path-ways that terminate in activation o Jun N-terminal kinase- (JNK) and inhibitor o kB kinase (IKK), the productso which alter signaling downstream o the insulin receptorand cause insulin resistance [, ]. Activation o thesekinases in obesity highlights the intertwined relationship o metabolic and immune pathways; JNK and IKK are the samekinases that are activated in the innate immune response,mediated by oll-like receptor (LR) signaling stimulatedby lipopolysaccharide (LPS), peptidoglycan, double-strandedRNA, and other microbial products (Figure ).

.. IKK Signaling Pathway. IKK can impact insulin sig-

naling through at least two pathways. First, it can directly phosphorylate insulin receptor substrate protein- (IRS-) onserine residues, leading to attenuation o tyrosine kinase-mediated signaling rom the insulin receptor, intererence o normalinsulin action, and subsequent insulin resistance [].Secondly, IKK leads to phosphorylation o the inhibitoro nuclear actor-B (IB). In the resting unphosphorylatedstate, IB orms a complex with nuclear actor-B (NF-B), preventing it rom entering the nucleus. However,phosphorylated IB dissociates rom NF-B and undergoesdegradation; ree NF-B translocates to the nucleus, binds toDNA, and activates inammatory mediators such as NFand IL- []. Arkan et al. showed that mice lacking IKK


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ER

IRE−1

PERK JNK

Ser-P

Insulin receptorTLR4GRP120

P

LPS, saturated FA

PPAR

AP1HIF

Inflammatory genes

FA,excess

nutrients,microhypoxia

ER stress

UPR ATF

IKK

IRS-1

NF-BIB

NF-B

- 3 F

A

- 3 F A

F : Various signaling pathways promoting or inhibiting inammatory signaling (green arrows represent activation, and red arrowsrepresent inhibition). Jun N-terminal kinase- (JNK) and inhibitor o kB kinase(IKK) are inammatory signaling pathways which promoteinsulin resistance. Activation o either pathway leads to serine phosphorylation o insulin receptor substrate protein- (IRS-), causingattenuation o insulin action. IKK also phosphorylates inhibitor o nuclear actor-B (IB) which essentially rees nuclear actor-B (NF-B), allowing it to translocate to the nucleus, bind to DNA, and activate inammatory mediators. JNK can also stimulate transcriptiono inammatory genes in association with transcription actor activator protein (AP). oll-like receptor (LR) activation, whichnormally binds lipopolysaccharides (LPS) and saturated atty acids (FA), results in activation o JNK and IKK. Endoplasmic reticulum(ER) stress, stimulated by FA, nutrient excess, and microhypoxia, leads to the unolded protein response (UPR). UPR comprises three mainpathways: inositol-requiring enzyme (IRE)-, protein kinase-like ER kinase (PERK), and activating transcription actor (AF) which alllead to activation o JNK and IKK. Hypoxia also activates the transcription actor hypoxia-inducible actor- (HIF-), which inducesexpression o various target genes. Conversely, insulin sensitivity is promoted by activation o the omega- atty acid receptor (GRP)which inhibits JNK and IKK. PPAR also promotes insulin sensitivity by interering with the NF-B and AP signaling pathways andsubsequent expression o inammatory genes.

in myeloid cells are insulin sensitive []. Moreover, whenthese myeloid-specic IKK knockout mice were placed onHFDs, they became just as obese as their wild-type coun-terparts but were protected rom obesity-induced glucoseintolerance and hyperinsulinemia [].

.. JNK Signaling Pathway. As seen in Figure , activationo JNK also results in inhibitory serine phosphorylation o

IRS-. In a manner similar to IKK, JNK can stimulatetranscription o inammatory genes in association withtranscription actor activator protein (AP) []. Knockout(KO) o JNK in nonhematopoietic cells protected mice romHFD-induced insulin resistance, in part through decreasedadiposity [, ]. By contrast, mice with JNK knocked outo hematopoietic cells (macrophage-specic cells) becameobese on HFD, with hepatic steatosis and increased intra-muscular triglyceride content, but were still protected againstinsulin resistance []. Protection against insulin resistancewas conerred to these hematopoietic cell-specic KO miceby a decrease in AM content and reduction in inammatory pathway gene expression []. Tis experiment demonstrates

that obesity and tissue lipid burden may not be sufficient tocause insulin resistance. Without the inammatory compo-nent, obesity does not lead to appreciably impaired insulinaction as demonstrated in macrophage-specic IKK andJNK-KO mice [, ].

.. oll-Like Receptors and Lipid Mediators. AMs existin a lipid-rich milieu, and ree atty acids, abundant in

that milieu, can have a variety o effects on macrophageinammatory pathways. For instance, omega- atty acids areanti-inammatory, polyunsaturated atty acids are weak orneutral, and saturated atty acids are proinammatory [].oll-like pattern recognition receptors recognize moleculesthat are broadly shared by pathogens. Specically, oll-like receptor (LR) is expressed on macrophages andrecognizes not only LPS produced by gram-negative bacteriabut also saturated atty acids; both o these ligands canactivate LR, resulting in activation o JNK andIKK. LRexpression is increased in obesity; when the gene encodingLR was deleted, HFD mice were protected rom insulinresistance and weight gain compared to controls [, ].


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Lipid species appear to regulate inammatory signalingin macrophages through non-LR pathways as well. Overex-pression o diacylglycerol transerase- (DGA-, which cat-alyzesthe nal stage in triglyceridesynthesis) in macrophagesprotects against adipose macrophage inltration, inamma-tion, and insulin resistance []. Tis suggests that the effects

o triglycerides on macrophages may not be as inimical as theeffects o the precursors o triglycerides, that is, atty acidsand diacylglycerols. Diacylglycerols in particular have beenimplicated in insulin resistance in liver and muscle []. Inaddition, ceramides have recently been shown to activate thenucleotide-binding domain, leucine-rich-containing amily,and pyrin-domain-containing (NLRP) inammasome [].NLRP activation ultimately leads to IL- and IL- secretion,a response that is generally stimulated by “danger signals”o nonmicrobial origin []. Finally, omega- atty acidshave anti-inammatory and antidiabetic effects in humansand mice. Activation o the omega- atty acid receptor(GRP) on macrophages and adipocytes reverses adiposeinammation and insulin resistance in obese mice [].

.. Endoplasmic Reticulum (ER) Stress. Multiple proinam-matory sources can lead to activation o AMs in obesity,including ER stress. ER stress can be stimulated by atty acids,nutrient excess, improperly olded proteins, and regionalareas o microhypoxia, all o which occur in obese adiposetissue. As obesity develops, protein biosynthetic pathways areupregulated, activating the unolded protein response (UPR)intheER[]. Te UPR comprises three main pathways con-trolled by ER membrane proteins: inositol-requiring enzyme(IRE)-, protein kinase-like ER kinase (PERK), and activatingtranscription actor (AF). All branches o the UPR can

directly engage inammatory pathways through activationo IKK and/or JNK signaling []. In summary, there arenumerous mechanisms propagating inammation in obesity,but most i not all appear linked to one o two nal commonpathways—JNK and IKK—which lead to the end-result o insulin resistance.

8. Mechanisms to CounteractInflammatory Signaling

.. Peroxisome Proliferator-Activated Receptors (PPARs).PPAR is a member o the nuclear receptor superamily o ligand-dependent transcription actors that is predominantly

expressed in adipose tissue and the intestines. PPAR isalso highly expressed in macrophages and is a naturalligand to FFAs and eicosanoids. PPAR and PPAR unctionas regulators o lipid metabolism and glucose homeosta-sis, respectively, and are targets or atty acid oxidizingbrates and insulin-sensitizing ZDs, respectively []. Asseen in Figure , PPAR activators inhibit the activation o inammatory response genes by interering with the NF-B and AP signaling pathways, thereby promoting insulinsensitivity []. Consistent with this effect, Hevener et al.demonstrated that macrophage-specic PPAR KO inducedglucose intolerance with skeletal muscle and hepatic insulinresistance in lean mice ed a normal diet []. Tis phenotype

was associated with increased expression o inammatory markers and impaired insulin signaling in adipose tissue,muscle, and liver. Furthermore, insulin resistance becamemore severe in mice lacking macrophage PPAR ollowingHFD eeding, and these mice were only partially responsiveto ZD treatment []. Another member o the PPAR amily,

PPAR /, is induced by IL- and IL- to promote alterna-tive activation o macrophages. Myeloid-specic deletion o PPAR / in mice has been shown to cause insulin resistancewith increased adipocyte lipolysis and severe hepatosteatosis[]. Tus PPARs unction in an anti-inammatory mannerand promote M polarization.

9. Other Immune Cells in Adipose TissueContributing to Insulin Resistance

As obesity develops, enlarging adipocytes secrete chemokinesthat attract immune cells. Macrophages are amongst the

earliest immune cells to inltrate adipose tissue, as theirnumbers increase afer one week o HFD []. Althoughmacrophages are vital in innate and adaptive immunity, theimmune response is a result o interactions between multiplecell types. Hence, regulatory cells, CD+ effector cells, Bcells, mast cells, and eosinophils within adipose tissue havealso been implicated in the pathogenesis o obesity-relatedinsulin resistance.

.. Lymphocytes. cells are involved in adipose tissueinammation and IR by modiying AM numbers andaffecting polarization states. -helper (

H) cells express the

cell surace marker CD and comprise H

cells (whichproduce proinammatory cytokines) and H cells (whichproduce anti-inammatory cytokines). Regulatory cells(regs), another CD(+) type, secrete anti-inammatory signals, inhibit macrophage migration, and induce M polar-ization []. Feuerer et al. discovered that regs were highly enriched in the VA o normal mice, but their numbers werestrikingly reduced at this site in HFD-ed and genetically obese mice []. Furthermore, reg deletion in mice inducedacute elevations o NF and IL- transcripts in VA, whileinhibiting insulin signaling in muscle and liver []. Incontrast to CD(+) cells, cells that express the suraceantigen CD (known as effector or cytotoxic cells) promoteAM accumulation and proinammatory gene expression

and are increased in number in obese adipose tissue [].Winer et al. highlighted the role o regs through analyseso -cell decient Rag-(−/−) mice []. When placed onHFD, Rag-(−/−) rodents were more insulin resistant thantheir controls. Adoptive transer o CD(+) to these rodentsreversed the insulin resistant phenotype and abrogatedVWA inammation; this was not observed with adoptivetranser o CD(+) cells in Rag-(−/−) rodents []. A criticalunanswered question in regard to these proound effects o cells is what in the milieu o adipose tissue activates themin the rst place. It would be important to determine i the activator is a specic antigen or whether some orm o completely antigen-independent cell activation takes place.


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B cells have also been ascribed unctions in promotingVA inammation during weight gain. Winer et al. iden-tied a VA B-cell population that expanded with HFDeeding, with parallel increases in tissue IgM and IgG levels.Immunohistochemistry revealed deposits o these antibodiesthroughout VA that mirrored the locations o CLS [].

Mice lacking the immunoglobulin mu heavy chain (B-nullmice) were protected rom HFD-induced insulin resistanceand displayed diminished VA inammation as indicatedby lower numbers o M-like macrophages and activatedCD(+) cells. Strikingly, reconstitution o B-null mice witheither wild-type (W) B cells or serum immunoglobulinsrom W HFD-ed mice was sufficient to restore the insulinresistant phenotype. Furthermore, adoptive B-cell transer tolean W mice induced insulin resistance []. Tese resultsdemonstrate inammatory pathways in which B cells andadaptive immunity play a role in insulinresistance.Again, thestimulus or B-cell activation, whether a specic antigen orotherwise, remains to be specied.

.. Mast Cells. Although mast cells are well known or theirrole in allergy and anaphylaxis, they seem to play a role inobesity as well. Altintas et al. ound that subcutaneous ato lean mice contained more mast cells, but ewer solitary macrophages and CLS than visceral at []. With obesity,there was no signicant change in mast cell density o subcutaneous at, but there was a substantial increase in mastcell number in visceral at. CLS became prevalent in visceralat o obese mice, andtheirdistribution paralleled that o mastcells. Immunouorescence staining and conocal microscopy demonstrated that a subset o mast cells in adipose tissuecontained and released preormed NF- as well []. In

summary, subcutaneous at differed rom visceral at by notonly immune cell composition but also by having a lowerprevalence o CLS both in lean and obese mice. Te increasein mast cells in visceral at o obese mice suggests a role inthe pathogenesis o obesity and insulin resistance. Liu et al.discovered that in mice ed on a Western diet, genetically induced deciency o mast cells or their pharmacologicalstabilization (with daily injections o disodium cromogly-cate) reduces body weight gain and levels o inammatory cytokines in serum and VA, in conjunction with improvedglucose homeostasis and energy expenditure [].

.. Eosinophils. Similar to mast cells, eosinophils mediate

allergic reactions in addition to combating parasites. Wu et al.demonstrated that eosinophils also participate in endorsing aM-like AM polarization state via IL- []. By analyzingVA o mice on a normal chow diet, these investigatorsound that >% o the IL--competent cells recovered wereeosinophils. Tere was a reciprocal relationship betweenadipose eosinophil quantity and mouse weight. When placedon a HFD, those mice that were genetically decient ineosinophils had increased body at, impaired glucose toler-ance, and insulin resistance in comparison to W controls.Wu et al. also observed thatmiceon a HFD whowere inectedwith helminths sustained a metabolic response characterizedby decreased asting glucose and improved insulin sensitivity

rom theearly postinection phase and sustainedup to daysollowing inection [].

10. Conclusion

At a histological level, adipose tissue inammation in obesity

is associated with macrophage accumulation and develop-ment o CLS. At a cellular level,the resultant insulin resistancecan be explained by activation o JNK and IKK, twocritical pathways mediating a range o inammatory andstress mechanisms activated in obesity. It is interesting tonote that many cellular and biochemical components o the immune system that normally protect the host romoreign pathogens, such as macrophages and LRs, also play a pathologic role in obesity-related inammation. Overall,adipose tissue inammation in obesity demonstrates that theimmune system and metabolism are highly integrated.

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