Leptin: Molecular Mechanisms, Systemic Pro-Inflammatory Effects

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discovery ofleptinhasdramatically changedtheunder discovery to beconceptualizedasanendocrine organ (1,2).The Leptin; immunity;inflammation;cytokines Keywords Leptina; imunidade;inflamação;citocinas Descritores Arq Bras Metab. Endocrinol 2012;56/9 ofthe adipose standing ofthe physiologicalimportance A INTRODUCTION associando-os aenfermidadesinflamatóriascrônicas. cutidos osmecanismosmolecularespelosquaisaleptinaregula aimunidadeeinflamação, reguladas porproteínasintracelulares,reduzindoasaçõesda leptina.Nestarevisão,sãodis pelaleptina:JAK-STAT,cascatas intracelularessãoativadas PI3KeERK1/2.Essascascatassão pelos quaisaleptinadeterminasuasaçõesbiológicasforamrecentementeelucidados,etrês tiposdecélulasdosistemaimunológico. Osmecanismosmoleculares distribuído emdiversos lidade. A leptinatambémregulaainflamaçãopormeio daaçãoemseureceptor, amplamente deficiências imunológicasemmodelosanimaisehumanos,levandoaoaumentodamorta imunidade edainflamação. Já foiamplamentedemonstradoqueaausênciadeleptinacausa pel importante nãosomentenaregulaçãodaingestãoalimentar, mastambémnocontroleda A leptina,umaadipocinaproduzidaprincipalmentepelotecidoadiposobranco,temumpa SUMÁRIO matory disorders. regulates immunityandinflammation,associatethosemechanisms with chronic inflam leptin biologicalactivity. Inthisreview, wediscussthemolecularmechanisms bywhich leptin PI3K, andERK1/2. These pathways arecloselyregulatedbyintracellularproteinsthatdecrease elucidated, andthreeintracellularpathways havebeenimplicatedinleptinactions:JAK-STAT, lecular mechanisms bywhich leptindeterminesitsbiologicalactionshavealsobeenrecently actions onitsreceptor, thatiswidelyspreadacrossdifferent immunecellpopulations. The mo human models,ultimatelyincreasingmortality. Leptin alsoregulatesinflammationbymeansof been widely demonstrated that the absence of leptin leads to immune defects in animal and butalsoincontrollingimmunityandinflammation.Ithas only intheregulationoffoodintake, Leptin, theadipokineproducedmainlybywhiteadiposetissue,playsimportant rolesnot SUMMARY Gilberto Paz-Filho inflamatórios sistêmicos eimplicações clínicas Leptina: mecanismosmoleculares, efeitos pró- and clinical implications systemic pro-inflammatory effects, Leptin: molecularmechanisms, Franco fat, overwhelming evidenceled theadiposetissue fat, overwhelming asasimplestorageof lthough initiallyconsidered 2 , Kevin Boyang Wang Arq BrasEndocrinolMetab. 2012;56(9):597-607 1 , ClaudioMastronardi 3 ,Ma-Li Wong 1 , Bertoldi Carina 1 , Julio Licinio Arq BrasEndocrinolMetab. 2012;56(9): 597-607 only synthesizes and releases dozensofothermetabo only synthesizes andreleases ithas beenshownthattheadiposetissuenot present, tothe thisseminaldiscovery (3).From gy expenditure foodintakeandener tosignal thebraintocontrol role thatplays acrucial thiskeyhormone sizes andreleases tissue, makingitclearthat theadiposetissuesynthe 1 - - - - - 2 1 Accepted onOct/24/2012 Received onMay/27/2012 [email protected] Acton ACT Australia0200, Building 131, Garran Road Gilberto Paz Filho Correspondence to: 3 School,Canberra, Australia National UniversityMedical ResearchUnit, Australian University,Canberra, Australia The AustralianNational School ofMedicalResearch, Medicine, The John Curtin University,Melbourne, Australia and HealthSciences,Monash EndocrinologyandDiabetes Departmentof Translational School ofMedicine,Nursing review 597

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 598 inadequate body weight–bothobesityand malnutri e andnutritionalstatus, (Th) 1immunerespons alinkbetweentheThelper Leptinexerts se isimpaired. low, leptinlevelsare tic restriction, andimmunerespon Underenerge including immuneresponse. processes, brain thatexcessenergy isavailableforseveralbiological nutrition,leptinsignalstothe During statesofnormal immune cells Molecular mechanismsofleptinandmodulation diseases. inflammatory leptin andchronic relationships between leptin andinflammation,the in theimmunesystem,molecularlinksbetween inflammationinobesity.chronic helpstoperpetuatetheloopof leptin, whichinturn of the synthesis and release cytokines increase matory -inflam pro bidirectional: leptin and inflammation are theinteractions between of inflammation. Therefore, withthelevel leptinlevels(9),whichcorrelate crease 1, lipopolysaccharide(LPS),andTNF-acanalsoin andinfectious stimuli,suchasIL- inflammatory certain responses. Concomitantly, leptin triggersinflammatory immunecelltypes, bydifferent R), whichisexpressed (Ob- of the leptin receptor acting on the long isoform (8).By and theircomplications,suchasatherosclerosis statethatisseeninobesity,matory metabolicsyndrome, (6,7). central hypothyroidism hypogonadism,and triglyceridemia, hypogonadotropic hyper tions, suchashyperglycemia, insulinresistance, obese andhaveseveralmetabolicendocrinealtera severely Leptin-deficientmiceandhumansare resistant. alsoleptin- elevated in obese patients, who are and are withfatmass correlated directly (5). Leptinlevelsare and intake,playingacentralactioninenergy balance caloric expenditure regulates mation (4). This hormone giogenesis, osteogenesis, wound healing, and inflam glucosehomeostasis,hematopoiesis,an reproduction, tions intheimmuneandendocrinesystems,including whiteadiposetissue,withvariousfunc differentiated racts withseveralphysiologicalsystemsoftheorganism. attention tofatasanimmunoendocrineorgan thatinte (IL-1RA), andIL6(1).Allofthesefindingsattracted (IL-1) alpha (IL-1α as tumor ofcytokinesandimmunefactorssuch it isalsoasource andadiponectin,but factors, suchasresistin lic-related Leptin andinflammation In this manuscript, we summarize the role ofleptin In thismanuscript,wesummarizetherole -inflam pro inthechronic Leptin playsamajorrole bythe predominantly Leptin isacytokineproduced necrosis factoralpha(TNF-a -necrosis ), IL-1β 1 receptor antagonist antagonist , IL-1 receptor 1 ), interleukin-1 containing several motifs required for signal transduc containing several motifs required cytoplasmicregion whichcontainsaprominent form, Ob-Rbistheonlylong (12). Ofalloftheseisoforms, oftheOb-Rgene splicedforms of sixalternatively allpro Rc, Ob-Rd,Re,andRf;theseare Ob-Ra,Rb, inrodents; of theleptinreceptor isoforms atleastsixdifferent are (NK) cells(11).There cells, mastdendriticcells(DC),andnaturalkiller subpopulations of T cells and B cytes, macrophages, mono byneutrophils, CSF). TheOb-Risexpressed (LIF), and granulocyte colony-stimulating - factor (G factor for IL-6, leukocyte inhibitory cludes the receptor (gp130) superfamily,I cytokine receptor which in similaritieswiththemembersofclass has structural 11, IL-12, and oncostatin M. Leptin receptor, -R, Ob of thelong-chainhelicalfamilythatincludesIL6, (10). both ininnateandadaptiveimmuneresponses influenceimmunecellfunction, tion –canimportantly quence homology with any other known protein, com quence homology withanyotherknown protein, nosignificantse the cloningofObgenerevealed weight non-leptin deficientindividuals. First, although inobese/over asananti-obesityhormone to perform and2)leptinresistance leptin tridimensionalstructure ger pathwaysismarkedbytwo fundamentalfactors:1) determined. tobe ofCRH1remains in Ob-Ractivation.Therole criticallyinvolved IIIdomain(FNIII)are fibronectin Ob-R. The immunoglobulin-like domain (Ig -like) and 2 (CRH2)isthemainbindingsiteforleptinon homology module Cytokine receptor 60, respectively). box 2motifs(intracellularaminoacids6-17and49 box1and naling takesplacebyactivationofconserved and lacksomeorallofthesemotifs.Transduction sig theothershavetransmembrane domains, tion, whereas for signal transduc containing several motifs required OnlyOb-Rbhasalongcytoplasmicregion C terminus. atthe extracellular, ligand-bindingdomains,butdiffer thesame identical with theexception of Ob-Rb, share actions in the brain and peripheral organs. All isoforms, involvedinmediatingleptin are tein. Theseisoforms asa plasmatic leptin-binding pro domains, and serves Re) thatlacksboththeintracellularandtransmembrane (Ob- form andaleptindegrader;secreted barrier theblood-brain across asaleptintransporter regarded Ob-Ra, Rc,Rd,andRf,ofwhichRais including way. forms, (short) fourtruncated are There tion andiscapableofactivatingtheJAK–STAT path Leptin has structural homologywiththecytokines Leptin hasstructural The elucidationofleptin-inducedsecondmessen Arq Bras Metab. Endocrinol 2012;56/9 ducts phosphorylated JAK2itself,independentofphosphor phosphorylated Arq Bras Metab. Endocrinol 2012;56/9 theothertyrosineresidues (Tyrphosphorylates tyrosine kinase2(JAK2)byauto-orcross-phosphorylation. JAK2then Leptin binds to the leptin receptor (Ob-Rb) and activates Janus-family Figure 1. LeptinandtheJAK-STAT pathway. ofTyr Janus-activated kinasephosphorylation 3)(15). phosphatidylinositol-3kinase (PI3K)(Figure 2),andtheactivationof nase (ERK)-1/2(Figure ki ways, namely the extracellular signal-regulated for leptin-inducedSTAT ofafunctionalOB-Rgenewasrequired the presence ob andWTmice,butnotindb/dbindicatingthat tration ofleptin-activatedhypothalamicSTAT outinmicehaveshownthatperipheraladminis carried activated theJAK-STAT pathway(14).In vivo studies tional withtheIL-6cytokinefamilyleadtofunc gene share similarities that leptin and the The structural thatsignalsviatheJAK-STATIL-6 receptor pathway. mology withgp130,thesignaltransducingunitof sequenceho shared thatleptinreceptor (12) revealed theendof1995 towards of theOB-Rgenereported STAT 1)(13).Moreover, pathway(Figure thecloning bundled cytokine,suchasthosethatactivatetheJAK- displayed tridimensional characteristics of a four thatleptin studiespredicted putational-based research tyrosine residues. (SOCS1 andSOCS3)suppresstheaction ofleptinbybindingtoJAK2and as apromoterforgenetranscription [4]. MembersoftheSOCSfamily undergoes dimerizationandtranslocates intothecellnucleustofunction 2 and subsequently binds to the phosphorylated 2 andsubsequentlybindstothephosphorylated Tyr Transducer and Activator of Transcription 3(STAT-3) isasubstrateof JAK act assitesforthebindingofintracellular signalingmolecules. Signal Leptin controls othertwokeysignaling path Leptin controls signaling studies that proved that leptin in vitrosignaling studies that proved P Ob-Rb JAK 2 Tyr Tyr Tyr 1138 1077 985 Leptin JAK 2 P P P P P -3 activationwithinthebrain. STAT 3 STAT 3 STAT STAT 3 STAT P 985 , Tyr , Regulation ofgene 1077 1138 transcription P P STAT 3 STAT , Tyr1 STAT 3 STAT . STAT-3 then -3 inob/ SOCS 1/3 138 985 ), which OB-R -helix (or (PI3K). ThispathwayoriginateswithJAK2autophos ing totheactivationofphosphatidylinositol3’-kinase dent ofTyr (SHP phosphatase tyrosine SH2-domain containingprotein ofthe forphosphorylation pathway asJAK2isrequired many similarities withtheJAK2/STAT3 shares It tors. activated bybothOb-RaandRbleptinrecep (17).TheERK/MAPKpathwaycanbe ferentiation T(T regulatory way isbelievedtobethemainmechanisminvolvedin tor binding-2(GRB2)(16).TheERK/MAPKpath factorrecep the ERKsignalingpathwayviagrowth SHP-2activates phosphatase). Then,phosphorylated tion ofSHP-2(src ylated Tyr kinase 1(PDK1), andproteinkinaseB(Akt), whichisactivatedbyPDK1. include theisoformsofproteinkinase C, phosphoinositide-dependent regulates proteinsthatcontainthepleckstrin homology(PH)domain. These 4,5-diphosphate (PIP2)formingPtdIns 3,4,5-triphosphate(PIP3), which The activep110subunitthenaddsa phosphate tothe3’positionofPtdIns phosphorylation, p85subunitofPI3K. whichthenbindstotheregulatory Both the leptin and insulin receptors play a role in the initial step of IRS 1/2 Figure 2. LeptinandthePI3Kpathway. signals (15). dylinositol 3’-kinase (PI3K) and activate downstream phosphati recruit IRSproteins Then, phosphorylated substrate(IRS)proteins. ofinsulinreceptor phorylation andphos whichleadstotherecruitment phorylation, of phosphorylation at tyrosine sitesonOb-Rb,lead attyrosine of phosphorylation the promoters for the transcription of c-fos, the promoters egr-1 Rho/Rac There isalsoonepathwaythatoccursindependently There - genes, fundamental in cell proliferation anddif genes, fundamentalincellproliferation 2) viapathwaysbothdependentandindepen EFFECT PDK1 985 985 ) leads to recruitment and phosphoryla ) leadstorecruitment (18). reg AKt ) cell regulation (11), by controlling (11),bycontrolling ) cellregulation containing tyrosine homology2-containingtyrosine PIP3 P receptor Insulin IRS 1/2 p110 PI3K p85 PTEN P Leptin andinflammation P PIP2 JAK 2 jun and Ob-Rb 599

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. a mechanismsimilartotheJAK2/STAT3 pathway. of thec-fosandegr-1 genes. SOCS3isaninhibitorofthispathway, with activates ERK1/2 of the MAPK family. ERK1/2 promotes the transcription SHP-2,these units can phosphorylate which further modulates GRB2 and of Stimulation ofOb-Rbpromotesphosphorylation Tyr985 byJAK2. Both Figure 3. LeptinandtheERKpathway. a slower process asitfunctionsbyalteringgenetran a slowerprocess inflammation, incontrasttoJAK2/STAT3, whichis 600 and clinical and experimentsthatobese rodents actin skeletonwithincells(15,19). the apoptosisandremodel of GTPases,whichregulate the Rho family has also beenimplicatedincontrolling ide (NO)mTORviap70S6K (19).ThePI3Kpathway Yandnitricox neuropeptide inregulating participant kinaseB(Akt).Aktisakey protein cially inregulating espe effects, 1 (PDK1),whichhasmanydownstream is akeyactivatorofphosphoinositide-dependentkinase 3)(19).PIP3 conversion ofPIP3backtoPIP2(Figure (PTEN) isanantagonistofthispathwayandfostersthe phate (PIP3)(19).Phosphataseandtensinhomologue PtdIns3,4,5-triphos 4,5-diphosphate (PIP2)toform ofPtdIns The chainofeventsinvolvephosphorylation ofproteins. of PI3Kisintracellularphosphorylation ing it.Onceactivated,themainmechanismofaction activat stimulate thep85subunitofPI3K,thereby ofIRS,whichthen inthephosphorylation participate scription (15).BothJAK2andtheinsulinreceptor Leptin andinflammation The PI3Kpathwayisanacutephasecontributorof Soon afterleptindiscovery, itbecameevidentinpre P JAK 2 Ob-Rb Tyr Tyr Tyr 1138 1077 985 Leptin JAK 2 P P P SOCS 1/3 P P SHP-2 c-fos GRB2 ERK1/2 egr-1 as itbindstoTyr negativefeedbacktothispathway, inproviding key role of cytokinesignaling(SOCS1-3)(20).SOCS3playsa STAT identified,namelythesupressors pathwaywere induced intracellularsignalinginhibitorsoftheJAK- taking place.Inthemid-90s,anewfamilyofcytokine was the putative mechanisms leadingto leptin resistance for Thus, the search humans displayed leptinresistance. tyrosine phosphatase1B(PTP1B)(24). Thisphospha tyrosine byprotein isorchestrated leptinresistance to control obesity (23). diet-induced leptinsensitivityandtoprevent increase to that lackofSOCS3withinthebrainwaseffective and thatoccursduringtheaging process, resistance was shownthatSOCS3couldalsobeinvolvedinleptin models,it intracellular signaltransduction.Inrodent of leptin-induced was involvedinnegativeregulation Moreover,gy expenditure. theyshowedthatSOCS3 offoodintakeandener forthecontrol relevant are that the inductionofhypothalamicSOCS3inareas that peripherally administrated leptin rapidlyincreased (22).Theydemonstrated tribute toleptinresistance hypothesized thatactivationofSOCSgenescouldcon leptin alsooperatesviaJAK-STAT, Bjorbaekandcols. theactivityofSHP-2(21).Since believed torepress lation ofSHP-2,thusstoppingthecascade.Itisalso dependently increases the proliferation ofcir theproliferation also dose-dependentlyincreases apoptosis (27). It CC-chemokine ligand, and prevents of cytokines, such as IL-1RA, IL-1, IL-6, TNF-a, and the secretion thesis, acts as a chemoattractant,increases Italsoinduceseicosanoidandnitricoxidesyn ve stress. oxidati phagocytosis by regulating nocytes, improving andmo inmacrophages Leptin bindstoitsreceptor Leptin andinnateimmunity knock-out studies(26). showninwhole-bodyPTP1B previously findings were in adiet-inducedobesityanimalmodel(25).Similar and insulinsensitivity, bodyweightgain preventing leptin deletionofPTP1Bincreased SOCS3, neuronal (24). Moreover,receptor similar to mice deficient in oftheleptin JAK2-inducedphosphorylation prevents it JAK2and,therefore, tase actsbydephosphorylating or LPS is synergistically improved by or leptin LPS (29). is Lep synergistically improved nocytes bythephorbol-12myristate13 -acetate (PMA) number,(28). Theincreased andtheactivationofmo tion markers,suchasCD69 andCD25,amongothers ofactiva culating cells,andstimulates theexpression Another intracellularmechanismthatwasshown 985 and JAK2 to prevent phosphory andJAK2toprevent Arq Bras Metab. Endocrinol 2012;56/9 (PHA) (36).Importantly, of leptin onlym theeffect such asconcanavalinA(ConA) orphytohemagglutinin withothergeneralimmunostimulants, co-administered human peripheralbloodlymphocytesifitis of mature andactivation leptin canonlyinducetheproliferation Arq Bras Metab. Endocrinol 2012;56/9 Tcells n ofmemory lations. Itinhibits theproliferatio subpopu isspecificto different phocyte proliferation CD4 double-positive incortical thereduction tin prevents lep quency ofinfections,andexogenousrecombinant andhigherfre leadstothymic atrophy by starvation activation ofTlymphocytes.Hypoleptinemiacaused the factor(36).Moreover,mocyte growth leptinaffects ofIL-7,athy thymicepithelialcell expression dullary onTcellsbystimulatingtheme anti-apoptotic effects viaitsdirect Leptin maintainsthethymicparenchyma Leptin andadaptiveimmunity andcytotoxicity (35). activation, proliferation, contributes toNKcelldevelopment,differentiation, involve interaction with monocytes (35). Finally, leptin tive oxygenspecies(ROS)viamechanismsthatmight ofreac induces chemoattractionandtheproduction crine fashion(34).Onpolymorphonuclearcells,leptin leptin actsonthembothinaparacrineand/orauto that Ob-R,anditisprobable Mast cellsalsoexpress Th1priming(33). themtowards thin DC,directing also inducesmorphologicalandfunctionalchangeswi apoptosis rates.Leptin CD1a andCD80;reduces molecules,suchas such asIL-6andTNFα;surface ofcytokines, theexpression On DC,leptinincreases infiltration(32). attractant formonocyte/macrophage -1 (MCP1),whichisaknownchemo tractant protein oncogene-α,andmonocytechemoat -related growth cytokinesIL-1β , IL-6,8, ofinflammatory release chemokinesis,andstimulatesthe and CD18,increases ofadhesionmolecules nophils, itinducestheexpression means ofPKCandNO-dependentpathways(31). by hormone of growth the production also increases acyltransferases-1, and cyclooxygenase 2 (30). Leptin tion ofleukotrieneB4,eicosanoids,NO,cholesterol theproduc stimulating phospholipase and increasing anddivision.Leptinstimulatesphagocytosisby growth cell rates,controlling rived signalstocellulargrowth factorandnutrient-de pathway thatintegratesgrowth -dependent which isanintracellularnutrient-response malian Target ofRapamycin (mTOR) kinasepathway, bymeansofthe mam tin alsoactivatesmacrophages Leptin actsonseveralotherimmunecells.Oneosi + CD8 + thymocytesubpopulation(37).However, system and modulate effector T cell responses. Inani Tcellresponses. system andmodulateeffector influence theactivitiesofcellsinnateimmune -in apro towards polarizes Th0cytokineproduction naive Tcells(CD4+CD45RA+).Thismeansthatleptin of (CD4+CD45RO+), butstimulatestheproliferation such asallergy andautoimmunity. Commonly, T immune responses, inappropriate rance, and prevent the peripheralimmunetole CD4+ T cells thatcontrol (38). On thesubpopulationof Th1 cells,leptinpromo even in the lack of monocytes is observed since this effect co-stimulated, Tlymphocyteswhentheyare circulating on IL-4, 10)(38).Itseemsthatleptinactsdirectly phenotype (Th2, itself), rather than anti-inflammatory CD4+CD25+ T polarization inthecellsofleptin-deficientmice(27). ofT wassuppression there in theTh2direction, after polarizingob/ intestinal inflammation. Indeed, from protected were Th1andTh2polarization,ob/ decreased nal inflammation,leptindeficiencywasassociatedwith example, inananimalmodelofTh2-dependentintesti tin isalsofundamentalforTh2celldevelopment.For Th2 cellsandIgG1switching(39).Additionally, lep IFN-γ tes IgG2aswitchinginBcellsandinducesTNF-α (Th1,TNF-α flammatory receptor mutation (41) lead to increased vulnerability vulnerability mutation (41) lead to increased -receptor In humans, congenital leptin deficiency (40) or leptin Congenital deficiency ofleptin LEPTIN ANDCLINICAL CONDITIONS innate andadaptiveimmunity. 3). Table(Figure on 1 summarizes the leptin effects andbothstimulateeachother bidirectional, tokines are Theinteractionsbetweenleptinandcy responsiveness. cytokine cytes, NKT and CD8+Tcells,andincrease ingly, isolatedT freshly absolutenumber,the percentage, andactivityofT leptinandOb-Rdeficiencies, mal modelsofchronic tration can stimulate the proliferation of B lympho tration can stimulate the proliferation (28). R, whichconstraintheirproliferation highdensityoftheOb- quantities ofleptin,andexpress humans, leptin has a similar effect onT humans, leptin hasasimilareffect tothesamelevelsfoundinWTmice.In cells returns the number ofT diseases. Whenleptinisreplaced, toautoimmune inresistance resulting cells isincreased, Furthermore, leptin is able to reduce thehuman leptinisabletoreduce Furthermore, Besides the effects onCD4+Tcells,leptinadminis Besides theeffects production, while it exerts inhibitory actions on actionson inhibitory whileitexerts production, reg cells, which are asmallsubsetof cells,whichare ob type (WT) T cells naive andwild-type(WT)Tcells reg cells can produce significant cellscanproduce , IFN-γ IL2, IL12, and leptin IL2,IL12,andleptin Leptin andinflammation reg cells.Interest ob reg cells mice mice and and cell -cell 601 reg reg

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 602 2: cyclooxygenase-2; TNF: tumor necrosis factor; ROS: reactive oxygen species; INF: interferon. IL: interleukin; NO: nitric oxide; LB4: leukotriene B4; CAT1: cholesterol acyltransferase 1; COX- Table 1. Leptineffectsoninnateandadaptiveimmunity andasthmaticcrises(43). dermatites recurrent numberofleukocytes, andimproved levels, increased ofIFN-γ particularly liferation andcytokineresponse, pro increased leptintreatment leptin-deficient children, (42).In pends onthegenotypeand genetic expressivity possiblyde leptin gene,inwhomtheimmuneprofile characteristicofpatientswithmutationinthe obligatory type (40).However, notan theseimmunedefectsare IFN-γ toseveralstimuli,with abolishment of nes in response ofcytoki production andreduced response proliferative Tcells.Inaddition,lymphocytesexhibitimpaired mory inCD4 a decrease dhood. Congenitaldeficiencyofleptinisassociatedwith to infectionswithelevatedriskofdeathduringchil Leptin andinflammation in the number of naive T cells, and an increase inme in thenumberofnaiveTcells,andanincrease reduction CD8+ T and B cells, as well as a pronounced Neutrophils Macrophages Monocytes macrophages Monocytes/ Natural killer Eosinophils Dendritic cells secretion, and a prevailing Th2 cytokine pheno and a prevailing secretion, Innate surface markers ↑Differentiation, ↑Formation and ↑Chemokinesis IL-1β,IL-6, IL-8 NO, LB4, CTA1, ↑Expression of ↑Expression of ↑Expression of release ofROS ↑Phagocytosis ↑IL1,IL6, TNF ↑Proliferation, ↑Eicosanoids, ↑ IL-1β, IL-6, ↑Proliferation ↑Chemotaxis ↑Maturation ↑Release of ↓Apoptosis ↓Apoptosis IL-8, IL-12, cytotoxicity ↑Adhesion maturation molecules activation, activation markers CD11b TNF-α COX-2 + T cell numbers, and an increase in in T cellnumbers,andanincrease

Naive T cells Naive T Thymocytes Memory T Memory activation NKT cells inhibition Th1 cell Th2 cell T B cells reg cells cell Adaptive ↑Hyporesponsiveness ↑TNF-α, INF-γ ↑IgG2a switch ↓Proliferation ↑Proliferation ↑Proliferation ↓IgG1 switch ↑Maturation ↓Apoptosis ↓Apoptosis ↓Apoptosis ↑Anergy prominent immunealterationsthanpatientswithcon prominent low body weight) present hypoleptinemia andlowle low bodyweight)present or exercise (e.g.,strenuous caloricrestriction chronic withexogenousleptin (44). byreplacement prevented tohypoleptinemia,and are exposure mitted tochronic phy. in patient sub pronounced more are These effects and thymic atro delayed-type hypersensitivity responses ased T development ofBcellsinthebonemarrow, anddecre isassociatedwithreduced tinemia causedbystarvation in humans and animals. Acute hypolep nossupression immu Malnutrition orcaloricdeprivationproduces Hypoleptinemic states (41). withleptinreplacement alsorestored alterations are inthenumberofBcellshavebeendescribed.These crease in afterantigeniccharge, andacompensatory production incytokine ber andfunctionofCD4+Tcells,adecrease reduction inthenum genital leptindeficiency(41).A vator inhibitor amyloid A), and plasminogen acti bin, SAA (serum factor),haptoglo migrationinhibitory (macrophage TNF-α protein, such asC-reactive markers tients exhibithigherlevel ofinflammatory byothertissues(2).Also,obesepa their production cytokines orcollaboratewith inflammatory to produce disease, sincethe adipose tissue is able inflammatory Obesity, especially visceral adiposity, an is considered syndrome Hyperleptinemic states:obesityandmetabolic andtype1diabetes(46). nephropathies, thyroidopathies, autoimmune diseasesincludinghepatitis, not showclinicalimmunedeficiency, andmaypresent wever, surprisinglydo lipodystrophy patientswithsevere TNF-α and improve ofBcells, thedisproportion NKT cellnumbers,correct CD4, CD8T, can increase cells. Leptin replacement and in TNF-α ofBcellsandreduction ne, suchasahigherpercentage inimmunemarkersatbaseli measurable abnormalities and lowleptinlevels.Ingeneral,thesepatientsexhibit racterized byanalmostcompletelackofadiposetissue thionyl humanleptin)(45). with r the treatment by normalized thatare vels ofsolubleTNF-αreceptor receptor mutation present less less mutationpresent Patients withleptin-receptor Women dueto withhypothalamicamenorrhea Congenital or acquired severe lipodystrophy ischa lipodystrophy severe Congenital oracquired lymphocyte subpopulation with impairment of of -lymphocyte subpopulation with impairment ar byperipheralbloodmononucle ar production 1. Furthermore, type2diabetes,athe -1. Furthermore, release tophysiologicallevels.Ho release metHuLeptin (recombinant me -metHuLeptin (recombinant Arq Bras Metab. Endocrinol 2012;56/9 , IL-6,18,MIF Arq Bras Metab. Endocrinol 2012;56/9 systemic inflammation, leadstoarisein plasma leptin. tion of LPS, commonly used to experimentally induce TNF-α bycytokines,suchas favored and sepsis,particularly conditions, suchascholecystectomy, acuteinfection, inacute inflammatory Leptin levelsrapidlyincrease inducedbyleptin(53). dismutase)are nese superoxide lin-2, PAP1, andMnSOD(manga preprotachykinin, (tissue plasminogen activator), fibrinogen-β suchastPAponse proteins nes encodingacutephaseres 4). state(Figure -inflammatory pro sustains achronic ofleptin,which theexpression cytokines alsoregulate interleukin 1(IL-1),and6).These factoralpha(TNF-α), cytokines suchastumornecrosis -inflammatory ofpro theproduction Leptin regulates Leptin andacuteinflammation possibly duetoadiposetissuedysfunction(52). metabolicsyndrome, incasesofsevere may beobserved hypoleptinemia but relative with metabolic syndrome, inpatients (51).Leptinisincreased phosphorylation substrate-1 of insulinsignalingatthereceptor of obesityviacentralobesity, possiblybyimpairment independent and metabolic syndrome insulin resistance ing plasmaglucoselevels(50).Leptinisassociatedwith plasmatriglycerides,andfast protein, with C-reactive correlated disease,anditslevelsare artery coronary with leptin(49). iftreated tein E-deficientmicedevelopatherosclerosis apolipopro spite all the metabolic risk factors, whereas Indeed, (48). theriskofatherosclerosis n, increasing sorelaxatio inendothelialcellsandinhibits va the oxidativestress stimulates angiogenesis,plateletaggregation, rophages, (47). (lipotoxicity) andinsulinresistance lin-sensitive organs, leadingtoaccumulationoflipids in lipid oxidation in insu contribute tothereduction cytokinesmay fattyacidandinflammatory levels offree associatedwithhigh leptinresistance well. Increased by theadipose tissue as leptin production promote on theotherhand,cytokinessuchasIL-6andTNFa cytokines, and ofinflammatory hances theproduction in obesity.state observed On the one hand, leptin en sub-inflammatory and with the chronic responses tory causally linkedtoinflammation. toobesityare andotherdiseasesrelated rosclerosis Many genes related toinflammation,includingge Many genesrelated In humans,leptinisanindependentriskfactorfor Moreover, uptakebymac leptininducescholesterol -inflamma with pro Hyperleptinemia is correlated , IL-6, and IL-1β mice are resistant to atherosclerosis de toatherosclerosis resistant ob/ob miceare (36). Parenteral administra (36). Parenteral , lipoca

be predictive of the severity of sepsis and increased sur oftheseveritysepsisandincreased be predictive there is increasing evidenceofanassociation bet isincreasing there cytokinethat helps thehostfightinfection, -inflammatory Together with the established function of leptin asa pro diseases Leptin inchronicinﬂammatory sepsis(30). in humans,HIVinfection,andnewborn conditions, includingacuteexperimentalendotoxemia leptinlevelsinspecificinflammatory found increased tality (38). On the other hand, some studies have not mor sponse insepsistolimitorgan damageand prevent re oftheimmune coordination forefficient is required in the CNS sepsis. A leptin-dependent neurocircuit from manner with significant protection functionally relevant ina systemicimmuneresponse into theCNScontrols in sepsis. Selective leptin administration mune response andsystemicim survival system (CNS)inregulating ofleptininthecentralnervous role isanimportant there functionisdiminished.Furthermore, neutrophil whereas in its absence, sepsis-induced organ damage is increased, and vival (54).Leptinisacriticalfactorinhostresistance mechanism forchronicinflammation. subsequently sustains production of leptin. This isthoughttobethe (IL-6). These cytokinesincreasetheexpressionofleptinmRNA, which tumor necrosis factor alpha (TNF-a), interleukin 1 (IL-1), andinterleukin cytokines,Leptin upregulatestheproductionofpro-inflammatory suchas Figure 4. Interactionbetweenleptinandcytokines. dotoxin priming(10). of amodulationTNF-α ofleptininthesecasesseemtooccurbymeans effects bytheadministrationofleptin.Theprotective reversed ghly susceptibletoLPS-inducedlethality, which canbe rapidly than WT mice. The more diseaseand die ofinfectionwithKlebsiella lop severe inleptin-deficientob/ob is observed ofleptinintheclearancepathogens role A protective Adipocytes Elevated levels of leptin are found in sepsis and may foundinsepsisandmay Elevated levelsofleptinare Leptin ↑ Expression Leptin mRNA 6 responses afteren andIL-6responses mice are also hi ob/ob mice are Leptin andinflammation mice, whichdeve TNF-a, IL-1, Il-6 Cytokines ween lep 603

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. patients with MS. This positively correlates withthese patients withMS.Thispositivelycorrelates fluid(CSF)ofnaive andthecerebrospinal both theserum in ofleptinisincreased thatthesecretion been reported 604 In experimen Th1 cytokine expression. fect by increasing role ofleptin. teric fat,suggestinganinflammatory mesen bythehypertrophic mRNA andleptinprotein ofbothleptin anoverexpression tients, itwasobserved fat, independentofthebody massindex.Inthesepa mesenteric visceraladipositywithhypertrophic creased followingenhanced systemicproduction. -brain barrier theblood across transport the CNSand/oranincreased in synthesisofleptinin situ suggesting possiblesecondary ofleptinintheCSFishigherthanserum, crease T ofcirculating the percentage ofIFN-γ cretion Table 2. diseases Leptinandinflammatory several experimentally-inducedautoimmunediseases. -deficient tionally, leptin-deficient ob/ob miceandleptinreceptor autoreactivity.indicated thatleptincanpromote Addi of leptinonthesusceptibilitytoautoimmunityhasclearly perimental animalmodels,theinvestigationofeffects conditions(Table 2).Inex inflammatory many chronic elevatedin leptinlevelsare autoimmune disease.Serum and inflammatory riskofbothchronic tin andincreased Leptin andinflammation Acute colitis Rheumatoid arthritis Pancreatitis Type 1diabetes Systemic lupuserythematosus Cognitive impairment Psoriasis Asthma disease Chronic obstructivepulmonary Osteoarthritis boweldisease Inflammatory Multiple sclerosis Sepsis Type 2diabetes Obesity Disease In human studies on multiple sclerosis (MS), it has (MS), ithas In humanstudiesonmultiplesclerosis In rheumatoid arthritis, leptin plays an important ef leptinplaysanimportant In rheumatoidarthritis, diseaseexhibitin byCrohn’s Patients affected mice are resistant to the development of tothedevelopmentof resistant db/db miceare in the CSF, and inversely correlates with intheCSF, with andinverselycorrelates Protection andanti-inflammation Prevention oferosivearthritis Pro-inflammation inanimals Protection andanti-inflammation anti-inflammation) Dual effect(pro-inflammationand Pro-inflammation andatherosclerosis Pro-inflammation ofgliacells Pro-inflammation Pro-inflammation function Pro-inflammation Reductionoflung and type2nitricoxidesynthase Increases matrixmetalloproteinases Pro-inflammation andanorexia Activation ofmyelin-reactive T cells Higher levelsassociatedwithsurvival Pro-inflammation andatherosclerosis Pro-inflammation andatherosclerosis Effects ofleptin reg cells.Moreover, thein the synovial liquid, and T cells presented decreased pro decreased the synovialliquid,andTcellspresented disease,withlowerlevelsofIL-1b severe ob/obanddb/dbmiceexhibitedless tal modelsofarthritis, ment ofhyperglycemia anddiabetesinspontaneousau of atherosclerosis. biomarkers andinflammatory lated withatherosclerosis positivelycorre whom theelevatedleptinlevelswere in in patients withsystemic lupus erythematosus ported duction ofleptin.Also,highleptinlevelshavebeenre higherpro present lage ofpatientswithosteoarthritis and type2nitricoxidesynthase.Moreover, thecarti of matrix metalloproteinases thritis via the production levels versustheactivityorseverityofdisease. between plasmatic and synovial leptin ing the relationship whenaddress results controversial studies havereported Ontheotherhand,clinical aTh2cytokineprofile. ward inducedbytheantigenandashiftto liferative response inflammatory role inthe exo an anti-inflammatory leptin mayexert -induced insulitis(57).Besides, exogenous ducing virus againsttype 1diabetesbyre Leptin maybeprotective cytokine Leptin asananti-inflammatory diseases. inflammatory chronic different ofleptinon (11,55,56)summarizetheroles References link betweenadiposetissueandpsoriaticinﬂammation. cells. Finally, itbeensuggestedthatleptinmaybea andoxidativepathwaysinmicroglia of inﬂammatory inobesityandhighfatdiet,bymeans observed pairment praphysiological levels. agentsandinsu conjunction withotherinflammatory in the lungs,butjustin and chemokine production sociated withobesity, bythestimulationofcytokine as hyperresponsiveness toairway Leptin isimportant IL-6andTNF -α. associatedtoserum ase, andwere dise pulmonary obstructive exacerbations ofchronic todevelopmentofautoimmunity.may berelated postnatal growth and increased dence that overnutrition withtheevi to developtype1diabetesinconcordance prone more ater weightgaininthefirstyearoflifewere withgre of leptinonTh1cellsinthisdisease.Children β by T -γ leptin totheseanimalsenhancedinterferon type 1diabetes.Inaddition,exogenousadministrationof toimmune non-obesediabetic(NOD)mice,amodelof inflammatory influence influence -inflammatory -cells, suggestingapossiblepro Leptin levels increased just before thecommence justbefore Leptin levelsincreased Leptin isinvolvedinthepathogenesisofosteoar Leptin may also be important inthecognitiveim Leptin mayalsobeimportant during acute reported High levels of leptin were cells, and expanded the autoimmune destruction of of -cells, and expanded the autoimmune destruction Arq Bras Metab. Endocrinol 2012;56/9 andTNF-a production production in in Arq Bras Metab. Endocrinol 2012;56/9 cytokines (TNF-a, IL-1, IL-6). Adapted from (11). monocyte proliferationrates, thereby increasingthelevelsofinflammatory anti-inflammatory. Additionally, leptinalsoincreasesmacrophage and Leptin inhibitsthetransformationofnaive T cellsinto Th2 cells, whichare (APC), theycandifferentiateinto T-helper cell type1(Th1)or2(Th2). level of T cells. When naive T cellsinteractwithantigen-presenting cells and decreasingratesofapoptosis, leading toanoverallincreaseinthe Leptin has a positive effect on thymocytes by increasing rates of maturation Figure 5. Leptinandtheimmunesystem. andcancer.ses, rheumatoidarthritis, inmorbidity, role portant disea suchascardiovascular inflammation playsanim with severaldiseaseswhere in statesofexcessadiposity, leptinhasbeenassociated actions.Inexcess,commonlyseen -inflammatory pro response, withmainly ofinflammatory jor regulator duetoinfections.Itisalsoama mortality increased leads toimmunedefectsthatultimatelytranslateinto 5).Theabsenceofleptin (TNF-α, IL1,6)(Figure cytokines thelevelsofinflammatory increasing thereby rates, and monocyteproliferation macrophage creases anti-inflammatory.which are Additionally, leptinin ofnaiveTcellsintoTh2cells, bits thetransformation levelofT cells,andinhi leading toanoverallincreased onthymocytes, mune system.Ithasapositiveeffect oftheim intheregulation Leptin playsamajorrole CONCLUSIONS ofleptininclinicalconditions.rizes therole inhumans(60).Tablerheumatoid arthritis 2summa oferosive form themostsevere tect thejointsfrom study showedthatendogenousleptinmaylocallypro axis (59). Another-adrenal) (hypothalamic-pituitary phil-dependent mechanismthatdependsontheHPA an experimentalmodelofacutecolitisviaaneutro mediated bythenitricoxidepathway(58). ratsagainstacutepancreatitis protecting crine pancreas, Adipocytes inflammatory effect in effect Leptin alsoplayedananti-inflammatory Leptin TNF-a, IFN-γ, IL-2, IL-12 Th1 memory Naive T Cell Naive T ↑Maturation IL-4, IL-5, IL-10 Thymocytes ↓Apoptosis Th2 memory APC Leptin Macrophage/Monocyte Adipocytes TNF-a, IL-1, IL-6 ↑ Proliferation 16. 15. 14. 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. REFERENCES was reported. relevant tothisarticle nopotentialconflictofinterest Disclosure: diseasesassociatedwithleptindeficiencyorexcess.to treat tion mightleadtothedevelopmentoftherapeutictargets immunity and inflamma nisms by which leptin regulates SOCS3. 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