the intake,storage,andmobilizationoffat(4). aswelladipocytes,cellsspecializedin pre-, stemcellsand bloods vessels,sympatheticinnervation, by amatrixofconnectivetissue,immunesystemcells, , hasamesenchymaloriginandismadeup The WAT, in describedasthemainenergy reservoir molecule (1-3). to thecarbonbackboneofaglycerol fatty acidsesterified neutral lipidsmade up ofthree white adiposetissue(WAT) (TAG), astriacylglycerols Arch Metab. Endocrinol 2015;59/4 ing onitsactivation status,perilipin1A mayprotect is themainperilipinfound in theadipocyte.Depend this monolayer, perilipin1Amaybeemphasized, as it thatmakeup acids (5-7).Amongtheseveral offatty thecytotoxiceffects tects cellorganelles from andenzymes,whichpro proteins, , structural byamonolayerofphospho cell , surrounded asadynamic isrecognized the cell.Thelipiddroplet of the nucleusandafinecytosollayertoperiphery let that takes up 85-90%of the and pushes P INTRODUCTION Adipose triglyceridelipase;hormone-sensitivemonoacylglycerolperilipin;triacylglycerolhydrolysis Keywords Arch EndocrinolMetab. 2015;59(4):335-42 emphasis in its role in and as a source of important signaling molecules. present hereanupdatedreviewofconceptsandregulationwhiteadipocytelipolysiswithaspecial in many non-adiposetissues,unveiling apreviouslyunderestimatedaspectoflipolysis. Thus, we identification of lipolyticproductsas signaling moleculesregulatingimportant metabolicprocesses involved, which reformulatedtheconceptoflipolysis.Novel findingsfromthesestudiesincludethe acterize theactionsofthislipase,aswellotherproteinsandpossible regulatorymechanisms of adiposetriglyceridelipase(ATGL) many studieswereperformedtoinvestigate in2004, andchar (MGL) For many itwaslipase(HSL)andmonoacylglycerol years, believedthathormone-sensitive isdefinedasthesequential oftriacylglycerol(TAG) storedincelllipid droplets. ABSTRACT Andressa Bolsoni-Lopes – An update Lipolysis andlipasesinwhite Adipocytes store TAGAdipocytes store in asingle,large lipiddrop those that are synthetized are stored mainly in the stored synthetized are those that are the diet or even lipids that come from re-formed ​​were the main catalyzing lipolysis in the white adipose tissue. Since the discovery 1 , IsabelC. Maria Alonso-Vale - - - - 2 and are in aconstantflow inthe are TAG-fatty acidcycle,de easier (7,8). However, after the discovery oftheadipose However, afterthediscovery themain enzymesinvolvedinWATwere lipolysis. (MGL) sitive lipase(HSL)andmonoacyglycerol (12,13). trophy, and obesity hyperlipidemia,insulinresistance, been associated with lipodys have frequently process energy substratestotissues.However, changesinthis as lipolysis isessentialtosupplyfattyacidsandglycerol longed periodsoffastingorhighdemandsenergy, opment ofobesity(11,12).Ontheotherhand,inpro mayleadtothedevel process Thischronic increases. foods addedtothelackofphysicalactivity, adiposity excessive consumption of high-calorie from result periodsofpositiveenergy balance,which In prolonged ofTAG,hydrolysis (1,9,10). fattyacids,andglycerol) inthecytoplasm),andlipolysis (the sequential droplet thesis, incorporation,andstorageofTAG inthelipid pends onthebalancebetweenlipogenesis(thebiosyn The amountofTAG intheadipocytes,which stored For manyyears,itwasbelieved thathormone-sen delimit the droplet, or make lipid hydrolysis ormakelipidhydrolysis delimit thelipiddroplet, - Diadema, SP, Brazil Federal deSãoPaulo (Unifesp), Farmacêuticas, Universidade Químicase Ambientais, Biológicas, Instituto deCiências Biomédicas, Biofísica, Instituto deCiências Accepted on Apr/22/2015Accepted Received onMar/9/2015 [email protected] 09913-030 –Diadema,SP, Brazil Av. SãoNicolau,210 Universidade Federal deSãoPaulo Químicas eFarmacêuticas, Instituto de Ciências Ambientais, deCiênciasBiológicas, Departamento Maria IsabelC. Alonso Vale Correspondence to: 2 1 DOI: 10.1590/2359-3997000000067 Paulo (USP),SãoPaulo, SP, Brazil Departamento deCiências Departamento deFisiologiae Departamento

Universidade deSão review 335 ------

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. times, released in the bloodstream andboundtoalbu inthebloodstream times, released 336 3-phosphate (17). generation of thatisdependent ontheintracellular tion, a process 30-40% ofthesefattyacids undergo thisreesterifica tomakeup reesterification TAG again.Approximately oxidationsubstratesorundergoing tion regulators, lipids involvedincellmetabolism),asgenetranscrip acids andlipids(includingmembraneother working assubstratesforthesynthesisofotherfatty cytes, acting as intracellular signaling mediators and However, ofthesemolecules iskeptinsideadipo part min tobeusedasenergy substratesby othertissues. monoacylglycerol; TAG:triacylglycerol. hormone-sensitive lipase;MGL: monoacylglycerollipase;MAG: FA: fattyacid; ATGL: adiposetriglyceridelipase;DAG: diacylglycerol; HSL: Figure 1. Sequentialhydrolysisoftriacylglycerol. 1). (9,13)(Figure andalast glycerol MAG,producing MGL hydrolyses second fattyacidbytheactionofHSL.Inend, (MAG)anda tomonoacylglycerol DAG isconverted tion mainlycatalyzedbytheenzymeATGL. Afterthat, (DAG)andonemoleculeoffatty acid, inareac erol TAGstage ofthisprocess, todiacylglyc ishydrolyzed enzymes.Inthefirst different ids, catalyzedbythree fatty ac andthree to itsconstituentmoleculesglycerol ofTAGLipolysis consistsofthesequentialhydrolysis LIPOLYSIS INWHITEADIPOCYTES of metabolichomeostasis. signalingmoleculesinthecontrol ofimportant source asa white adipocytes,withspecialemphasisinitsrole in of lipolysis concepts and regulation updated review an here wepresent ted aspectsoflipolysis.Therefore, ­ underestima non-adipose tissues,unveilingpreviously inmany metabolicprocess important that regulate mayactassignalingmolecules in thelipolysisprocess ing energy, generated products finalandintermediate evidence wasfoundthatindicatedthat,besidesprovid Duringthisperiod, concept oflipolysiswasproposed. mechanism,anew ization of itsactionsandregulation lipase (ATGL) in 2004 (14-16) and the later character Lipolysis inwhite adiposetissue Fatty acids derived from lipolysis are, mostofthe lipolysisare, Fatty acidsderivedfrom ------conditions. However, inbasalconditions,theco-acti the lipolyticactivityfoundbothinbasalandstimulated of TAG forlarge part anditisresponsible hydrolysis, (7).ATGLof thelipiddroplet ishighlyspecificfor foundonthesurface tive geneidentification58),are domain-containing 5), also calledCGI-58(compara ATGL anditsco-activator, Abhd5(abhydrolase perilipin, inthecytosol,whereas dominantly remains (19,20).Inbasalconditions, HSLpre by hormones ulated (basalconditions)orinconditionsstimulated still insideofthiscell(18). into TAG by lipolysis may be recycled produced erol oftheglyc adipocytes raisedthehypothesisthatpart 3-phosphate,anditsactivityin into glycerol ,anenzymetheconverts glycerol of thepresence (3).Recently, withthediscovery in mainly functionsassubstratesforglucoseproduction and intothebloodstream cess, mostofitisreleased for the hydrolysis ofthelong-chain fattyacidesters(16 for thehydrolysis 2). (Figure fattyacid (13,19) andafree sion ofMAGintoglycerol catalyzing thefinalstepof lipolysis, thatis,theconver and showsspecificityforMAGhydrolysis, id droplet, ofthelip the cytosolofcellandonsurface though. MGL,ontheotherhand,islocatedbothin TAGalso hydrolyze and MAG,withlowerefficiency, theactionofthislipase(13,19,22). increasing binds toATGL, anactivecomplexandsteeply forming and ofperilipin, CGI-58 isreleased phosphorylation making TAG bythelipaseseasier. hydrolysis the With changes, sition ofthiscompoundonthelipiddroplet Similarly, of perilipin, the po afterthephosphorylation ofTAGsponsible forabout95%ofthehydrolysis (23). Together,the lipolyticprocess. ATGL re andHSLare andactstogetherwithATGL, accelerating HSListranslocatedintothe After phosphorylation, ofHSLandperilipin(19,21,22). the phosphorylation kinaseAandG(PKA/PKG),which promotes protein that culminates in the activation of cellular reactions action ofcatecholamines,leadingtoaseriesintra mainlybythe isstimulatebyhormones, lipase (9,19). activityof inactive complex),thatlimitsthehydrolytic an boundtoperilipin (forming vator CGI-58remains In relation to glycerol produced inthelipolyticpro produced toglycerol In relation Lipolysis is a process thatoccursundernon-stim Lipolysis isaprocess ATGL specificityand/orselectivity shows strong andmay specificforDAGhydrolysis, HSL ismore In periodsoffastingorhighenergy demands,the Arch Metab. Endocrinol 2015;59/4 ------taining protein A1toA9(PNPLA1-9) (14-16).ATGL,taining protein pholipase A2 or patatin-like domain-con them, ATGL, desnutrin,calcium-independentphos names,among different ized anewlipasethatreceived character groups independentresearch In 2004,three FUNCTION ANDREGULATION ADIPOSE TRIGLYCERIDE LIPASE (ATGL) – Arch Metab. Endocrinol 2015;59/4 A; PKG: proteinkinaseG; TAG: triacylglycerol. ;MAG: monoacylglycerol;PlinA: perilipin1A;PKA: Fsp27: -specificprotein27;HSL: hormone-sensitive lipase;MGL: comparative gene identification 58; FABP4: fatty acidbinding protein 4; acid; ATGL: adiposetriglyceridelipase;DAG: diacylglycerol;CGI-58: by MGL, withthereleaseofthreeFA andoneglycerolmolecule. FA: fatty MAG bytheactionofHSL. The lipolyticprocessends withMAGhydrolysis complex andincreasing TAG hydrolysis. DAGsarethentransformedinto that, CGI-58isreleasedfromPlinAandbindsto ATGL, forminganactive andundergoesachangeinstructure.also phosphorylated Becauseof and, initsactiveform, migratestothesurfaceoflipiddroplet. PlinAis stimulated status, byakinase(PKAand/orPKG) HSLisphosphorylated surface ofthelipiddroplet. HLandFABP4 areinthecytosol. Inthe (non-stimulated), ATGL, perilipinandCGI-58formacomplexonthe different proteinsanchoredtoit: PlinAandFsp27/Cidec. Inbasalstatus The lipiddropletissurroundedbyamonolayerofphospholipidswith adipocytes. Figure 2. Non-stimulated(basal)andstimulatedlipolysisinwhite HSL (24). substrateof leasing 2,3-DAG,whichisthepreferential fattyacidsalsofoundinpositionsn1,re to hydrolyze the otherhand,afterbindingtoCGI-58,ATGL starts during theTAG cycle.On hydrolysis/reesterification zymes ATGL andDGAT fashion actinacoordinated acyltransferase 2(DGAT2). Thissuggeststhattheen ential substrate of the lipogenic diacylglycerol is1,3-DAG,theprefer ofthisreaction main product mitoleic acidfollowedbypalmiticandstearicacid.The ofpal backbone, whichmainlyincludesthehydrolysis or 18carbons)foundinpositionsn2oftheglycerol HSL MGL Glycerol Basal FA FA FA Lipid droplet Stimulated FA FA FA Glycerol MGL HSL ------which hasamolecularweightof54kDa,isfoundpre expression induced by RNA interference inanexperi inducedbyRNAinterference expression both infastingandnot(25).Similarly, ATGL reduced fattyacidsintheplasma, concentrationoffree reduced incubation medium.Besides, these animals presented inthe fattyacidsandglycerol offree release by reduced gonadaladiposetissue,asevidenced cytes isolatedfrom basalandstimulatedlipolysis inadipo showed reduced studies, geneticallymodified ATGL-deficient mice inlipidhomeostasis.Inthese and theirparticipation ize anddescribebiologicalfunctionsoftheseenzymes ofATGL outtocharacter overexpression carried were co-activator, lipolysis(7,22). inhormone-stimulated CGI-58,its bytheinteractionwithprotein increased in basallipolysis.However, itsactivityissignificantly important makingthislipasevery the lipiddroplet, thatinvolves barrier place independent of the protein activity on TAG its hydrolytic 9,13). Therefore, takes ofadipocytes(1,7- is mainlylocatedinthelipiddroplet forTAGthe mainenzymeresponsible and hydrolysis, and skeletalmuscle(9).ATGL isnowadaysconsidered muscle, islets,cardiac seen in the testicles, pancreatic adiposetissue,butisalso dominantly inwhiteorbrown show reduced plasma concentration of free fattyacids plasmaconcentration offree show reduced type (α)(28). proliferator-activatedperoxisome (PPAR) receptors withagonistsofnuclear aftertreatment reverted are dysfunctions that and macro-endothelial velop micro- (27).Besides, ATGL-deficient failure cardiac micede theaccumulation ofTAG reverts andassociated heart death. ReestablishmentofATGL onlyinthe expression followedbypremature failure content, causingcardiac ATGL ofupto20timesTAG leadstoanincrease hours (25). forfive whenexposedtocoldenvironments pothermia ofATGLmice withlowerexpression hy showsevere Therefore, fatty acids for mitochondrial respiration. of free offer lation in theseanimals,due to thereduced thermoregu TAGreduced negativelyaffects hydrolysis and othermetaboliccomplications(19,25).Still,this cytes andothertissues,favoringobesitydevelopment duction isthemassiveaccumulationofTAG inadipo ulated byforskolin(26). inbasallipolysisandhalted lipolysisstim to adecrease mental modelofhumanadipocytes,hMADScells,led Studies in animal and cell cultures with reduction or withreduction Studies inanimalandcellcultures As for the lipid profile, As for the lipid profile, ATGL-deficient animals muscle,forexample,the lackof In thecardiac The mainphenotypicalconsequenceofATGL re Lipolysis inwhite adiposetissue 337 ------

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 338 suchasADP-ribosylation factor1,GTB- lipid droplet, ATGL tothe transport the endoplasmic reticle from that oftheproteins andcontrol involves theexpression ATGL(39). Another important mechanism regulation ing itsactivityand,consequently, lipolysis decreasing interactswithATGLfound inthelipiddroplet, reduc patatinedomainofATGLwith theN-terminal (38). ATGL actionbyphysicalinteractionofitsN-terminal G0S2 inhibits and mitochondria. In the lipid droplet, cytoplasm,endoplasmic reticle adipocyte lipiddroplet, G0toG1inthecellcycle,islocated sition from gene 2 described) and G0/G1 switch 58, perilipin (previously suchasCGI- fied byitsinteractionwithotherproteins, oftheadipocytes (37). tion inthelipiddroplet the activityoflipasenegatively, hinderingitsloca 372 modulates at threonine ATGL phosphorylation the otherhand,Xieandcols.,in2014,identifiedthat demonstratedforHSL.On lipolysis (36),aspreviously pable ofpositivemodulationthislipase,accelerating activationisca ing thatB-adrenergic/ at serine406ofATGL isalsoaPKAtarget, confirm thatphosphorylation (32). Pagnonandcols.observed ATGL itsactivity atserine406,increasing phorylates demonstrated that AMPK phos dated, it was already efficient ATGL activity has not been completely eluci for ofthesephosphorylations Although theimportance described(32,36,37). 406 and430havebeenrecently (17,31-35). lin, activationofmTORcomplex1,andfoodintake byinsu reduced kinase (AMPK),andfasting;are type elevated, forexample,bythe action ofPPAR agonists levels ofmessengerRNA(RNAm)thisenzymeare andATGLof geneexpression activity. hydrolytic The TAGand reduced depositionandadipocytesize(30). basal andstimulatedlipolysis(19),fattyacidoxidation, cy, ATGL isassociatedwithincreased overexpression thedeficien from PPAR typedelta(δ)(29).Different thatdependson (GSIS),aneffect secretion molecules thatmodulatepositivelyglucose-stimulated moted byATGL isessentialtogeneratesignalinglipid islets,lipolysispro tein (HDL)(19).Inpancreatic (VLDL)andhighdensitylipopro density TAG, Lipolysis inwhite adiposetissue Additionally, 27(FSP27),also fat-specificProtein Evidence alsoindicatesthatATGL activityismodi sites,including Eight ATGL phosphorylation regulation Several factorshavebeenidentifiedinthe , , AMP-activated protein AMP-activatedprotein α andg,glucocorticoids, -hidroxybutirate, total , very low very totalcholesterol, β-hidroxybutirate, (G0S2). G0S2, a protein thatactsinthetran (G0S2). G0S2,aprotein ------binding protein 1 (SAR1), and golgi-brefeldin Aresis 1(SAR1),andgolgi-brefeldin binding protein involved inTAG asATGL hydrolysis, hadnotbeendis themainlipaseofadipocytes,andonlyone sidered of81 kDa,wascon At thatmoment,HSL,aprotein Dr. (41)describingHSLandMGL. Steimberg’s group stimulation.Aclassicalstudy waspublishedby hormone lipolytic activityintheadiposetissuewasinducedby that In thebeginningof1960s,itwasobserved AND REGULATION HORMONE-SENSITIVE LIPASE (HSL)–FUNCTION sues. tis indifferent inphysiologicalprocess well asitsrole the activity ofthislipase,as mechanisms thatregulate toclarifythe outinorder beingcarried studies are forTAGenzyme responsible Still,many hydrolysis. tance factor(GBF-1)(40). pholipase A2 (AdPLA), reducing adenylatecyclaseac pholipase A2 (AdPLA), reducing adipocyte-specific phos and increases the lipid droplet FSP27in inprotein anincrease (45). Insulinpromotes activity, HSLand perilipinphosphorylation reducing AMPcandPKA terase 3Bactivation,which decreases ofinsulin ismediatedbyphosphodies lipolytic effect by PKGactivation(9,45).Ontheotherhand,anti- HSLandperilipin.ANPstimulateslipolysis phorylates consequently, PKAphos activatesPKA.Onitsturn, thelevelsofAMPcand, enylate cyclase, whichincreases G, activating ad protein tors that bind to stimulatory recep HSL (17).Catecholaminesbindtoβ-adrenergic inhibitorof activators.Insulinisanimportant portant im (GH)are hormone peptide (ANP),andgrowth oftheadiposetissue),atrialnatriuretic innervation sympathetic medullaorbydirect leased bytheadrenal Amongthem,(re enced byhormones. stimulatedlipolysis(44). increased basallipolyticactivity, thislipaseshownormal press and stimulated lipolysis(43).Similarly, micethatoverex (43). DAG hydrolysis thehighspecificityofHSLin therefore, determining, Differently, they accumulated large amounts of DAG; did notaccumulateTAG inadiposeandothertissues. thatanimals cols., usingHSL-deficientmice,observed activity(42).Haemmerleand forhydrolytic important whichserine660and663seemto beparticularly from sites, yet.HSLhasatleastfivephosphorylation covered All thesefindingspointoutto ATGL asthemain The regulation ofthislipaseactivityishighlyinflu The regulation reduced hormone- HSL-deficient miceshowed Arch Metab. Endocrinol 2015;59/4 ------Arch Metab. Endocrinol 2015;59/4 scribed throughout the text, when it is phosphorylated thetext, whenitisphosphorylated scribed throughout foundin theadiposetissueandliver(7,53).Asde are perilipin 2 and perilipin3 and skeletalmuscle,whereas of highoxidativecapacity, adiposetissue suchabrown Perilipin 5,orOXPAT, intissues ismainly expressed foundinWAT.with perilipin1Aasthemainisoform perilipin1A,1B,and1C, isoforms: which includesperilipins1to5.Perilipinhasthree belongthePATlation (8,52).Theseproteins family, inlipolysisregu the lipids,haveafundamentalrole thecytotoxicitycaused by tecting cellorganelles from besidespro associatedwiththelipiddroplet, Proteins PROTEINS ASSOCIATED WITHTHELIPIDDROPLET transcription ofthislipaseinWAT (51). lipolysisandRNAm kg for7 days), positivelyregulates aPPARing ratswithrosiglitazone, g agonist(15mg/ mones. Inspiteofthis,itwasdemonstratedthattreat MGL activityisinfluencedbycellenergy statusorhor the endocannabinoidsystem(50).Itisstillunclearif systemandin onthe central nervous enced byitseffect influ MGL-deficient phenotypeinanimalsispartially byHSL (50).The reverted MGL activityispartially reduced of glucoseintoleranceandinsulinresistance; the development from MGL showed to be protected (49).Animalsdeficientin testicles, brain,andheart intheWAT,is widelyexpressed lungs,liver, kidneys, It in theplasmamembraneandlipiddroplet. (49). Atthecelllevel,MGLislocatedincytoplasm, specificallyMAG,andaffects TAG orDAG hydrolyses (41).EvidenceshowsthatMGL superfamily lecular weightis33kDaanditbelongstotheserine andfattyacid.Itsmo intoglycerol is, MAGhydrolysis MGL catalyzesthefinalstepof that TAG hydrolysis, AND REGULATION MONOACYLGLYCEROL LIPASE (MGL)–FUNCTION (48). the lipiddroplet thedimerizationofenzymein and/or byaffecting fattyacids negative feedbackforHSLbytransporting However, a itsactionasitpromotes FABP4regulates insideofthecellafterlipolysis. ty acidtobetransported makingiteasierforfat HSL whenitisphosphorylated, FABP4 binds to via FABP(fattyacidbindingprotein). AMPc andPKAactivity(46,47). tivity and,consequently, cytoplasmiclevelsof reducing Another known form of regulation ofthisenzymeis ofregulation Another knownform ------by PKAorPKG,perilipinundergoes achangeinposi change stimulatedlipolysislevels(39,56). basallipolysis anddoes not deficiency leadstoincreased adiposetissue.Its inwhiteandbrown highly expressed intheWAT.not expressed Ontheotherhand,Cidecis adiposetissueand the liver, found in brown are but are Cidea, Cideb,andCidec/Fsp27(7).CideaCideb members: TheCIDEfamilyhasthree like effector). ily (cell death-inducing DNA fragmentation factor-a- havebeendescribed,suchastheCIDEfam droplet in basallipolysis(55). stimulatedlipolysiswithoutchanges leads toreduced (54). Ontheotherhand,perilipin1overexpression HSL activityandtotheATGL/CGI-58 interaction lipolysis,attributedtogreater pin 1leadstoincreased binds toATGL. ofperili intheexpression Areduction easier.the droplet CGI-58, which Besides, it releases makingHSLinteractionwith tion on the lipiddroplet, In this context, our group has recently demonstrated hasrecently In thiscontext, ourgroup mechanisms thatinvolvethe activationofPPARα (34). and fattyacidoxidationinepididymis adiposetissueby thanolamine inthesmallintestine stimulateslipolysis Besides, anendogenouselevation ofthelipidoleoyle ofinsulin inWATpolysis speedinthepresence (59). of30%inli fenofibrate, inducesasignificantincrease tabolism (33). ATGL isamediatorofthePPAR inlipidme g effects adipocytes,invitroandvivo,suggestingthat mature contentofATGL RNAmandtheprotein regulates in Kershaw andcols.demonstratedthatPPARg positively ATGL thisstudy, eMGLinvivo(51).Corroborating of RNAmexpression stimulates lipolysisandincreases sis (51,58). have alsobeendescribedtopositivelymodulatelipoly inthe adipocytes, PPAR effects g andα their important activity highlyinfluencedbynutritionalstatus.Among and known aslipidsensors,and have their production are (57).Thesenuclear receptors and differentiation tion oflipidmetabolism,inflammation,andcellgrowth intheregula genesthehavefundamentalroles trolling thatactastranscriptionfactors,con nuclear receptors PPARs RECEPTORS (PPARS) ANDLIPOLYSIS PEROXISOME PROLIFERATOR-ACTIVATED Recently, associatedwiththelipid newproteins Similarly, ofratswithaPPAR treatment α agonist, PPAR for example, g activation with rosiglitazone, α, are membersofthelarge familyof g, andδare Lipolysis inwhite adiposetissue 339 ------

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 340 of ATGL in at serine 406,expressively phorylation and cols.,AMPKactivation with AICARleadstophos 565 (65).However, asdemonstratedbyAhmadian ofHSLatserine phosphorylation motes inhibitory imidazole-4-carboxamide), an AMPanalogue,pro activation withAICAR(5-amino-1- β-D-ribofuranosyl- studyfoundthatacuteAMPK (32,63,64). Aprevious the WAT metabolism,including lipolysisregulation (32,35,63,64). andoxidationoffattyacidsglucose) cose capture ones (ATP inglu generation–suchastheincrease pathways (ATP catabolic consumption)andincreasing theanabolic toenergy metabolism,decreasing related proteins andregulate molecule isabletophosphorylate intheATP/AMP toreduction and responds ratio.This cell energy balance.Itissensitivetonutritionalstatus of moleculeintheregulation AMPK isanimportant LIPOLYSIS AMP-ACTIVATED PROTEIN KINASE(AMPK)AND (28,29,60). thephysiologicalfunctionof thesetissues promising endothelium, andPPAR deeplycom δ inthepancreas, PPAR andvascular to reduced α activationintheheart PPARα signaling (60). Besides, ATGL deficiency leads reduces (17,32,61,62). HSL deficiency also moderately er, adiposetissue,isreduced andbrown macrophages, of substratesseveraltissuesandcelltypes,suchasliv duction in PPARα signaling.Consequently, oxidation ATGL-deficientre animals, which causes important lipolyticactivityfoundin bythereduced was proven ecules to actasPPAR ligands(17,60).Thishypothesis forthesemol cycleisnecessary cation andhydrolysis toPPARnot binddirectly (17).Afattyacidesterifi and cols.,plasmafattyacids,whenenteringcells,do PPAR important toZechner activators.According are (57). function, respectively lators of adipogenesis and as positivemodu pose tissue,besidestheirknownroles of the lipolysis in the white adi regulators important PPAR determine Overall, theseresults g andPPARα as serine 660byaPPARα-dependent mechanism(58). at content of ATGLprotein and HSL phosphorylated andthe tions andafterstimulationwithisoproterenol, lipolysis, under basal condi mitoleic acid increases in andin vivo vitro withpal that adipocytetreatment Lipolysis inwhite adiposetissue Studies revealed important effects ofAMPK in effects important Studies revealed lipolysis On theotherhand,fattyacidsderivedfrom β-oxidation/mitochondrial ------This phenomenon is the proof of the important contri of the important This phenomenon is the proof ofATPproduction energy homeostasis. toreestablish mechanism by which thiskinasefavors the increased tissuesmaybeanother as energy substratesindifferent to beused of fattyacidsand glycerol the offer increasing consumption (64). ofenergy storageandATP insteadofroutes production of thesecells,potentiatingcatabolicpathwaysATP ofthemetabolism adipose tissueinducedremodeling (64). Additionally, activationofAMPKinthe chronic ofPPARand α, PPARδ, and PGC-1 α lipolysis,ATGLkg) showedincreased content, protein a singleintraperitonealinjectionofAICAR(0.7g/ with AICAR (0.5mM)for15hours,orratstreated of epididymis adipocytes by the treatment another study, activationofAMPKinduced prolonged sis inHEK293cellsand3T3-L1adipocytes(32).In lipoly theactivityofthislipaseand,therefore, creasing Acipimox suchasnicotinicacid anditsanalogue, these drugs, of objectionstotheefficacy are eases, althoughthere ofthesedis been atherapeuticstrategy in thecontrol lipolytic activityhas thatreduce of drugs prescription (12).Becauseofthat, emias, andinsulinresistance high plasmaconcentrationsoffattyacids,dyslipid associatedwith acids foundinlipolysiswaspreviously tissues. stasis indifferent for energy homeo lipolytic activityseemstobecrucial lipolysis.Normal endothelium associatedwithreduced liver, and vascular damage found in the pancreas, heart to the WAT, notrestricted sis are bysevere asproven ing, forexample,PPARs oflipoly (17,52).Theseroles systemic and intracellular signaling pathways, includ inmultiple and theirderivatives)haveessentialroles (fattyacids tissues,butthatlipidproducts in different cess that supplies energy substrates for ATP generation recently.proteins, numberofenzymes,kinases,andregulatory a growing in lipolysis characterization, besides revealing progress outleadingtowide ber ofstudieshavebeencarried ofATGL in2004,alarge num Since thediscovery FINAL REMARKS the energy metabolism. of bution oflipolyticactivityandlipasesinthecontrol AMPK effect intheactivationoflipolysisWAT,AMPK effect On theotherhand,excessivemobilizationoffatty It is clear, nowadays, that lipolysis is not only a pro ® (13,66). Arch Metab. Endocrinol 2015;59/4 in vitro with ------that show increased lipolytic activity have reduced adi lipolyticactivityhavereduced that showincreased Arch Metab. Endocrinol 2015;59/4 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. REFERENCES was reported. relevant tothisarticle nopotentialconflictofinterest Disclosure: tuccia forhiscommentsandsuggestionsthisarticle. Acknowledgements: we would like to thank Dr. T. William Fes tiple signalingpathwaysofbodytissues. oflipolysisonmul tion, aswellontheimportance and itsregula knowledge on this lipolytic machinery ofobesity.for thetreatment therapeuticstrategies promising in whiteadipocytesare capableofactivatinglipolysis thatare drugs/substances that inside the adipocytes (58,67-69). 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