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European Journal of Endocrinology -18-0847 of time ( overshortandprolonged periods stability isobserved constant aroundaset-operatingpoint( is underhomeostaticcontrol,maintainedrelatively mechanisms underlyingpotentialtreatmentsforweight-relatedproblemsinhumans. further studiesarerequiredtounravelthephysiology,pathophysiologyandneurobehavioral network. Itiscriticaltostudythesesystemsforthetreatmentoftypicalobesity.Althoughprogresshasbeenmade, the reward,attention,memoryandemotionsystemsareinvolved,participatinginacomplexcentralnervoussystem evidence suggeststhatregulationofeatingbehaviorinhumansisnotlimitedtohomeostaticmechanismsand that treatment forcongenitalleptindeficiencyandstatesofacquiredsuchaslipodystrophy.Current states. Whileleptinreplacementtherapyfailstoprovidesubstantialbenefitincommonobesity,itisaneffective andneuroendocrineresponseinstatesofleptindeficiencytoalesserextenthyperleptinemic Fluctuating leptinlevelsprovidemolecularsignalstothebrainregardingavailableenergyreservesmodulating energy ,revealingadiposetissueasanendocrinesystemthatregulatesappetiteandbodyweight. The discoveryofleptin,anadipocyte-secretedhormone,setthestageforunravelingmechanismsdictating Abstract Beth IsraelDeaconessMedicalCenter/HarvardSchool,Boston,Massachusetts,USA 1 Aimilia Eirini Papathanasiou inhumans function, energyhomeostasisand Novel pathwaysregulatingneuroendocrine GEOFFREY HARRISPRIZELECTURE2018 Department ofPediatricNewbornMedicine,BrighamandWomen’sHospital/Harvard MedicalSchooland https://doi.org/ https://eje.bioscientifica.com Review currently inPhaseIIIclinical trials. the physiologyanddevelop astherapeuticsleptinandothermedications,including CHRS-131, translational workonleptin, adiponectinandotherkeymoleculesinhumanshashelped elucidate 71,000 citationsinGoogle Scholar, PhDs.His and hasreceivedseveralawardsandhonorary novel compoundsandhaspublishedextensivelyinthe fieldofmetabolismwithmorethan SchoolofPublicHealth.Hehasstudiedphysiologyanddeveloped asaProfessoratHarvard served Medical Schoolandthe Boston UniversitySchoolof andhasconcurrently atHarvard Human NutritionatBethIsraelDeaconessMedicalCenter. asProfessorofMedicine Heserves Dr Mantzoros Invited Author’s profile Under stableenvironmentalconditions,bodyweight 2 ). The energy homeostatic system is a complex 10.1530/EJE istheChiefofEndocrinologyatVA BostonHealthcareSystemandChief of -18-0847 2 © 1 2019EuropeanSociety ofEndocrinology , Eric Nolen-Doerr others A EPapathanasiouand 1 Printed inGreatBritain ). Thisweight 2 , Olivia M Farr ( complicated inhumansthanrodentsorotheranimals either energy abundance or deficit and is much more integrating peripheralmetabolicfeedbacksignalsof system(CNS)circuitry actively array ofcentralnervous metabolism Energy homeostasisand 1 Published byBioscientifica Ltd. ). Accordingtothesesignals,adaptivechanges 2 and Christos SMantzoros 2 Division ofEndocrinology, Downloaded fromBioscientifica.com at10/03/202104:01:00AM

2 (2019) Endocrinology European Journalof 180 180 :2 , R59–R71

R59 –R71 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com current energystatus( ) alsorepresentfeedbacksignalsregarding (GIP), (e.g.GLP-1,gastricinhibitory adipose tissueandskeletalmuscle-derived and ( attention andemotions,aswelltherewardsystem cognitive functionssuchascontrol,memory, process, implying that appetite is regulated by higher several corticalandsubcorticalnetworksintheeating setpoint ( systems maybeenactedtomaintainthebodyweight not thecase( expenditure anddecreasingappetite,thisistypically defending theenergybalancebyincreasing such asobesity, leptinwouldbeequallyeffectivein it mightbeassumedthatinstatesofenergyabundance expenditure isnotappreciablyaltered( intake maybedecreasedinresponsetoleptin,energy inhumansindicatethatalthoughenergyobservations mice ( to increaseappetiteand decrease energy expenditurein or leanness,lowleptinlevelstriggerthehypothalamus states ofacuteenergydeficitand/orlowbodyfatmass intake andexpenditureinmiceleanhumans( derived leptinis a feedbacksignalregulatingenergy around thissetpoint( appetite andenergyexpendituremaintainbodyweight 10 Review , In terms of CNS mechanisms, human studies implicate One suchperipheralsignalisleptin.- 11 5 ). Otherperipheralsignalssuchasgastrointestinal, ) andinhumans.Ourpublishedunpublished 8 , 9 ). 8 , 9 12 ). Otherperipheraland/orCNS 3 ) ( , 13 Fig. 1 , 14 ). ). Here,webegindiscussing others A EPapathanasiouand 6 , 7 ). Although 4 ). In

body weightwithafocusonhumanphysiology. central mechanismsthatmaybeatplayinregulating of tolerance or resistance, and the other peripheral/ leanness beforediscussingtypicalobesity, whichisastate leptin asawell-studiedperipheralsignalanditsrolein leptin ( consumption arealsoreflected bycirculating levels of a longer-termenergysignal,abruptchangesincaloric proportional tototalbodyfatmass( status, thecirculating concentrationofwhichisdirectly of energystoredinadiposetissueandacutenutritional to theCNSregardingcurrentlyavailableamount derived ( organ. Circulating leptin,theprototypicaladipocyte- storage organ,maynowrepresentitslargestendocrine ,onceconsideredtobeaninerttriglyceride Leptin biology metabolism Energy homeostasisand activates severalintracellularsignalingpathwayssuch to ( impact onthehumanbodyrangingfromreproduction in humantissues,highlightingthediversityofits early nocturnalsleepperiod( circadian rhythm,reaching itsmaximumlevelduringthe energy balanceandmetabolism( changes infatmass,indicatingitsoverallinvolvement leptin levels,atagreater level thanwouldbeexpectedfrom Leptin receptors are almost ubiquitously expressed 17 ). Foodrestrictionresultsinasharpdeclineof 20 ). The leptin–leptin complex creativecommons.org/licenses/by/3.0/ Commons license( illustrations throughtheCreative Art Databasewhichprovidesthese been downloadedfromServier Medical inputs. Some of the illustrations used have alter thissetpointbyalteringthese to thispoint.Treatmentsnowattempt changes) thatwillbringbodyweightback (EI), energyexpenditure(EE),brain mechanisms (hormones,energyintake or belowthissetpoint,therearecertain changes. Whenbodyweightgoesabove hormonal inputandneurocognitive which isindividualizedbasedongenetics, Body weightisdeterminedbyasetpoint, Figure 1 15 ), constitutesamolecularsignal Downloaded fromBioscientifica.com at10/03/202104:01:00AM 19 ). 17 , https:// 18 180 16 ). Leptinalsohasa :2 ). Beyondbeing R60 ). via freeaccess European Journal of Endocrinology Morphologically, congenitalleptindeficiencyleads study brain structure andactivation in humans ( as MRI,whichallowinvestigators tononinvasively neurocognitive andneuroimaging techniques,such However, the utilizationofcontinuouslyevolving and metabolismofwhicharedifferentthaninhumans. cognitive andphysiologystudiesinrodents,thebrains leptin actsintheCNSisprimarilybasedonbehavioral, expected withgreatanticipation. confirmed inhumansandthusrelevanthumantrials are These data, largely derived from mice, have not yet been leptin resultsintheoppositeaforementionedtrends( energy deprivationandlowbodyfatlevels,levels of suppressing appetite) ( NPY neuronsaresuppressed(inhibitingenergyintakeby intake and promote energy expenditure), while the AgRP/ stimulate thePOMC/CARTneurons(inhibitingenergy higher bodyfat,thesubsequentlyelevatedlevelsofleptin 38 or anorexogenic states, respectively ( synthesis ofneurotransmitterspromotingorexogenic pro-opiomelanocortin (POMC) are responsible for the cocaine- andamphetamine-regulatedtranscript(CART)/ Y (NPY)/agouti-relatedprotein(AgRP)neuronsand receptor-expressing neurons in the ARC, sensitivity tocirculating leptin( brain barrier, exhibiting increased accessibility and in thearcuate nucleus(ARC) projectoutsidetheblood– , a subpopulation of hypothalamic neurons midbrain andhindbrain( the CNS, in the hypothalamus as well as in cortex, In ratmodels,leptinreceptorsareexpressedthroughout Central actions ( and activationofcellularproliferationpathways glucose andfattyacidmetabolism,insulinsecretion energy homeostasis,/orexigenicpathways, aforementioned molecularsignalingpathwaysregulate kinase (AMPK)–acetyl-CoAcarboxylase(ACC)( and 5 (SHP2)-mitogen-activated proteinkinase(MAPK)( ( substrate (IRS)-phosphatidylinositol3kinase(PI3K) transcription 3(JAK2-STAT3) ( as Januskinase2-signaltransducerandactivatorof 21 24 Review , , ), SH2-containingproteintyrosinephosphatase2 Our knowledgeregardingthespecificregionswhere 39 24 ). Thus,instatesofpositiveenergybalanceand ′ , adenosinemonophosphateactivatedprotein 27 , 28 ). 35 , 38 ). As anticipated, in states of 29 21 , , others A EPapathanasiouand 32 22 30 ). Two typesofleptin , , 23 33 31 ), insulinreceptor , ). Within the 34 , 35 , 26 36 ). The , 41 40 25 37 ). ). ). ) ,

dysregulation. between axes,speciesandetiology ofleptinbiologyand organ axes( but alsotoinfluencehypothalamus–pituitary–endocrine places leptininpositiontocommunicateenergybalance in theregulationofenergybalance( expressed inthehypothalamusincludingnucleiinvolved The longactiveleptinreceptorisoformisprimarily Leptin –regulationofneuroendocrineaxis these linesareanticipatedwithgreatinterest. extent unknown,andongoinghumanstudiesalong obese (leptin-tolerant)humansremainstoacertain body weightandfatmassinlean(leptin-sensitive)vs feeding behavior( the initialetiology, butregardless,mayhelpdictate the complexityofleptin’s interactionmaydependon leptin topre-weightlosslevels( weight andthenaregivenleptinatadosetoreturn inpatientswithobesitythatloseto patternsobserved decreased saliency of food images ( therapyinthesewomen,suggestinga after andinsularcorticeswasobserved somatosensory connectivity ofthehypothalamuswithmidcingulate, repletion ( of leptinreceptorsandeventuallycorrectswith response tochronicleptindeficiencywithupregulation increased sensitivity to leptinmaybe explained as a of metreleptinuseincomparisontocontrols( controls atbaseline,however, decreasesafter24 weeks paradoxically increaseswhenviewingfoodcomparedto investigated, and,withmetreleptin,administration were decreased( reward processinginresponsetovisualfoodstimuli leptin administration,areasrelatedtofoodsaliencyand is expectedtobemoresalient( related evaluativeprocesseswhilefasting,whenfood the activationofcorticalareasresponsiblefordecision- patients, short-termadministrationofleptinincreased pre nor post leptin treatment ( not associatedwithstructuralbraindifferencesneither acquired hypoleptinemia in three female patients was related brainregions( administration affectsfood-rewardandhomeostatic leptin administration( the regulationofeatinginadults,thatreverseswith to atrophy of gray matter in regions responsible for metabolism Energy homeostasisand 45 49 ). Additionally, adecreaseinthefunctional ). Asoutlinedbelow, thisinfluencecanvary 45 45 ). Hypothalamicactivitywasalso ). Whetherandhowleptinalters Downloaded fromBioscientifica.com at10/03/202104:01:00AM 43 42 , , 44 43 https://eje.bioscientifica.com 46 ). Ontheotherhand, ). Inaddition,leptin ). Thesetrendssuggest 45 45 47 45 180 ). With long-term ). In these same , ). This is opposite 48 :2 ). Thislocation 45 ). This R61 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com to fasting-inducedhypoleptinemia ( administration blunts the decrease of TSH in response two studies.Inleanmen but notleanwomen,leptin and womenafteracutecaloric deprivation,weperformed To investigateeffectsleptinhasonTSHchanges inmen effect is ameliorated by leptin administration ( hypoleptinemia depressesT4levelsinrats,andthis function tests(TFTs) ( with congenital leptin deficiency with normal with congenitalhypothyroidismthatcontrastschildren ( (proTRH) geneexpression,whichproducesmatureTRH Leptin stimulatesratpro-thyrotropin-releasinghormone rhythm that becomes disrupted in deficiency ( leptin releaseexhibitsapulsatilepatternandcircadian thyroxine (T4) within the thyroid gland. Like TSH, hormone (TSH)whichthenstimulatesassemblyof (TRH) inducingproductionofthyroid-stimulating The HPTaxisbeginswiththyrotropin-releasinghormone Hypothalamus–pituitary–thyroid (HPT)axis randomized studies. HPA axistoasmallextentandcanbedetectedinlarger, the effectismoreprofound,leptinaffectshuman men ( inversely relatetothoseinACTHandcortisolhealthy demonstrate thatfluctuationsincirculating leptinlevels decreases incortisollevels( hypothalamic amenorrheainducedstatisticallysignificant controlled trial, leptin administration in women with of thisaxis( leptin deficiencydonotindicatesignificantimpairment ( has notbeenseeninsmall-scalestudiesofleanhumans activation diminisheswithleptinadministration,which mice, the stress response HPAIn acutely starved axis also witnessedinleanratsafteran18-hfast( CRH secretionand leptin administration, a phenomenon 50 leptin receptorisexpressedintheadrenalgland ( gland,whileonlythe hypothalamus andthepituitary Leptin and its receptor are both expressed within the turn stimulatestheadrenalglandtoreleasehormones. adrenocorticotropic hormone(ACTH)release,whichin corticotropin-releasing hormone(CRH)causing The hormonescontributingtothispathwayinclude Hypothalamus–pituitary–adrenal (HPA)axis 5 60 , Review , , 7 51 61 , 19 54 ). ). Ob/obmicedisplaystrikingfeaturesconsistent ). Itappearsthatunlikerodentstudiesinwhich ). Non-randomizedinvestigationsofcongenital In vitro 55 , 56 studiesdemonstrateadirectrelationof , 57 ). Inourlargerandomized,placebo- 56 , 58 57 ). Inasimilarmanner, we others A EPapathanasiouand , 62 7 ). Fasting-induced , 54 ). Comparing 52 5 29 , , , 63 59 53 30 ). ). ). ). , This axisbeginswithgrowthhormone-releasinghormone (HPGH) axis Hypothalamus–pituitary– thyroid hormonesisratherlimited. in humanmodelswheretheeffectofleptintoregulate models; however, thistrendisnotconsistentlyobserved replacement restoresitsfunctionuniformlyinrodent hypoleptinemia downregulatestheHPTaxisandleptin deficiency ( between relative acute hypoleptinemia and complete also exhibits variable responses to leptin administration hormone levelsmaybevariable( at higher levels; however, its role in downstream HPT HPT axis( suggest athresholdwhichleptinexertsaneffectonthe not reachthesamemagnitudeasmenandthus,may these results,leptinlevelsintheleanwomenstudieddid may againhighlightathreshold forleptinactionon administration betweenour studiesinmenandwomen ( as hypothalamic amenorrhea and anorexia nervosa same istrueforstatesofacquiredleptindeficiency, such IGF-1 levelsand increased IGFBP3( of GHsecretionandtotalproductiondecreased demonstrate increasesinGHpulsatility, enhancement rodents, humanswithfasting-inducedhypoleptinemia tissue, leadingtoweightlossandaleanerphysique( they increasemusclegrowthandlipolysisinadipose key rolesinbodycompositionaswellgrowthwhere understand thelevelsofIGFBPs.GHandIGF-1play the levelsofIGF-1intotaloractiveformsbutalsoto actions; thus,itisimportantnotonlytounderstand (IGFBP1–6), whichcanhinderand/orpromoteIGF-1 is associated with at least six IGF-binding proteins -like growthfactor1(IGF-1)production.IGF-1 the pituitary, whichinteractswiththeliver, increasing (GHRH) causinggrowthhormone(GH)productionat GH pulsatility is observed ineithersex ( GH pulsatilityisobserved in menbutnotwomen;however, noameliorationof leptin ( levels of IGFBP1,4 and 6did not show changes with driven, pubertalgrowthspurt( adult heightisdecreasedduetoabsent,sexhormone- normal lineargrowthduringchildhood;however, final Patients withcongenitalleptindeficiencypresent secretion thatreverseswithleptinadministration( Fasting-induced hypoleptinemiainratsinhibitsGH metabolism Energy homeostasisand 71 , 72 70 , 7 73 ). LeptinadministrationrestoresIGF-1levels , 54 6 ). The varying IGF-1 responsetoleptin). Thevarying , ). LeptinmayregulatehumanTSHsecretion 27 , 64 ). Collectively, thesedatasuggest Downloaded fromBioscientifica.com at10/03/202104:01:00AM 56 6 , , 57 27 180 , , 68 67 64 :2 , ). In contrast to ). TheHPTaxis 7 69 , 54 , 70 , 70 ). Total ). The R62 65 66 via freeaccess ). ). ). European Journal of Endocrinology implications. important pathophysiological andpotentiallytherapeutic axis in humans, and this physiological function has ( HPG functionwhichisrestoredwithleptintherapy caused byhypothalamicamenorrheahavedysfunctional administration. Women withchronic hypoleptinemia decline inleptinlevels,whichisamendableto develop hypothalamicamenorrhearelatedtoasevere Women experiencingchronicenergydeprivation may restores to baseline with leptin administration ( peak frequency decreases, and in both cases, leptin hypoleptinemia inleanmen,whilewomenLH levelsoccurduringfasting-induced dynorphin viaKiSS-1neurons( nucleus neurons expressing , and afferent tothem,suchasAGP/NPY, POMC,andarcuate upon GnRHneuronsbutratherinteractswith It hasbeensuggestedthatleptindoesnotdirectlyact receptors onGnRH-secretingneurons( restoration afterleptintreatmentdespiteabsent hypogonadotrophic hypogonadismwithaxisfunction deficiency displayasimilarreproductivephenotypeof 76 exists( progression whenadequateenergyreserve and ovulationbyactingasagatekeeper, permitting influence overreproductiveprocessesincludingpuberty ( therefore, istightlyassociatedwithenergybalance biology demandssubstantialenergyinvestmentsand, to produce androgens or . Human reproductive (FSHs) whichinteractwithsex-specificgonadalstructures luteinizing (LH)andfollicle-stimulatinghormones stimulates thepituitary’s gonadotropestoproduce -releasing hormone(GnRH)which The hypothalamiccomponentofthisaxisis Hypothalamus–pituitary–gonadal (HPG)axis studies areunderway. between leptinandtheHPGHaxisinhumansthese be investigatedtounravelthecomplexrelationship above, otherIGFBPs(totaland/orintact)remainto its bindingproteins( secretion, butratherGH-associatedIGF-1secretionand may notdirectlybeinvolvedwithGHRH-mediatedGH this axis( 88 74 Review , , ). Inrodentmodels,leptindemonstratesprofound Disruptions in LH pulsatility and decreases in 77 89 , ). Thus, leptin strongly influences the HPG 78 56 , , 79 57 , ). Ourgrouphypothesizedthatleptin 80 ). Humanswithcongenitalleptin 70 ). Asidefromthosementioned 83 others A EPapathanasiouand , 84 , 56 85 , , 57 86 , ). 81 7 , , 82 54 , , 83 87 75 ). ). ). , abnormal glucose(insulinresistance,), to 70%( antiretroviral therapywithaprevalencerangingfrom13 and areoftenseeninpatientsreceivinghighlyactive ( often requiringlong-termfollow-upforconfirmation objective diagnostic criteria are not yet established, this tissue ( lipodystrophy describeslocallossandredistributionof body subcutaneousadiposetissuelosswhile partial acquired. Generalizedlipodystrophyindicateswhole generalized orpartialformsandcanbecongenital Lipodystrophy canbebroadlycategorizedinto and lowleptin Lipodystrophy: thecaseoflackadiposetissue Hypoleptinemic states metreleptin’s safety, efficacyandcost-effectiveness ( needed ongoing RCTs will moreclearly evaluate sample sizes( treatment havebeenopen-labelindesignwithsmall supported theapprovalofmetreleptinforlipodystrophy Medical DevicesAgency(PMDA)( of lipodystrophybytheJapanesePharmaceuticalsand lipodystrophy, andinJapan,itisapprovedfor alltypes the treatmentofcongenital and acquired generalized Drug Administration approved metreleptin in 2014 for of leptin-neutralizingantibodies,theUSFoodand resistance ( in mostmetabolicabnormalities,includinginsulin in lipodystrophydemonstratedramaticimprovement methionyl leptin(metreleptin)asareplacementtherapy increases IGF-1levels( dysfunctions, and leptin treatment only significantly thyroid, adrenalandGHaxesdonotexhibitprofound can becorrectedwithleptintreatment( hormone, irregularmensesandamenorrhea,allofwhich attenuated LHresponsetoluteinizinghormone-releasing development is appropriate, these patientsstill have neuroendocrine axisabnormalities.Whilepubertal endocrine organ( highlights theimportanceofadiposetissueasanactive correlates with the amount of adipose tissue loss and hypertriglyceridemia andnonalcoholicfattyliverdisease, metabolism Energy homeostasisand 91 ). Conversely, acquiredformsaremorecommon Complication severitywithlipodystrophy, including The firststudiesinvestigatingrecombinanthuman Patients withlipodystrophycanalsopresent 92 80 , 90 93 ). Given the observed potentialdevelopment ). Giventheobserved 80 ). While lipodystrophy is considered rare, ). , 93 98 , , 94 99 95 ). Downloaded fromBioscientifica.com at10/03/202104:01:00AM , , 100 96 ). , 101 https://eje.bioscientifica.com ). Resultsfrommuch- 180 97 ). Studies,which :2 80 , 95 ). The 90 R63 ). via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com HA primarily in the HPG, HPT, HPA and to a lesser extent influences neuroendocrine abnormalities associatedwith ( reinforcing the leptin-independent nature of this system administration improvedonlylevelsofactivinB,again 70 IGF1:IGFBP3 ratioanddecreasedcortisollevels( neuroendocrine dysfunction with increased fT3 levels, ofmenstruationand improved leptin resultedinrecovery leptin asapossibletreatmentofforHAdemonstratedthat subsequent randomized,placebo-controlledtrialassessing fully elucidated. total vsintactcomponentsoftheIGFaxisremainstobe ( levels, basal IGF-1 concentration is significantly decreased and increasedreverseT3( the HPTaxisoccurswithlow-normalTRH,decreasedT3 sensitivity to ACTH ( levels ofCRH,ACTH,cortisolandincreasedadrenal occurs inresponsetothisstress,identifiedbyincreasing for homeostaticmaintenance.ActivationoftheHPA axis hypothalamic axesareaffectedasanadaptivemechanism of theHPGaxis;however, itappearseachofthe in chronicenergy-deficientstatesillustratesimpairment cell development( hormone production, Sertoli cell proliferation and germ gland andthegonadstodecreasefolliculargrowth, of the HPG axis through interactions with the pituitary of energy deprivation with subsequent downregulation all, excludingfollistatin,decreaseinresponsetostates activin B,follistatinandfollistatin-like3(FSTL3)ofwhich states ( the HPGaxisduringacuteandchronichypoleptinemic largely leptin-independentsystemthatalsomodulates activin-follistatin system,havebeenimplicatedasa pulsatile secretionofGnRH( from anabsentLHsurge,aconsequenceofimpaired their eumenorrheiccounterparts( Amenorrheic athletesdisplaylowerleptinlevelsthan and directly relatedto leptin levels ( body ,exercise intensityisinverselyrelatedtoserum abnormalities andosteoporosis( or excessivestresscausinginfertility, neuroendocrine energy expenditure,decreasedcaloricconsumption energy-deficient stateassociatedwithexcessive Hypothalamic amenorrhea(HA)representsachronic Hypothalamic amenorrhea 104 70 Review , , Our group’s proof-of-conceptpilotstudyand functionresults The dysregulationofovulatory 73 ). Theseresultsillustratethat chronichypoleptinemia 109 ). Regarding the activin-follistatinsystem,leptin 104 ), but the exact effect on free IGF-1, IGFBPs, and ). HormonesofthissystemincludeactivinA, 104 107 , 105 , 108 88 , 106 ). Despiteincreased24-hGH ). Conversely, suppression of 88 ). The development of HA others A EPapathanasiouand ). Otherhormones,the 103 89 ). Independentof ). 5 , 6 102 , 54 ). ). , ( are postulated in being beneficial to bone metabolism treatment ( levels weresignificantlydecreasedafter36 weeks ofleptin kappa- hormone (iPTH)andreceptoractivatorofnuclearfactor at thelumbarspineby4–6%( treatment significantlyincreasesbonemineraldensity bone resorptionmarkers( during the study period without significant effects on bone formationwhichremainedsignificantlyelevated weeksinHAwomenresultsincreasedmarkersof 4 regulate bonemetabolism( bone health.Inthesemodels,leptinactstopositively and decreasedestrogenlevelsinHAisimpairments which remainstobefullyelucidatedbyongoingstudies. axis( the hypothalamic–pituitary–GH to leadingcausesofpreventable deathincluding isaworldwidehealth problemdirectlyrelated Common obesity concerns. antibodies couldpotentiallyalleviateimmunogenic into alternativeleptinanalogsnottriggeringanti-leptin efficacy could be assessed ( dose adjustmentsneedtobeconductedsoassafetyand study periodswithcarefulmetabolicmonitoringand remained unchanged or increased. Larger studies for longer the weightlostwasprimarilyfatmasswhereaslean increase above the upperphysiological level. Moreover, restored, andweightlossoccursonlywhenleptinlevels levels, neuroendocrine abnormalities and fertility are leptin levels remain within arange of physiological leptin in leanbodymass( bone metabolism outcomes ( maintaining thedesiredhormonal( adjustments onecouldavoidweightlosswhilestill 115 formulation ofleptinasatreatmentforHA( cognitive behavioraltherapylimittheuseofcurrent compound andalternativetherapeuticoptionssuchas antibodies duringtreatmentwiththecurrentlyavailable small yetsignificantweightloss,developmentofleptin in adolescentsandwomenwithfunctionalHA.The improvement ofbonemetabolismorfertilitytreatment Practice guidelines,leptinisnotrecommendedforthe metabolism Energy homeostasisand 111 ). We haveshown,however, thatwithleptindose According tothe2017EndocrineSocietyClinical dysfunction Another consequence of ovulatory , 112 Β ligand(RANKL)toosteoprotegerin(OPG)ratio , 113 111 ). ). ThesetrendsofiPTHandRANKL:OPG 116 ). Inotherwords,whenachieved Downloaded fromBioscientifica.com at10/03/202104:01:00AM 114 6 , 110 58 73 ). Moreover, investigations ) without any decreases ). Two-year metreleptin ). Leptintreatmentfor 58 ). Intactparathyroid 6 180 ) andmetabolic 6 :2 ) –theeffecton 97 , R64 114 via freeaccess , European Journal of Endocrinology typical obesity, othereffectivemedicationshavebeen While leptintreatmentalone maynotbefeasiblein anti-obesity medicationin clinical practice( not well tolerated, thus limiting its application as an significant weightlossonly withsupraphysiologicdoses results fromclinicaltrialsintypicalobesitydemonstrate of leptingeneratedhopessuccessfullytreatingobesity, be ananti-obesityhormone( with congenitalleptindeficiency, leptinwas assumedto effects ofleptinadministrationinrodentsandhumans inneedofeffectivetherapies. epigenetic andothermechanismscreateacomplex and central mechanisms in combination with genetic, these cnditioms( hypothesized tounderlecaloricintake,whichleads in fasting subjects with obesity and prediabetes are related putamen and salience- and reward-related insula including post-prandialdecreasedactivationinreward- With theuseoffunctionalMRI(fMRI), internalfactors individuals are allfactorspromotingobesity ( food consumedatirregularmealpatternsbysedentary Larger portionsoflow-nutrient,high-caloric,palatable and physicalactivityhavealsobeenlinkedtoobesity. cardiometabolic outcomes( pregnancy resultedinlowerchildadiposityandimproved adherence to a Mediterranean diet in early stages of factor, two pregnancy cohorts suggested that maternal metabolic outcomes ( with obesityandmaybetargetstopreventfutureadverse in utero this pathology ( obesity byidentifyinghundredsofSNPsassociatedwith association studiessupportapolygenicnatureforcommon less than10%extremeobesitycases( receptor ( the leptin–melanocortinpathwayencodingMC4R cause ofmonogenicobesityresultsfrommutationsin the rolegeneticshasinobesity( following Mendelianpatternsofinheritancestressing are reportedintheliteraturewithasubstantialportion ( highlighting theroleofgeneticcontributioninobesity estimate heritability of BMI between 40 and 70%, scientific organizations( problem, obesityhasbeendeclaredasadiseasebyseveral an efforttoaddressthecomplexityofthischronicmedical cardiovascular disease,type2diabetesandcancer( 117 Review Following observations ofdramaticweight reducing Following observations Environmental factorsrelatedtodiet,foodintake Evidence fromadoption,twinandfamilystudies ). Seventy-ninesyndromesassociatedwithobesity andpostnatalexposureshavealsobeenassociated 119 ). However, thesemutationsaccountfor 120 124 ). Modifiable epigenetic changes from ). Altogether, theseenvironmental 121 3 ). ). Looking at this modifiable 122 125 ). ). Although the discovery ). Althoughthediscovery 118 others A EPapathanasiouand ). Themostcommon 3 ). Genome-wide 126 , 3 127 123 ). In ). ). with attentionandsaliency, again,highlightingmore decreased foodcueactivation ofbrainnetworksassociated 140 possibly through stimulation of POMC neurons( 2C(5HT2C)receptoragonist a 5-hydroxytryptamine peripherally andcentrallytoinduceweightlossthrough /naltrexone). to alterappetite(e.g., /topiramate, obesity target the brain directly, instead of theperiphery, treatment of obesity. Othermedications approved for or are being developed (, GIP, etc.) for the Many ofthesemoleculeshavebeen(GLP-1asliraglutide) combination therapiesofGLP-1withleptinanalogs( levels inappetiteandprovidesatheoreticalrationalefor ( decreased activation of attention-related brain areas increased activationofreward-relatedbrainregionsand hypoleptinemia in response to treatment, ( reward networks,inresponsetohighlydesirablefoodcues and similarcorticalareas,therefore,theattention Liraglutide treatmentdecreasesbrainactivationofthis in severalbrainareasincludingtheparietalcortex( trial todemonstratethatGLP-1receptorsareexpressed demonstrated. We performedarandomized,controlled peripherally in cortical areas of the CNS, as we recently humans, thereappearstobeadditionalGLP-1actionmore interaction withcorticalcentersinrodents( circuits where GLP-1 acts; however, there is minimal This pathwayhighlightsjustoneofthemanyneural reward pathwayscausingdecreasesinfoodintake( input destinedforthemesolimbicdopamineneuronsof ( the hypothalamus,medullaandparietalcortexofhumans ( while alsodisplayinginteractionwithcorticalareasinmice its interplaywithPOMC/CARTandAgRP/NPYneurons oxyntomodulin, GIPandpeptideYY(PYY)( to, leptin,,,,GLP-1, ( peripheral hormone changes following bariatric surgery obesity treatmentlargelydistillsfromobservational 130 investigated fortheirpotentialuseinobesity( as receptor , are currentlybeing may stillbeeffectiveattreatingobesity, andsome,such developed. However, downstreameffectorsofleptin metabolism Energy homeostasisand 11 136 136 135 132 ). This highlights the compensatory roleoflow leptin ). Thishighlightsthecompensatory ). Ourgroupdemonstrated inaRCTthatlorcaserin , Lorcaserin isamedicationwhichactscentrallyas Liraglutide isaGLP-1receptoragonistthatacts Pointed investigationofpharmaceuticaltargetsfor ). Thesehormonesinclude,butarenotlimited ). Interestingly, the amplification of fasting-induced ). Inrodentmodels,GLP-1suppressestheexcitatory ). OurgroupidentifiedpresenceofGLP-1receptorsin 131 ). Downloaded fromBioscientifica.com at10/03/202104:01:00AM https://eje.bioscientifica.com 180 :2 133 128 138 , , R65 136 137 134 ). In 139 129 11 via freeaccess ). ). ). ). , , European Journal of Endocrinology https://eje.bioscientifica.com compounds with less immunogeniceffects are ongoing. substances for synergistic and/or development of novel Further investigationintocompounding leptinwithother for disease states other than complete leptin deficiency. formulation limitswidespread useandendorsement profile andimmunogenicityofthecurrentlyavailable treating obesityandleptin-deficientstates,thesideeffect energy balance. of pathwayscontributingtothebody’s responsetoward energy homeostasis proves daunting given the complexity medical therapiestoaddresstheproblemofdysregulated and obesity. Treating underlying pathology with novel elucidate pathwaysresponsibleforweightregulation in humanbrains,andthefuture,mayhelpfurther the neurophysiologicalunderpinningsofweightbalance other noveltechniques,allowforin-depthinvestigationof availability ofneuroimaging,suchasfMRI,PETscansor with historicalmethods.Rapidadvancementand apparently overcoming theinconsistenciesassociated that wouldbeperformedinanethicalmannerbut the necessityfornoveltranslationalmethodsandefforts in rodentsintofindings and datain humansindicating difficult todirectlytranslatehypothesesraisedbystudies not directlytranslatetohumanphysiology, makingit hypotheses andprovidemechanismsthatmayor Ultimately, experimentaldatafromrodentsgenerate Conclusions mechanisms. complementary to effectivesingleorcombinationtherapiesleveraging as theexperimentalmodeltodate,andthus,couldlead differentfromthebrainsinrodentsthathaveserved very underlying mechanismsinhumans,whichhavebrains fMRI and/orPETimaging,canleadtotheelucidationof medications worktotreatobesityinhumans,using therapies. Definingthebrainareasinwhichdifferent the brain areas which are impacted by anti-obesity food cues( decreasing theemotionalsignificanceofhighlypalatable with lorcaserin, suggestingitdecreasesfoodintakeby system) wasdirectlycorrelatedtoweightlosssuccess the amygdala(acomponentofemotional/limbic study further determined thatbaseline activation of differences of brain complexity/function ( andhighlightsinterspecies activation wasnotobserved contrast torodent studies withlorcaserin, hypothalamic interactions with cortical systems in humans ( Review While metreleptinshowsclearevidenceofefficacyfor 10 ). Futureresearch willcontinuetodelineate others A EPapathanasiouand 10 , 10 141 , 11 ). Our ). In

be abletoprovidetangiblebenefitssufferinghumans their analysisandreductiontopracticeinorderforus collected wouldrequirenovelmathematicalmodelingfor and neurosciencesthevastamountsofdatatobe human physiologyandtherapeuticsbutalsoinbiology combination of efforts of scientists working not only in environment. Analysisofthesedatawillrequirea to shapeourbodyanditsresponseinanever-changing of hormones,receptors,neuronsandcellsallcoordinate external environments. A seemingly infinite interplay amounts ofdatareflectingthestatusourinternaland is complicated,involvingtheintegrationofmassive effective. of patient registries worldwide may prove to be more databases aswellreal-worldtrialsand/ortheleverage and thus power are needed and appropriate use of the future, more RCTs with greater number of participants Ultimately, in order to further investigate leptin’s role in References in thepreparationoffigure. The authors would like to thank Maria Papakonstantinou for her assistance Acknowledgements This manuscriptwasfundedinpartbyNIH2K24DK081913. Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisreview. no is there that declare authors The Declaration ofinterest in thenotsodistantfuture( metabolism Energy homeostasisand 6 5 4 3 2 1 Chou SH, Chamberland JP, Liu X,Matarese G,Gao C,Stefanakis R, Ahima RS, Prabakaran D,Mantzoros C,Qu D,Lowell B, Zhang Y, Proenca R,Maffei M,Barone M,Leopold L& Upadhyay J, Farr O,Perakakis N,Ghaly W&Mantzoros C.Obesityas Bray GA. Weight homeostasis. Woods SC &D’Alessio DA.Centralcontrolofbodyweight and 6585–6590. effective treatmentforhypothalamic amenorrhea. Brinkoetter MT, Gong H,Arampatzi K &Mantzoros CS.Leptinisan org/10.1038/382250a0) response tofasting. Maratos-Flier E &Flier JS.Roleofleptinintheneuroendocrine org/10.1038/372425a0) its humanhomologue. Friedman JM. Positionalcloningofthemouseobesegeneand doi.org/10.1016/j.mcna.2017.08.004) a disease. 205–216. Supplement 1)S37–S50. appetite. Appetite andbodyweightregulationinhumans Journal ofClinicalEndocrinologyandMetabolism Journal (https://doi.org/10.1146/annurev.me.42.020191.001225) Medical Clinics of North America Medical ClinicsofNorth (https://doi.org/10.1073/pnas.1015674108) Nature Nature (https://doi.org/10.1210/jc.2008-1630) 1996 Downloaded fromBioscientifica.com at10/03/202104:01:00AM 1994 Annual ReviewofMedicine 142 382 372 250–252. , 143 425–432. 2018 180 ). (https://doi. 102 :2 (https://doi. PNAS 13–33. 2008 1991 2011 (https:// 93 42 R66 108 (11

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