Arch Metab. Endocrinol 2019;63/6 infastingmice(5).During GH pulsatility issuppressed (3), starvation baseline GHlevelsduring prolonged in cancausea tonic increase (4). Althoughghrelin GHsecretion doesnotregulate fasting, ghrelin term (3).However, food restriction prolonged duringshort- GH levels during for increasing is required secretion (2).Inaddition,ghrelin GHsecretion induces robust administration in thestomach,andsystemicghrelin Hormone-RELeasINg ( ghrelin Forexample,thehormone secretion. GH factorsalsoregulate andhormonal neuropeptides (1,2).However, GHsecretion other on pituitary effect haveaninhibitory neurons (SST)-expressing somatostatin whereas induceGHrelease, neurons (GHRH)-expressing hormone GH-releasing regard, cells.In this ofGHbysomatotropic and release thesynthesis systemtoregulate the hypophysealportal into neuropeptides orinhibitory stimulatory secrete that byhypothalamicneurons iscontrolled secretion G INTRODUCTION [email protected] –SãoPaulo, SP,05508-000 Brasil Av. Prof. LineuPrestes, 1524 Jose DonatoJr. Correspondence to: (USP), SãoPaulo, SP, Brasil Universidade deSãoPaulo Instituto deCiênciasBiomédicas, 2 Paulo (USP),SãoPaulo, SP, Brasil Biomédicas, Universidade deSão Biofísica, Instituto deCiências 1 DOI: 10.20945/2359-3997000000184 on Aug/29/2019Accepted Receivedon Aug/8/2019 Departamento deFisiologiae Departamento Departamento de Anatomia, Departamento secreted by the anterior pituitary gland. GH gland.GH bytheanteriorpituitary secreted (GH)isthemostabundantfactor hormone rowth p eptide GH; cytokine;brain;STAT5; metabolism Keywords Endocrinol Metab. 2019;63(6):549-56 metabolic stresstopromoteappropriatephysiological adjustmentsthatrestorehomeostasis. deficient GHsecretion. Furthermore, GHactsinspecificneuronalpopulationsduringsituations of or withexcessive central nervous systemcanexplainsomedysfunctionspresentedbyindividuals adaptions. Therefore, thebrainisanimportant targettissueofGH,andchanges inGHactionthe and counter-regulatory responsestohypoglycemia, andtheycanmodifygestationalmetabolic conditions,neuroendocrineadaptionsduringfoodrestriction, duringglucoprivic impair foodintake disruptions inGH signaling in specific neuronalpopulationscanaffect axis and thereproductive changes andmetabolism.Dataobtainedfromexperimentalanimalmodelshaveshownthat brain regulatesthephysiology ofnumerousfunctionssuch ascognition,behavior, neuroendocrine importance ofGHactionin thecentralnervous system. We provide evidencethatGHsignalinginthe brain. ofthepresentreviewistosummarizeThe objective anddiscussthepotentialphysiological are spreadover theentirecentralnervous system,suggestingthattheyhaveimportant rolesinthe regenerationandproliferation.However,the regulationofcelldivision, neurons GH-responsive Growth hormone(GH)isbestknownforitseffect stimulatingtissueandsomaticgrowththrough ABSTRACT https://orcid.org/ 0000-0002-6183-3861 Jose Donato Jr. https://orcid.org/ 0000-0002-0877-8453 Renata Frazão https://orcid.org/ 0000-0001-7310-6760 Frederick Wasinski the central nervous system Effects ofgrowth in hormone ) is mainly produced ) ismainlyproduced 2 1 1 Growth Growth (10). The activation of GHR induces IGF-1 expression (10). Theactivation ofGHRinducesIGF-1 expression factor-1 insulin-like growth another hormone, (IGF-1) (13). Importantly, mediatedby ofGHare several effects anddiabetesmellitus GH levelscancauseinsulinresistance high in skeletal muscle (12). Therefore, insulin resistance stimulated hepaticgluconeogenesis (10,11)orincreased manifestedeitherby whichare hyperglycemic effects, in thesubcutaneousadiposetissue(11).GH also has body adiposity, exhibit increased frequently particularly receptor (GHR)-knockoutanimals GH-deficient orGH fattyacids.Accordingly, free lipolysis andcirculating increases Inthissense,GHsecretion metabolic effects. in varioustissues(10).GHalsopossessesnoteworthy and proliferation of cell division, regeneration regulation the through whichisrealized tissue andsomaticgrowth, (9). (8)andpregnancy (7), physicalexercise includehypoglycemia GHsecretion induce increased (5).Inadditionto fasting, otherconditionsthat receptor GHpulsatilityviatheactivationofY1 decreasing for is responsible become active(6),andNPYsecretion neurons Y(NPY)-expressing fasting, neuropeptide The most well-known function of GH is related to to The mostwell-knownfunctionofGHisrelated review Arch 549

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 550 optic tract;PVH, paraventricular nucleus; VMH, ventromedial nucleus. ScaleBar=200µm. Figureadaptedfromthestudyby Furigoandcols. (47). ventricle; ARH, arcuatenucleus;CEA, central nucleusoftheamygdala;DMH, dorsomedialnucleus;fx, fornix;MEA, medialnucleusoftheamygdala;opt, Mice received an intraperitoneal injection of 20 µg of porcine GH per gram of body weight, followed by perfusion 90 minutes later. Abbreviations: 3V, third photomicrographs of brain sections showing the distribution of pSTAT5 immunoreactive cells insaline-injectedmice(A-D) or inGH-injectedmice(E-H). Figure 1. (1,16). the sitethatcontainsmostGHRHneurons nucleusofthehypothalamus (ARH), in the arcuate feedback (15).Accordingly, GHRishighlyexpressed vianegative GHsecretion pituitary levels andregulate tosense GH neurons enabling theneuroendocrine for is important GHRs (1).BrainGHRexpression muscle andbone(10).However, thebrainalsoexpresses mediated bytheliver, whiteadiposetissue,skeletal ofGHare The mostwell-knownbiologicaleffects THE BRAINISAGH-TARGET TISSUE system(CNS). the centralnervous of GHactionin discuss thepotentialphysiologicalroles review,In thepresent ouraimistosummarizeand functions. severalmetabolicandgrowth GH, regulates ofIGF-1that,togetherwith and thehepaticsecretion theactivationofGHRinseveraltissues, GH secretion, ofpituitary be summarizedbythehypothalamiccontrol axiscan thesomatotropic hypothalamus (15).Therefore, glandand feedback loops,possiblyinvolvingthepituitary vianegative GHsecretion that IGF-1alsoregulates in liver-specific GHR-knockout mice (14), indicating observed and length (14). Of note, high GH levelsare bodyweight IGF-1andreduced levels ofcirculating low liver-specific GHR-knockoutmice exhibit very levels(10).Asaconsequence, IGF-1circulating regulates GH action in the liver liver into the blood. Therefore, the from or paracrineaction,IGF-1canbesecreted tissues.IGF-1canhavealocalautocrine in numerous Effects ofGHinthebrain Distribution ofGHresponsivecellsin differentbrainareasofmiceviathedetectionSTAT5 (pSTAT5). phosphorylation A-H. Brightfield intracellular pathway induced by GHR activation. intracellular pathway induced by GHR activation. kinases (10),STAT5 themostrelevant isconsidered signaling molecules,includingSTAT1, STAT3 andSrc severalintracellular the activationofGHRrecruits (10).Although pathway toinduceitsintracellulareffects signal transducerandactivatoroftranscription(STAT) mostlyonthejanuskinase2(JAK2)/ family andrelies GHRs(1,16,18). brainstem, alsoexpress thalamus,amygdala, hippocampusand terminalis, includingtheseptum,bednucleusofstria areas, tothehypothalamus,andseveralbrain not restricted feedback (17).However, cellsare GH-responsive playinmediatingGHnegative SSTneurons key role GHpulsatility,which increases demonstratingthe hypothalamic SST expression, GHR mRNA decreases GHR mRNA(1).Centraladministrationofantisense the paraventricular and periventricularnuclei coexpress in 70%oftheSSTneurons In addition,approximately GH-responsive cells in the mouse brain (Figure 1). 1). cellsinthemousebrain(Figure GH-responsive (pSTAT5). Thus, pSTAT5 can be used as a marker of todetectSTAT5histologically processed phosphorylation thebody,time forGHtoactthroughout thebrainis acute systemicinjectionofGH,andafterasufficient the mousebrain(18).Usingthistechnique,micereceive cells in strategy to identify GH-responsive an alternative employed atthecellularlevel,our group good resolution Since classicalmethodstodetectGHRdonotenable similartothatcausedbyGHR deficiency (19). growth Accordingly, STAT5-knockout miceexhibitreduced GHR is a member of the type I cytokine receptor GHR isamemberofthetypeIcytokinereceptor Arch Metab. Endocrinol 2019;63/6 Arch Metab. Endocrinol 2019;63/6 signaling inthebrain. Figure 2. a secondary, factor. indirect The major confounding causedbythelackofGHRsignaling are whethertheeffects todetermine making itdifficult multiple endocrineandmetabolicabnormalities, cognitive functions,GH-deficientindividualspresent ofGHon therole model tousefordetermining However, althoughGHdeficiencyisaninteresting typicalofelderlypeople (20). inGHsecretion decrease possiblyassociated withthe consequences ofagingare andsomecognitive effects, GH hasneuroprotective 2).Additionally, (Figure attention-deficit disorders well-beingandmood and decreased sleep problems, includingpoormemory,abnormalities, tiredness, may exhibit several cognitiveandneurological indicatethatGH-deficientindividuals reports Previous COGNITIVE EFFECTSOFGH thought. thanpreviously relevant likely more functionssuggestthatcentralGHactionis different involvedwith cellsinbrainstructures of GH-responsive the brainisaGH-target tissue,butthelarge number notonly 1).Therefore, oftheCNS(Figure structures widely distributed in numerous cells are responsive demonstratedthatGH- GHRandfurther to express shown previously cellsinbrainareas GH-responsive thedistributionof weconfirmed Using thisapproach, STAT5 ablation Brain-speci c GH de ciency GH receptor ↑ Ghrelin (humans) secretion knockout Chronic Stress (mice) (mice) (rats) (rats) Scheme thatsummarizesthecognitive effectsinducedbyGH ↑ GHintheamygdala ↓ HippocampalGH ↑ Insulinsensitivity ↓ IGF-1levels inoldanimals ↓ ↔ IGF-1levels ↓ Insulinsensitivity ↓ IGF-1levels Insulin sensitivity Posttraumaticstressdisorder • lncreasedfearmemoryformation • Memoryde cits • lmpairedhippocampalfunction • inammation diet-inducedhypothalamic Protectedfromage-andhigh-fat • declineinmemory Protectedfromage-induced • inthehippocampus ReducedIGF-1expression • Memoryde cits • Attention-de citdisorders • Sleepproblems • • Tiredness Memoryde cits • per se orby Importantly, inthese GHactioninthebrainisimpaired (26). exhibit lateonsetobesityandinsulinresistance levels, althoughbrain-specificSTAT5-knockout mice IGF-1 andserum bodygrowth mice havenormal studyhadshownthatthese mouse (25). Aprevious generatedabrain-specificSTAT5-knockoutgroup IGF-1(25).Thus,our ofcirculating brain, regardless ofGHonthe waytostudytheeffects alternative manipulating thistranscriptionfactormaybean theSTAT5receptor, recruits signalingpathway, Alzheimer’s disease(23,24). contribute tothecognitivedeclineinpatientswith andthesedefects associated withIGF-1resistance, functions (22).Moreover, is braininsulinresistance ofmolecularfactorsinvolvedincognitive expression the (21)andregulates effects has neuroprotective 2)sinceIGF-1also IGF-1levels(Figure circulating factor associatedwithGHdeficiencyisdecreased in aged GHR-knockout mice may be related to thein agedGHR-knockout micemayberelated againsthypothalamicinflammationand protection (27,30). The“paradoxical” cognitiveimprovement and high-fat-inducedhypothalamic inflammation age- from alsoprotected GHR-knockout miceare inthehippocampus(28,29).neurotransmission possiblybecauseofchangesinglutamatergicretention, age-induceddeclineinmemory from protected (20),GHR-knockoutmiceare abnormalities andothercognitive memory impaired present IGF-1levels. ofcirculating GH signaling,regardless by seems to be regulated projections of ARH neuronal IGF-1 levels(27).Thus,thedevelopment circulating reduced specific GHR-knockout micedespite their Importantly, inliver- normal are theseprojections (27). totarget areas ARHneurons that extendfrom developmentof the projections mice havesuppressed aspectsinthebrain,GHR-knockout neuronal regulates theideathatGHdirectly 2).Corroborating (Figure formaintainingmemory isimportant production suggesting thatGH-mediatedhippocampalIGF-1 in the hippocampus, IGF-1 expression decreased (25),thesemutantmiceexhibit isnormal neurogenesis fear conditioning test (25). Although hippocampal mazeand test,Barnes the novelobjectrecognition from byresults asdetermined formation, and memory specific STAT5 learning ablation leads to impaired by GHRisnonfunctional.Wethatbrain- observed mice sincethemajorintracellularpathwayrecruited Since theactivationofGHR,butnotIGF-1 Although GH-deficientindividualsfrequently Effects ofGHinthebrain 551

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 552 foundinindividuals sexual maturation andtheinfertility toexplainthelateonsetpuberty,not sufficient the lackof is inthegonads,thiseffect Although GHactsdirectly (35-38). problems forfertility-related being treated stimulationinwomen of theovariestogonadotropin thesensitivity GHtherapy canimprove Furthermore, mice. in GH-deficientwomenordwarf andfertility thetimeofpuberty individuals andrestore onsetinhealthy GH therapycanacceleratepuberty release (35). alsomodifiesGH puberty whereas estradiolsynthesis, affects cycle (15).GHsecretion mediationoftheovulatory maturation andsexsteroid forsexual componentrequired GH isahormonal reproduction, Among themultiplefactorsthatinfluence GONADAL (HPG)AXIS GH MODULATES THEHYPOTHALAMIC-PITUITARY- 1). (18)(Figure GHR expression functional cells and therefore number ofGHresponsive including the medial and central nuclei, contain a large oftheamygdala, the hippocampusandseveralareas (33,34).Notably,disorder showedthatboth ourgroup such as posttraumatic stress stress, following prolonged the amygdalamaybeinvolvedinmaladaptivechanges in GH expression animals (34).Thus,ghrelin-induced inghrelin-treated alsoobserved fear,increases aneffect ofGHintheamygdala overexpression Virus-mediated (33). formation number ofcellsactivatedbyfearmemory the ofGHintheamygdalaincreases upregulation (32). In contrast, resilience stress promoting impairments stress-related Restoration of hippocampalGHreverses (32). andlearning function, includingmemory in hippocampalGHlevelsandimpairs causes a decrease stress Chronic hippocampal neurons. 2). insulin sensitivity(Figure tochangesin maybesecondary though theseeffects duringaging,even andmemory spatial learning cognition, while inhibition ofGH action can improve indicate thatexcessGHhasanegativeimpacton (31).Thus,thesestudies retention memory impaired and GH causedinsulinresistance overexpressed whereas insulinsensitivityandlearning, improved aGHRantagonistexhibited mice thatoverexpress (23,24). Accordingly, 12-month-oldtransgenic cognition andisariskfactorforAlzheimer’sdisease hasbeenlinkedwithimpaired (11) asinsulinresistance in these animals higher insulin sensitivity observed Effects ofGHinthebrain GH can also be synthesized by brain cells, including GH can also be synthesized by brain cells, including acting signalingpathways(40,43).Interestingly, the modulationofmembraneionchannelsbyfast- that wouldrequire aneffect PMv orGnRHneurons, membrane potentialofthe hypothalamic kisspeptin, GHR agonistdoesnotacutelychangetheresting in AVPV/PeN orPMvcells,a kisspeptinneurons systemic GHinjectioninducesSTAT5 phosphorylation STAT5 signalingpathway. Inthissense,whilea likelymediatedbytheJAK2/ of theHPGaxisare (41,42). maturation andthemaintenanceoffertility forsexual required andare neurons (LepR)-expressing containeitherkisspeptinorleptinreceptor These areas nucleus(PMv)andARH (18,40). premammillary periventricularnuclei(AVPV/PeN),and rostral ventral periventricular of the anteroventral including neurons to GH, responsive the HPG axis are that regulate populations describedthatcriticalneuronal we recently with G cycles inadult animals. sexualmaturation andtheestrous affect may indirectly alterations induced by the disrup timing ofpuberty. Ontheotherhand,metabolic forthe although centralGHaction isnotrequired GH canmodulatebraincomponents oftheHPGaxis, time(44).Thesefindingssuggestthat at thenormal puberty brain-specific GHR-knockoutmiceunderwent the leptinlevels(44).Despitetheseeffects, serum uterinemassandlower was accompaniedbyincreased Augmented GH secretion GHsecretion. increased negative feedbackinthehypothalamus,leadingto GH braindisrupted theentire of theGHRfrom cycle(44).Ablation in theestrous disruption presented delayed sexualmaturation.Moreover, someindividuals leptinlevelsduringdevelopment, whichledto serum cells wasassociatedwithlowerbodyweightandreduced In contrast,ablationofGHRintheLepR-expressing cycle(44). mediationoftheovulatory or thesexsteroid forsexualmaturation kisspeptin cellswasnotrequired and femalemice,includingthe pubertal axisin tothereproductive ofgenesrelated expression inthehypothalamic kisspeptin cellscausedareduction brain.GHRablationinthe cells andintheentire we ablated GHR in kisspeptin cells, LepR-expressing GH signalinginthecentralcomponentsofHPGaxis, AVPV/PeN toGH(40). responsive directly are pSTAT5, ofthe indicatingthatonlykisspeptinneurons GH-induced donotexpress ARH kisspeptinneurons The effects ofGHonthecentralcomponents The effects To of understandthephysiologicalrelevance further Esr1 H deficiency or resistance (37,39).Accordingly,H deficiencyor (44).Despitethesechanges,GHsignalingin Arch Metab. Endocrinol 2019;63/6 tion of GH signaling Gnrh1 , Kiss1 , Nos1

Arch Metab. Endocrinol 2019;63/6 order torestorethe homeostasis. metabolic stresstopromoteappropriate physiologicaladjustmentsin Figure 3. (49).Ofnote,GHR-knockout AgRP/NPY neurons Finally, alsostimulatesfoodintakeviaARH ghrelin oftheactionpotential (47). thefrequency increasing membrane potential and depolarizing theirresting excitation in25%oftheARHAgRP/NPYneurons, Agrp of thehypothalamic expression injection increases (48) orGH-inducedpSTAT5 acuteGH (47).Third, intheARHexhibiteitherGHRexpression neurons of foodintake(6).Second,95%theAgRP/NPY potentinducers are that ARHAgRP/NPYneurons peptide(AgRP).First,it iswellknown agouti-related NPYandthe thatcoexpress induced byARHneurons ofGHispossibly effect 3).Theorexigenic (Figure byGHtomodulatemetabolism pathways recruited thenutrientsneededforgrowth. food intaketoprovide ofGHwithhigher effects to linkthegrowth-promoting perspective,itisadvantageous CNS. Inanevolutionary inthe response anorexigenic (47). Thus,GHproduces foodintake24hoursaftertheinjection GH increases administrationof (45,46). Anintracerebroventricular foodintakeinmiceandcarps,causing obesity increases inthebrain 3).GHoverexpression in theCNS(Figure itsaction metabolic changesintheorganism through (10,11,13). GH also causes induces insulin resistance and actions; inparticular,GHhasalipolyticeffect As mentionedearlier, GHhasmarkedmetabolic GH ACTIONINTHECNSREGULATES METABOLISM Food restriction Hypoglycemia Condition of Pregnancy metabolic Recent studies have started to unravel the neural tounraveltheneural Recent studieshavestarted stress and GH actsinspecificneuronalpopulations duringsituationsof Npy secretion transcripts, and GH induces significant transcripts,andGHinducessignificant ↑ GH ↑ GH ↑ GH ↑ GH GH neurons neurons neurons POMC AgRP Brain VMH GH target neuron Gestationalinsulinresistance • Fatdeposition • Gestationalhyperphagia • expenditure Suppressionofenergy • andreproductiveaxes Suppressionofthyroid • thermogenesis Suppressionof • lncreaseinfoodintake • glucoseproduction lncreasehepatic • responsetohypoglycemia counter-regulatory Regulatethe • Glucoprivichyperphagia • Metabolic functions regulated byGHvia a centralaction reproductive axes during food restriction, theAgRP- axesduringfoodrestriction, reproductive adiposetissue(BAT)in thebrown and andthyroid markers thethermogenic animalssuppressed control adaptations tothiscondition.Insense,whilethe thetypicalneuroendocrine unabletopresent mice were the AgRP-specific GHR-knockout to food restriction, mice (47,51).However, exposed whenthesemicewere orglucosehomeostasisinmalefemale expenditure body weight,composition,foodintake,energy AgRP-specific GHRablationcausednochangesin (47). specific ablationofGHRonlyinAgRPneurons a micecarrying produced homeostasis, ourgroup ofenergy for the regulation ARH AgRP/NPY neurons ofGH. effects mediators oftheorexigenic important are indicate thatARHAgRP/NPYneurons thesestudies onfoodintake(50).Therefore, of ghrelin fortheeffects suggesting thatGHsignalingisrequired ofghrelin, effect totheorexigenic unresponsive mice are be used as a marker of hypothalamic AgRP expression, be usedasamarker ofhypothalamicAgRP expression, showed thatplasmaAgRPlevels inhumans,whichcan studyalso food-deprived wild-typemice (47).Arecent of theenergy expenditure antagonist, isabletoincrease showed thatadministration ofpegvisomant,aGHR ofobesity.for thetreatment ourgroup Inthisregard, therapeuticapproaches efficient development ofmore maypotentiallyhelpinthe during foodrestriction of the factors that cause these metabolic alterations (52).Thus,theidentification the energy expenditure ofobesitybyreducing adaptions hinderthetreatment intimesoffamine,theseenergy-saving of survival thechances value,possiblyincreasing evolutionary 3).Althoughtheseadaptionshadgreat (Figure accordingly energy expenditure canregulate neurons these Therefore, aboutfoodrestriction. NPY neurons ARHAgRP/ new biologicalfunctionofGH:italerts a mice(47).Thus,thisstudy revealed in thecontrol totheweightchanges compared during foodrestriction weight loss which led to increased energy expenditure, specific GHR-knockout mice maintained a higher the AgRP- whereas during food restriction, expenditure theirenergy decreased animalsprogressively the control the AgRP-specificGHR-knockoutmice.Consequently, in was prevented hypothalamus duringfoodrestriction in the increase to compared intheir BAT 1expression uncoupling protein andhadunchanged T4andtestosterone circulating specific GHR-knockoutmicesustainedhighlevelsof To ofGHactionon the the importance determine ad libitum Agrp and fedanimals(47).Additionally, Npy expression inthe expression Effects ofGHinthebrain 553

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 554 glucoprivicallyinduced hyperphagia did notaffect (54),GHR-ablated VMHneurons the POMCneurons inducedbyGHRdepletion in (56). Unliketheeffects defects causedbyGHRablationintheVMH regulatory thecounter- system prevent parasympathetic nervous blockersofthe In addition,pharmacological inmicewithGHR-ablatedVMHneurons. neurons hyperactivity intheparasympatheticpreganglionic abnormal infusion of2-deoxy-D-glucoseproduced system.Inthissense, by theparasympatheticnervous likelymediated are response on thecounter-regulatory ofGHregulation glucose injection(56).Theeffects inducedby2-deoxy-D- response counter-regulatory the significantly decreased induced hypoglycemiaand insulin- from the capacityofmicetorecover impaired absence ofGHactionintheVMHneurons glucosetolerance orinsulinsensitivity,not affect the did Although ablationofGHRinVMHneurons tohypoglycemia(57). response the counter-regulatory station thatregulates hypothalamus (VMH),akeyrelay nucleusofthe foundintheventromedial are neurons we showed thata large number of GH-responsive study(56), unknown.Inarecent hypoglycemia are of activated by GH that contribute to the recovery hypoglycemia (3,55).However, themechanisms to response and impairsthecounter-regulatory and GH deficiency causesspontaneous hypoglycemia duringhypoglycemia (7), secreted (54). GHisrobustly foodintakeinspecificsituations regulates neurons 3),indicatingthatGHaction inPOMC cells (Figure attenuated inmicelackingGHRtheirPOMC issignificantly response), counter-regulatory robust thatcausesglucopeniaandinducesa glucose (adrug situation, caused by the administration of 2-deoxy-D- However, thehyperphagiainducedbyaglucoprivic energy orglucosehomeostasisunderbasalconditions. of for the regulation in POMC cells is not necessary pSTAT5 after aninjection of GH(54).action (POMC)intheARH express pro-opiomelanocortin thatexpress 60%oftheneurons that approximately Inanotherstudy,to AgRP/NPYneurons. weshowed energy metabolism. ofGHon mediatetheeffects that AgRPneurons additionalevidenceinhumans These findingsprovide (53). after surgical orpegvisomanttreatment decreases high plasmaAgRPlevelsandconcentration have IGF-1 levels (53). Individuals with acromegaly GHand withcirculating exhibit apositivecorrelation Effects ofGHinthebrain In the ARH, GH responsive cells are not restricted notrestricted cellsare In theARH,GHresponsive signaling intheLepRcells. ofthemicewithdiminished GHR insulin resistance cells mediatethe it islikelythatotherLepR-expressing GHR intheAgRP/NPY, POMCandVMHneurons, inthemicewithablated this phenotypeisnotobserved sensitivity andperipherallipidmetabolism(58).Since hepaticinsulin cellsimpaired in theLepR-expressing These authorsfoundthatthelackofGHsignaling cells. ablation of GHR in all LepR-expressing carrying cells,Cadyandcols responsive the LepR(6).To whetherGHactsonleptin determine populationsandperipheralcellsalsoexpress neuronal and glucosehomeostasis(6).However, severalother ofenergy fortheregulation populations isimportant addition, theactionofleptinintheseneuronal ofLepR.In istheexpression and VMHneurons 3). (Figure specificeffects population inducesvery (56), demonstratingthatGHactionineachneuronal behavioral, neuroendocrine andmetabolicfunctions. behavioral, neuroendocrine key physiologicalaspectssuchascognitive, regulate target ofGHto animportant should beconsidered GH ontheCNS.We evidencethatthebrain provided In this review, of we summarized the known effects CONCLUDING REMARKS 3). mice(Figure inpregnant observed in foodintake,bodyadiposityandinsulinresistance mediates the increases GH action in the brain partially glucose homeostasisduringpregnancy. Specifically, energy and indicate that central GH action regulates (51).Thesefindings sensitivity ofVMHneurons leptin depletion of GHR inthe LepR cells increased intake andbodyadiposityduringpregnancy, whereas food inactivation ofGHRinthebrainledtodecreased mice(51). Furthermore, insulin sensitivityofpregnant thesystemic cellsimproved brain orinLepR-expressing study, weshowedthatablationofGHRintheentire (9).Inarecent inbothhumansandrodents pregnancy during alsosecreted (59). HighamountsofGHare pregnancy, andplacentallactogens principallyprolactin during secreted thought to be mediated by hormones (59,60). These adaptations are insulin resistance food intake, accumulate body fat and develop transient their animalsusuallyincrease pregnant In thisregard, organism fortheenergy demandsoftheoffspring. thematernal metabolic adaptationsthatprepare One aspect shared betweenAgRP/NPY,One aspectshared POMC Pregnancy isaconditioncharacterized bymarked Pregnancy Arch Metab. Endocrinol 2019;63/6 . (58)studiedmice Arch Metab. Endocrinol 2019;63/6 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. REFERENCES was reported. relevant tothisarticle nopotentialconflictofinterest Disclosure: support. 17/21840-8 toR.F. and17/02983-2toJ.D.)forthefinancial ch Foundation (FAPESP; grants number: 16/20897-3 to F.W.; Acknowledgments: wewouldliketothanktheSãoPauloResear orfooddeprivation). (e.g., aging,pregnancy in pathologicalconditionsorphysiologicalsituations either caused by excessive ordeficientGH secretion, contributes totheunderstandingofdysfunctions ofGH oftheCNSforeffects of theimportance be mediatedbyGHviatheCNS.Theknowledge thatmay othereffects todetermine stillnecessary are 3).However, (Figure to berevealed additionalstudies ofGHisbeginning population mediatingtheeffects played by each specific neuronal thought. The role thanpreviously signaling inthebrainislikelygreater ofGH CNS,suggestingthattheimportance entire G H-responsive neurons are spread over virtually the overvirtually spread are neurons H-responsive Duran-Ortiz S,Noboa V, Kopchick JJ. 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