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European Journal of Endocrinology 10.1530/EJE-18-0018 for longitudinalgrowthandorgandevelopment,butone acquired a truer identity of not just a hormone responsible of animalandhumandata.Intheprocess,GHhas cognate receptor(GHR)hasyieldedatremendousamount focusing on growth hormone (GH) and its last 70 years An extensivebodyofbasicandclinicalresearch overthe Introduction GH actionmaybebeneficial. several issuesdealingwiththesebiologicaleffects ofGHandattempttoanswerthequestionwhetherdecreased dealing withmetabolism,obesity, cancer, diabetes,cognition andaging/longevity. Inthisreview, wehavediscussed on GH-resistantLaronSyndrome(LS)patientshavehelpeddefinemanyphysiologicalactionsofGHincludingthose of GHresearchoverthepast70 years.Work ontheGHreceptor(R)-knockout (GHRKO)miceandresultsofstudies treatment andlong-termfollow-upstudiesextensiveuseofanimalmodelsGHactionhaveshapedthebody Growth hormone(GH)isproducedprimarilybyanteriorpituitarysomatotrophcells.Numerousacutehuman(h) GH Abstract *(R BasuandYQiancontributedequallytothiswork) Osteopathic Medicine,OhioUniversity, Athens,Ohio,USA 1 Reetobrata Basu of endocrinedefects? gene-disrupted mice:are there benefits Lessons from growth hormone receptor MECHANISMS INENDOCRINOLOGY Edison BiotechnologyInstitute,OhioUniversity, Athens,Ohio,USAand https://doi.org/10.1530/EJE-18-0018 www.ej Review than 350 scientific articles and serves or has served ontheEditorialBoardsofmanyprestigious journals. orhasserved than 350scientificarticlesand serves (pegvisomant forinjection),which ismarketedforpatientswithacromegaly. Dr Kopchickhaspublishedmore a company, Sensus,which appliedhisresearch tothedevelopmentofanFDA-approveddrugcalledSomavert he and Ohio Universitywereawardedseveral US and European patents.Healso was instrumental in finding and hisgroupwerethefirsttodiscover andcharacterizeGHreceptorantagonists,anaccomplishment forwhich University in Athens, Ohio. He is an internationally recognized leader in the growth hormone field. Dr Kopchick Biology inTheEdisonBiotechnologyInstituteandtheHeritage CollegeofOsteopathicMedicineatOhio John JKopchick Invited Author’s profile e-online.org 1 , hassince1987beentheGoll-OhioEminentScholarandDistinguished Prof.ofMolecular *, Yanrong Qian 5 © 2018EuropeanSociety ofEndocrinology R Basu,YQianandothers 1 , * and Printed inGreatBritain John J Kopchick 2 Ohio UniversityHeritageCollegeof 1 mutations ontheGHRgene(Laronsyndrome;LS)( GH resistance/insensitivityduetomultipleinactivating adenoma (acromegaly) ( hypersecreting pituitary The clinicalconditionsofGHexcessusuallydueto a tissue typesandthroughout the lifespanofan individual. with distinctcatabolicandanabolicrolesacrossmany , Lessons from 2 Published byBioscientifica Ltd. GHR -disrupted mice Downloaded fromBioscientifica.com at09/29/202110:18:07AM (2018) Endocrinology European Journal of [email protected] Email to JKopchick should beaddressed Correspondence 178

178 :5 , R155–R181

R155

1 –R181 2 ) or of , 3 , via freeaccess 4 )

European Journal of Endocrinology www.eje-online.org on theEcuadoriancohort( and Guevara’s subsequent22-yearfollow-upstudy the actionofGH. from miceandhumanswho areinsensitive/resistantto distill thelessonsonGH’s roleinphysiology derived toon the recent advancesin this field of study and try aging. Inthefollowingsectionsofthisreview, wefocus world –obesity, diabetes,cancer, memory, cognitionand top-ranking pathological challenges of the modern Finally, GHisintricatelyassociatedwith several ofthe human conditionsofacromegalyandGHD,respectively. 28 competitive antagonistofGHR(theGHAmouse)( ( transgenic forthebovine(b)GHgene(thebGHmouse) our colleaguesthroughouttheworld,havestudiedmice in adecreaselifespan( associated metabolicdysfunctionsultimatelyresulting childhood, gigantismcanoccur( insulin resistant.Ifthisconditionisleftuntreatedduring and bones,largermuscles,increasedleanmassare as seeninpatientswithacromegaly, havethickerskin hand, individuals with elevated levels of GH and IGF-1, with arelativelyhigh-fatpercentage ( sensitive, haveshorterbones,lessmuscleandareobese patients havereducedIGF-1andinsulin levels, areinsulin and bones( lipolysis, whilepossessingananaboliceffectonmuscle has acataboliceffectonadiposetissues,promoting weight, bodycompositionandenergymetabolism.GH GH as well as IGF-1 deficiency affects bodylength and growth andorgandevelopment( mediatorsofGH-regulatedlongitudinal of theprimary signaling anddepressedIGF-1production.isone largely due to suppression of GH-induced intracellular suppressed comparedtocontrolindividuals( ( and cognitivesimilaritiesthatwillbedescribedbelow and GHRKO mice share several physical, metabolic growth factor-1(IGF-1)activities.BothhumanLSpatients instrumental in helping to define GH and insulin-like ( agoinourlaboratory developed 21 years with extensiveworkGHR-knockout(GHRKO)mice work withtheIsraelicohortofLSpatients( to studythespectrumofGHactions.Laron’s seminal (GHD) ( or congenitaladult-onsetacquiredGHdeficiency 14 26 Review ). Thesemicearedwarfandpartiallyrecapitulatethe , ) andmicetransgenicforaGH-analogactingas Growth ofGHRKOmiceandLSpatientsissignificantly 15 , 5 16 , 6 , , 20 17 7 , , ). 8 21 ) havebeenandareofcriticalimportance , 22 ). Asexpected,GHRKOmiceandLS 25 ). Additionally, we,aswell 11 , 12 R Basu,YQianandothers ) ofLSpatientsalong 23 18 , 15 , 24 ). Ontheother 19 ) withseveral 13 ). Therefore, ) havebeen 3 , 4 , 4 , 11 9 , , 15 10 27 ) ) ,

insulin levels(aboutonethirdofcontrols)( low In contrast,EcuadorianLSindividualshavevery ( subunit ofPI3Kinmouseadiposeandmuscletissues GH are still not entirely clear as GH perturbs the regulatory activity ( molecule ( in theseanimals. concerning theregulationofglucoseandlipidmetabolism the GHRKO mice and have prompted multiple studies insulin sensitivityandobesityarehallmarkfeaturesof 36 and obeseyetinsulinsensitive( mice aswellEcuadorianLSpatientsareresistanttoGH fat mass and are insulin resistant. In contrast, GHRKO with acromegalyhaveincreasedleanmassanddecreased effects onmuscle( GH hascataboliceffectsonadiposetissueswhileanabolic Obesity anddiabetes lowered GH and IGF1 levels ( complication inLSpatientsand adultGHDpatientswitha with excessivenutritionalintake( 38 incidence of diabetes than their non-LS relatives ( obese, theyhaveenhancedinsulinsensitivityandlower are insulinsensitive.Infact,thoughtheseLSsubjects levels aresimilartocontrols,suggestingthatLSsubjects level remainslowintheLSsubjectsasbloodglucose glucose tolerancetestsorafterahighcaloriemeal,insulin have beenreportedintheIsraelicohortofpatients( ( similar trendofglucoseincreasingasafunctionage glucose levelscomparedtocontrolsandalsohavea Israeli LSpatientshavelowerfastingandpostprandial until theyaresimilartothoseofWTcontrols.Similarly, in olderGHRKOmice,glucoselevelsincreasegradually type (WT)controls( young GHRKOmicearesignificantlylowerthanwild- 29 are insulinsensitiveandhavelowlevels( the mechanism,GHRKOmiceandLSpatientsgenerally GH-induced insulinresistanceinhumans( in skeletalmusclearethoughttobethemechanismof ( Lessons from 44 51 20 , , , , ). With aging,diabetes and associatedcomplications , 39 30 37 Decades ago,GHwasshowntobeadiabetogenic Nonalcoholic fattyliverdisease (NAFLD)isafrequent Fasting andnon-fastingbloodglucoselevelsin 45 47 , , , , 40 31 ) and reduced pyruvate dehydrogenase activity 38 46 42 , , 42 , 41 ) while increased lipolysis and free fatty acids 32 , 39 GHR 43 ). Itinhibitsinsulinactionorhasanti-insulin ). TheobesityofLSpatientsisnotassociated , , ). However, theanti-insulinmechanismsof 33 40 -disrupted mice , 20 37 , 41 , 29 , 21 38 ). Interestingly, thecoexistenceof , ). Therefore,bGHmiceorpatients Downloaded fromBioscientifica.com at09/29/202110:18:07AM 31 , 39 , 32 , 54 40 , , 55 , 33 3 41 , 53 , , 29 56 , 34 ). 49 178 , , , 31 57 , 35 :5 50 , , , 58 32 , 48 36 51 ). Six-month , 37 ). Whatever ). However, 33 ). ). During 3 , , 34 R156 17 3 , , , 52 37 27 35 via freeaccess ). , , , European Journal of Endocrinology including immune cell infiltration, senescence and fibrosis ( brown adipose tissues are also increased in GHRKO mice implying thattheGHRKOmice areobesebuthealthy. The those inWTmicewhennormalizedtobodyweight( metabolic diseases( which isknowntobecorrelatedwithcardiovascular or body weight( controls ( the kidneys)are increased in malemice compared with Also, theretroperitonealadiposetissues(fatpadsnext to adipose tissuesweightismorethanthoseinWTmice. than normallittermates,theabsolutesubcutaneous Because theGHRKOmicehavemuchsmallerbodysize depot is significantly increased relative to controls. these dwarf animals. Forexample, the subcutaneous differences among different adipose tissuedepotsin mice ( Total adiposeweightissignificantlyincreasedinGHRKO Adipose tissueofGHRKOmice tissue, muscle,liverandpancreaticisletswillbediscussed. action oninsulin-sensitivetissues,includingadipose induced hepaticinflammationoroxidativestress( of IGF-1wasinsufficienttoprotectagainststeatosis- hyperinsulinemia andhyperglycemia,therestoration liver leadstoincreaseinlipiduptake, effect ofGHandIGF-1suggestedthatGHRablationinthe a liver-specificGHRablationmouselinetodistinguishthe of IGF-Iintheseconditions( animal models,suggestingpotentialclinicalapplications nonalcoholic steatohepatitis(NASH)andcirrhosisin fibrosis. IGF-Itreatmenthasbeenshowntoimprove and inducescellularsenescence,thereforeameliorating of NAFLD( have been associated with increased histologic severity and decreasingfibrosis( patients showedimprovingserumliverenzymelevels with 24-monthGHreplacementtherapyinadultGHD reflection ofthelipolyticpropertiesGH.Anotherstudy inflammation andballooningnecrosis,whichcouldbea GH replacementtherapydiddecreasesteatosis,fibrosis, Histological studiesofliverbiopsyspecimensshowedthat and alanineaminotransferase liver enzymesincludingserumaspartateaminotransferase improve hepaticlipidprofileandoxidativestress,aswell GH replacement therapy in GHD patients was found to 64 Review , In thefollowingsections, the effectsoflackGH GH affectsmultipleaspects ofadiposetissues 68 29 ). , 62 62 , , 60 63 63 29 ). IGF-Iinactivateshepaticstellatecells , ) butnotchangedwhennormalizedto 64 , 35 , 65 66 ). However, theepididymaldepot, ). Interestingly, therearesignificant , 59 67 ). Also,lowserumIGF-1levels ), issmallerorsimilarthan 57 ). Amechanisticstudyusing R Basu,YQianandothers γ -GTP concentrations. de novo lipogenesis, 61 ). 65 ) decreased musclemasssimilar tothatseeninGHRKOmice mass inGH-deficientpatients ( recombinant hGHtreatment isknowntoincreasemuscle protein synthesisintheskeletal muscle( IGF-1 excesshaverecentlybeen foundtohavedecreased these dwarfmice.Infact,bGHmicewithlong-termGH/ suggesting betterendurance,balanceandstrength in bGH orGHAmiceat6-month-old(unpublisheddata), performed betterontheRotarodtestcomparedwithWT, due to the age difference. Interestingly, GHRKO mice the differencebetweenthesetwostudiesinprobably plantaris andgastrocnemiuswerenotchanged( old GHRKOmicesuggestedthatthefibertypesinsoleus, However, the resultsfromanotherstudyusing4-month- or differentiationofmyoblastprecursorcells( of myoblaststomyotubes,butnottheproliferation GH increases myofiber size by stimulating the fusion In hindlimbmusclecellsfrom4-week-oldWTmice, lesser extent( while theotheradiposetissuedepotsareincreasedtoa preferentially increasedsubcutaneousadiposetissues, in adiposetissues.LSpatientsalsohaveimpressivelyand GH actionsignificantlyaffectstheextracellularmatrix while decreased in GHA or GHRKO mice ( is correlatedwithobesity. ItisincreasedinbGHmice senescent cellscomparedwithWTcontrols( ( there arelesssenescentcellsinmostadiposedepots arrest andresistanttoapoptosis( state. Senescenceisastateofirreversiblecellgrowth of GHactionappearstogenerateananti-inflammatory tissue havereducedIL-6levels( ( macrophages in the GHRKO mice relative to controls mediated inflammation inbonemarrow andepididymal ( old GHRKOmiceswitchedfromtypeItoII( fiber typesinsoleusandtibialisanterioroftwo-month- generate energy promptly through glycolysis. The muscle while type II can through oxidative phosphorylation, and typeII.Type Ifibersproduceendurancebutlowforce GHR ( in the cells from GHRKO mice due to absence of observed contrast, the increased fusion induced by GHwasnot numbers of muscle fibers ( size but conserved have decreasedmusclemass( GH has anabolic effects on muscle. Thus, GHRKO mice Muscle ofGHRKOmice Lessons from 72 69 65 ). However, dwarfGHAmicehavesimilarlevelsof ). Also,theirepididymalandperinephricadipose ). Forexample,thereislessNLRP3inflammasome- 77 ). Therearetwosubtypesofmusclefibers:typeI GHR 75 -disrupted mice ). Downloaded fromBioscientifica.com at09/29/202110:18:07AM 13 79 70 , ), whileLSpatientshave 31 71 ), suggestingthatlack 178 , ). InGHRKOmice, 63 www.eje-online.org :5 ) duetosmaller 78 65 ). Clinically, 73 , 76 74 ). Fibrosis 76 ). Thus, 77 ); thus, R157 , ). In 77 77 via freeaccess ). ). European Journal of Endocrinology www.eje-online.org tests. Therefore,theyareglucose intolerant( the highlevelofglucosefound intheglucosetolerance amounts ofinsulininashort periodoftimetohandle ( These features suggest lower insulin production capability cells mass,aswelldecreasedinsulincontent( mice display smaller islets, smaller cell size, smaller beta Consistent withlowercirculating insulinlevels,GHRKO Pancreatic isletsofGHRKO mice their extendedlongevity( matched littermatecontrols,whichmaycontribute to of steatosisandinflammationinlivercomparedwithage- (~50% ofoveralllifespan)GHRKOmicehavelowerlevels than WT controls ( at allagestested,GHRKOmicearemoreinsulinsensitive gluconeogenesis andlipidoxidationintheliver. However, in olderGHRKOmicefurtherindicatesashifttoward and cAMP response element-binding protein (p-CREB) ( cascades werealsoreducedcomparedwithyoungcontrols mice astheyage,theactivationofinsulinsignaling Consistent withincreasedbloodglucoselevelsinGHRKO not alteredinGHRKOmicecomparedwithWTcontrols. domain-containing-transforming proteinC1(SHC)were the MAPKsignalingpathwayandlevelsofSrc homology2 insulin signalingcascadewasnotaffected.Inaddition, insulin sensitivity ( increased comparedwithWTcontrolssuggesting IRwereboth receptor (IR)andtyrosine-phosphorylated In theliversofyoungGHRKOmice,levelsinsulin Liver ofGHRKOmice increased insulinsensitivityinmuscles. skeletal muscleinGHRKOmice( gluconeogenesis and glycogenolysis, were lower in the Foxo3, transcription factors involved in the regulation of induced intracellular signaling. Also, levels of Foxo1 and old GHRKOmice ( GLUT4 levelswereincreasedinthemuscleof14-month- p-AKTand WT mice,levelsofp85/IRS-1phosphorylation, sensitive thanthoseincontrolmice( that endocrineIGF-1isimportantformusclesize( IGF-1 levelsinthemusclesofGHRKOmice,suggesting circulating IGF-1, there is no significant changes in protein treatment ( ( 15 50 17 Review ). Infact,GHRKOmiceare not abletoproducelarge ofAMPK ). Inaddition, increased phosphorylation , The musclesofGHRKOmicearemoreinsulin 33 , 65 , 80 80 ). Thoughthereisasignificantdecreasein ), whichcanberescuedpartiallybyIGF-1 27 17 , 27 , 34 27 ) suggesting increased insulin , 84 , 83 34 ). ). However, the downstream , 83 R Basu,YQianandothers ). Finally, two-year-old 82 27 ) againsuggesting ). Comparedwith 50 ). Also,GH 29 81 , ). 50 ). skeletal muscleofGHRKOmice, Foxo1andFoxo3protein insulin sensitivity( deficiency usenon-overlapping mechanismsregulating However, otherfindingssuggestthat CRandGHR responsible for this ‘lack of effect’ may be overlapping. ( lifespan orimprovedinsulinsensitivityofGHRKOmice However, CR doesnotfurtherincreasetheextended GHRKO micehaveincreasedlifespan(discussedbelow). mice andWThavesignificantlyincreasedadipose weeksof age, both GHRKO weeks starting at 10 for 12 and type2diabetes( Generally, high-fat(HF)dietsleadtodiet-inducedobesity High-fat diet longevity. been fedtothesemicestudyinsulinsensitivityand but healthyGHRKOmice,multipletypesofdietshave Due to the unique profile of adipose tissuein theobese The influenceofdietsonGHRKOmice pancreatic whether long-termGHstimulationwoulddamagethe scenario, theinsulinlevelwillbeincreased;however, secretion ( promotes the proliferation of pancreatic and extendedlifespanfromwormstomammals( an importantroleintheimprovedinsulinsensitivity to decreased circulating insulin and IGF-1, which plays mechanisms arenotcompletelyunderstood.CRleads glucose homeostasis and longevity though its specific Caloric restriction(CR)hasbeenwidelyusedtostudy Caloric restriction homeostasis andprotecttheanimalfromdiabetes. action orGH’s diabetogeniceffectmaymaintainglucose on HF diet ( GHA micearealsoresistanttodiet-inducedtype2diabetes altered whileWTmicebecameinsulinresistant.Similarly, homeostasis inthesedwarfmicewasnotsignificantly of different fat depot increases ( 17 weeks startingat14 weeks ofageshowedsimilartrends Another studyofmaleGHRKOmiceonaHFdietfor increase intheir epididymal andretroperitoneal depots. in theirsubcutaneousdepotwhileWTmicehaveagreater ( tissue weightscomparedwithmiceinlow-fatdietgroup Lessons from 19 3 5). Interestingly, GHRKOmiceshowaspecificincrease , 29 , 94 , 85 99 β cellsandleadtodiabetesisnotknown. GHR ) implying that in an acuteGHstimulation 90 ) suggestingthatthemolecularmechanism(s) , -disrupted mice 91 17 ), implying that the absence of GH , 86 82 , Downloaded fromBioscientifica.com at09/29/202110:18:07AM , 87 95 , ). Asdiscussedearlier, inthe 88 , 89 83 ). WhenonHFdiets ). However, glucose 178 β :5 cellsand insulin 92 R158 , 93 via freeaccess ). European Journal of Endocrinology mouse modelsofmodified GH action,havebeenvaluable The GHRKOmouse,alongwith theGHA,bGHandother Cancer studieswiththeGHRKO mouse newfound rolesoftheGH–GHRaxisincancer. antagonist pegvisomantandsummarizetheknown with the GHRKO, GHA and bGH mice, studies using GHR data in vivo ( nerve 130 ( ( also been reported in cancers of breast ( dysregulated or higher than normal GHR expression have to breastcancer( highest pathwayassociatedwithenhancedsusceptibility GH-induced intracellularsignalingnetworktobethethird genome wideassociationstudy(GWAS) hadreportedthe in recentyears( 113 cancer was found, based on available data ( primary no associationofGHtreatmentanddevelopment GH-treated patientswithchildhood-oradult-onsetGHD, of theanticancereffectsattenuatingGHaction.In 108 acromegaly ( specific cancers(colorectal,thyroid)inpatientswith epidemiological studiesreportinganincreasedriskfor LS individuals( progression intheGHRKOmouse( The reportsofremarkablylowcancerincidenceand Cancer lifespan throughGHRdeficiencyandCR. involved inimprovedinsulinsensitivityandextended of PPAR with WT mice; however, CR has no effect on the level PPAR improve insulinsensitivity( and decreasescirculating fatty acidsandtriglyceridesto participates intheregulationoffattyacid(FA) oxidation transcription factorhighlyexpressedintheliverwhereit peroxisome proliferator-activatedreceptors protein levels in either GHRKO or WT mice ( however, CRdidnotsignificantlyaffectFoxo1orFoxo3 levels were reduced (see ‘Muscleof GHRKO mice’ section); 126 121 Review , ). Severalexcellentreviewshavediscussedthetopic , xenograft studies. We havesummarizedthecollective ), pancreas ( , α 131 122 109 intheliverofGHRKOmiceiselevatedcompared 138 Table 1 α , ( ), colon( , 132 ), meninges( 95 110 ) indicating that differentmechanismsare 100 ), liver( . Below, wefocusontherecentworkdone , 24 , 14 111 127 119 123 101 , , 114 ) collectivelyofferanindication ), endometrium ( ). IncreasedlocalGHlevelsanda ), pelvis( 102 133 , 139 102 , , , 115 134 ) andglia( 103 , 96 , 103 , 124 ) coupledwithhuman 116 ). Theproteinlevelsof 135 R Basu,YQianandothers , ), stomach( , 104 , 117 136 97 140 , 128 , ) aswellin ), kidney( 105 118 120 ) including α ), skin ( (PPAR , ). Arecent ), prostate 125 106 82 ). Also, ), lung , α 137 ) isa 129 112 107 in ), , , , adult bGHmicelivershaveshownenlargementof adult-onset isolated GHDmice ( ( by thecarcinogen, dimethylbenz[a]anthracene (DMBA) tumorformationinduced significantly lowermammary Pollak andcoworkershadshowntheGHAmicetohave compared toeightintenTag/WT mice( eight Tag/GHRKO animalsdevelopingaprostateneoplasm offspring ofthesamemousemodelfoundonlyonein in Tag/WT counterparts( GHRKO animalsbeingtentimessmallerthanthesame to teninTag/WT mice( found todeveloponlythreetumorspermousecompared SV40 largeT-antigen ( and prostateneoplasmsinmalesduetotheexpression of neoplasmsinfemales spontaneously developmammary GHRKO mice( cancer ( for studyingtheimplicationsofGH–GHRinteractionin and a44%decreaseintumor weightcomparedto pegvisomant, hada39% decrease intumor-volume cancer cellsinathymicnude mice,whentreatedwith cancers ( growth andprogressionof breast( The GHRantagonistwasfoundtomarkedlyinhibitthe or pegvisomant(pegylatedB2036)inhumancancers. highlighted thepotentialof GHR antagonist, B2036, Several Cancer studiesusingGHRantagonistpegvisomant be determined. compares intheadult-onsetGHRKOmodelsremains to life GHexposurefollowedbytheabsenceofaction repair genesincluding contributor inoncogenesisthroughdysregulationofDNA mice andLewisdwarfratswasfoundtobeapotential ( animals, respectively, comparedtotheirWTlittermates tumor proliferationintheliverofmaleandfemalebGH (DEN) induced2.6-foldand4-foldhigherratesofhepatic bGH mice( higher hepatocellularproliferationandinflammationin this fact,livercarcinogenesis was precededbyamarkedly and increasedlevelsinbGHmice( confirmed bydiminishedEGFRlevelsinGHRKOmice hepatic EGFR expression and downstream signaling, AKT andmTOR( c-Jun andupregulatedactivationstatesofSTAT3, c-SRC, hepatocytes andincreasedlevelsofPCNA,Cyclin-D1 Lessons from 145 134 ), which was also observed in identical studies with ), which was also observed ). Interestingly, peripubertalexposuretoGHinSnell 24 in vitro 152 , 133 141 GHR ). XenograftsofCOLO-205 humancolon ), whilethecarcinogen diethylnitrosamine 13 ). Swansonandcolleagueshadcrossedthe -disrupted mice and ) withtheC3( 147 , Gadd45a 143 in vivo 148 Downloaded fromBioscientifica.com at09/29/202110:18:07AM 143 143 ). TheTag/GHRKO micewere ). Additionally, GHincreases ). Similarstudieswithmale ) withtumorsizesinTag/ xenograftstudieshave and 1 )/Tag mice( 146 149 Bbc3 178 151 ). Recently young ). Consistentwith www.eje-online.org :5 ( 150 ) andprostate 144 142 ). Howearly ). Likewise, ), which R159 via freeaccess European Journal of Endocrinology www.eje-online.org and GHR-expressing humanendometrial cancer cell vitro of GH-GHR-expressinghuman meningiomacultures untreated controls( Stomach cancer Lung cancer Glioma Neuroblastoma Meningioma Endometrial cancer Pancreatic cancer Melanoma Colon cancer Prostate cancer Liver cancer Breast cancer Cancer type Table 1 Review ( 139 List ofstudiesonGHRexpressionandfunctioninhumancancers. ) and

in vivo 153 ( Patient tissue In vitro In vitro In vitro In vivo In vitro In vivo In vitro In vitro In vitro In vivo In vitro In vitro In vitro In vivo In vivo In vivo In vitro In vitro In vivo In vivo In vitro In vitro In vitro In vitro In vivo In vivo In vitro In vivo In vivo In vivo In vitro In vitro In vitro In vitro Type ofstudy ). B2036alsoabrogatedgrowth samples 154 ). AsimilarstudywithGH , , , In vivo In vivo In vivo R Basu,YQianandothers Autocrine GHincreasedtumorigenicityofxenograftsinnude GH increasesradiotherapyresistance Autocrine GHincreasedviability, proliferation,survival,and siRNA-mediated GHRknockdowninhibitproliferation, High melanomaGHRexpressionandGHproductioninlungs GHRKD decreasesmultidrugtransporterexpressions,increases siRNA mediatedGHRknockdowninhibitsproliferation, High levelofGHRexpressioninhumanmelanoma GH suppressedtumorp53andapoptosispromotedEMT siRNA-mediated targetingofGHRdecreasedxenograftgrowth, Pegvisomant suppressedxenograftgrowthinnudemice GH de-sensitizestoradiotherapybyblockingDNAdamage Increased proliferation,migration,invasion,clonogenicity, MMP Xenograft growthattenuatedinGH-deficient Male C3(1)/Tag-GHRKO micehad8Xfewer andsmallerprostate GH-stimulated IGFandestradiol-driventumorproliferation Autocrine GH-GHR-drivenproliferationofprostatetumors Autocrine GH-stimulatedcancerstemcellpropertiesby Autocrine GHincreasedoncogenicityandxenograftgrowthin DEN-induced hepatomaratesweresignificantlylowerin bGH micehadincreasednumberofliverneoplasmsthanWT Autocrine GH-stimulatedmigration,invasion,tumorigenesisand Female C3(1)/Tag-GHRKO micehad3 Reduced DMBA-inducedtumorigenesisinGHAandGHDmice Pegvisomant attenuatedxenograftgrowthinnudemice GH increasesresistancetomitomycin-Candradiotherapy Pegvisomant increaseddoxorubicinefficacy oncells Autocrine GHincreaseshTERT stabilitythrough Autocrine GHandGHRexpressiondrivesproliferation, Type ofeffect Significantly higherGHRexpressioninmajorityofgastric P495T SNPinGHRmarkedlyenhancesGHsignaling GHR iscytoplasmic,notnuclear High levelofexpressionGHandGHRincells; High levelofexpressionGHandGHRincells Pegvisomant significantlyreducedvolume,weightandgrowth GH actiononGHR-expressingmeningiomasincreasedcell mice; B2036expressionreversedthesame clonogenicity inculture;B2036expressionreversedit migration, invasion,clonogenicity, EMT drives metastasesofmousemelanomainDJ1-KOmice drug retention,lowersEC migration, invasion,EMT; GHtreatmenthasreverseeffect and oncogenesis;tumorgrowthreducedinGH-deficientmice volume, andsizeinnudemice expression: Pegvisomanttreatmentreversedtheeffects neoplasms thanC3(1)/Tag-wildtype mice STAT3-mediated claudin-1suppression nude mice;hGH-G120Rexpressionreversedtheeffects and significantlyhigherinbothsexesofbGHmice metastasis incultureandnudemice mammary neoplasmsthanC3(1)/Tag-wildtype mice apoptosis migration, invasion,angiogenesis,reducesoxidativestressand adenocarcinoma thansurroundinggastricmucosa of primarytumorxenograftsinnudemice growth; B2036inhibitedthesame in in demonstrated thatinduced expressionofB2036blocked treatment withB2036 ( of cellproliferationandclonogenic capacityfollowing lines, AN3andRL95-2,reported markedsuppression Lessons from 50 GHR × fewerand10 -disrupted mice lit/lit α Downloaded fromBioscientifica.com at09/29/202110:18:07AM CP1, mice × 128 smaller α CP2

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122 320 146 319 158 326 132 ) , ) ) ) ) , 324 318 R160 ) ) via freeaccess European Journal of Endocrinology 7. 6. 5. 4. 3. 2. 1. and relapseoftumors: affecting incidence,proliferation,responsetotreatment been studiedandreportedbydifferentgroupsworldwide GH-dependent cancer-supportingmechanismsthathave 118 effects aswellanumberofIGF-independent( as wellIGF-mediatedmitogenicandproliferative The oncogenic processes regulated by GH include direct enhanced bindingtonuclearGHRs( in tumorcellsthanendocrineGH( found tobeapotentinducerofoncogenicsignaling 157 paracrine GHindifferentcancertypes( colleagues haveunderlinedtheroleofautocrine/ A significantbodyofwork,especiallybyLobieand Mechanisms ofGH–GHRactionincancer the studysponsors( on atimelybasisaswellbusinessreasons’statedby study wasterminated‘duetoinabilityrecruitpatients colorectal, prostate,sarcoma) ( antibody directed against solid tumors (breast, lung, and figitumumab,anIGF-1R-specificmonoclonal Germany, foracombinationtherapyofpegvisomant in 2009byPfizer, acrossUS,Canada,Finland and ( anticancer therapeutic agents in human cancer patients the efficacyofa combinationofGHRantagonistand toevaluatedesigned clinicaltrialswouldbenecessary 7404 humanhepatomacells STAT3-mediated oncogenicityofautocrineGHinBel- 155 Review receptor levels( Driving theoncogenicHGF-cMET loopandEGF dependent manner( transition (EMT)(reviewedin ( Direct upregulationofepithelial-mesenchymal and transcriptase (hTERT) mRNA via induction of Increased stabilityofhumantelomerasereverse Enhanced stemnessduetoGHaction( reducing apoptosis( ERK1/2-mediated resistancetooxidativestressinturn and adverseprognosis( production, whichinitselfincreasecancerincidence Induction ofhepaticaswellperipheralIGF-1 141 (p44/42 andp38)PI3K-AKT-mTOR pathways( Activation ofJAK2,STATs 1,3 and 5,SRC,MAPK , , ). One such large-scale clinical trial was launched 141 158 , α 162 CP2 ( ) oncoprotectivepathways.Belowarelistedthe , 159 , 163 166 , 160 ). ). 130 ). Tumor-secreted autocrineGHwas 156 , 99 168 149 ). , 98 127 , ). 169 ). in vitro , 164 156 ). R Basu,YQianandothers 167 ). ). Unfortunately, the ( )) possiblybyap53- 135 157 135 ). Appropriately ) partlydueto 136 128 , , , 161 165 136 , ). , α 162 130 114 138 CP1 ). , , , that thedrugresistanceinMCF7cellswaspossiblydue by treatmentwithpegvisomant( resistance inMCF7cellsculturethatwasameliorated had reportedendocrineGH-stimulateddoxorubicin cancers havebeenscarce ( chemotherapy andradiotherapyrefractorinessinhuman ( to thetargeted-andimmune-therapyapproaches( knocking downGHRonhuman melanomacellspotently like doxorubicin, paclitaxel, cisplatin or vemurafenib, dose ( ABC familyleadingtoincreased drugefficacyatalower direct downregulationofspecificdrugeffluxpumps the attenuated GHRinhumanmelanomacellsleading to resistance inhumanmelanoma( we reportedaGH–GHR-dependentmechanism of drug evasion inseveraltypesofcancers( mechanism ofphenotypeswitchandchemotherapy of EMTmarkers( during melanogenesis( expression ofarepertoiredrugeffluxpumps( in cancerincludesbutarenotlimitedto(i)abundant ( tumor cells against radiation in a dose-dependent manner where recombinanthumanGHtreatmentprotectedthe of GH was also seen in HCT-8 colorectal cancer cells against DNAdamage( mitomycin-C (MMC)-inducedapoptosisbyprotecting breast cancercells(MCF7,T47D,andMDA-MB-231)to identified autocrineGHcausingincreasedresistanceof ( which wassignificantlyabrogatedusingpegvisomant apoptosis inestrogenreceptor-negativebreastcancercells, protective effect of GHininhibiting doxorubicin-induced treatment ( also increasedthenumberofviablecellsindoxorubicin to GH-induced IGF-1 expressionas IGF-1 independently 179 172 186 Despite the discovery ofnewcancertherapeutics( Despite thediscovery Role ofGH–GHRincancertherapyresistance 9. 8. Lessons from 180 183 182 A differentiallyregulatedautophagymechanism( 131 transporter expressionandEMTontumors( efflux viaupregulationof ATP-binding cassette(ABC)- Driving drugresistance, through increasingdrug ) including the development of drugresistance , , ). Data depicting an association of GH action and ). Mechanismsofchemotherapeuticresistance ). In an 173 187 131 , 167 , ), (ii)sequestrationofdrugsinmelanosomes ). In response totreatmentwithanticancer drugs 174 ). GHR 181 , 175 in vitro ). Zatelli’s groupalsodemonstrateda -disrupted mice 159 , 176 , study, Lobie and colleagues had 160 190 , 177 188 Downloaded fromBioscientifica.com at09/29/202110:18:07AM ). Theidenticalprotectiveeffect , ), thereareexistinglimitations 191 , 141 189 , ). Zatelliandcoworkers 192 181 ) and(iii)upregulation 130 , ). Thegroupinferred 178 130 193 , www.eje-online.org :5 , 131 , 131 194 ), wherewe ). Recently, ), acritical 184 170 R161 , , 99 185 178 171 130 via freeaccess ). , , , ,

European Journal of Endocrinology patients Acromegaly Human subjects Subjects Table 2 Ames GHA Adult-onset-GHRKO cohort Krk GHRHKO lit/lit Snell GHRKO bGH Mouse lines pygmies African cohort Swiss cohort Sindh cohort Itabaianinha www.eje-online.org drug resistance in several types of cancers overexpressing define the mechanism(s)underlyingthedevelopment of ( recent reviewofGHandEMTincancernormaltissues in melanoma( also reportedthatGHupregulatestheprocessofEMT values forvemurafenibandupregulatingEMT( resistance inhumanmelanomacells,increasingtheEC (3-week) treatmentwithGHaloneincreasedthedrug GH alonehadareverseeffect( of drugsduetoreduced drug efflux( significantly, therebyincreasingtheefficacyofsamedoses retention increased markedly and cell viabilityreduced GHR downregulationinmelanoma,intracellulardrug of thepresenceGH.AsaresultsiRNA-mediated ABCC2, ABCG1 and ABCG2 transporters irrespective blocked theincreaseofexpressionABCB1,ABCC1, 167 Laron Syndrome–Israelicohort Offspring ofLeidenLongevityStudy Laron Syndrome–Ecuadoriancohort Ashkenazi JewsCentenariancohort, Review French Long-livedStudy Cardiovascular HealthStudy, Old OrderAmish(AFCS), ). Thecombinationoftheaboveresultsmayhelpto List ofstudiesshowingchangesinlifespanduetodirectGH-GHRaction. 130 , 131 ) andreferthereaderstoour

R Basu,YQianandothers 131 131 ). Infact,achronic GH resistance GH deficiency GH excess GH-GHR action Type ofchangein GH deficiency GH deficiency GH resistance GH deficiency GH resistance Differential Differential GH deficiency GH deficiency GH deficiency GH deficiency GH deficiency GH deficiency GH resistance GH excess 6-week age starting at ). Treatment with 131 ). We Mutated non-functionalGHR Lower GHsecretion,tighter Hypersecreting pituitary action Causes ofchangeinGH/GHR PROP1 mutant;lacksGH,PRL, Transgenic mutantGHacting Tamoxifen-inducible global PROP1 mutation;lacksGH, Mutated non-functionalGHR GHRH mutation GHRHR mutation PIT1 mutation Mutated non-functionalGHR Transgenic expressionof Exon-3-deleted GHRisoform SNPs inGHR,IGF1locus GH1 mutation GHRHR mutation GHRHR mutation 50 feedback inhibition adenoma TSH as aGHRantagonist age GHRKO startingat6-weeks PRL, TSH,FSH,LH bovine GH

reason.com/archives/2004/08/18/methuselah-mouse a title awarded by the Methuselah Foundation ( Mouse Prize as the world’s mouse, longest-lived laboratory In fact,theGHRKOmousecurrentlyholdsMethuselah GHRKO micelive21%(females)to40%(males)longer Results ofseveralstudiesaresummarizedin results areinconsistentinGHDhumans( have consistently shown an extended lifespan, while the ( position inthestudyofaging,healthspanandlongevity In miceandmen,thesomatotropicaxisoccupyacentral Aging andlongevity therapy resistance. ofGH-associated GHR andtheearlierobservations Lessons from 195 , 196 , 197 GHR , 198 -disrupted mice , 199 Shorter/normal Longer Shorter (untreated) Effect onlifespan Longer Normal Longer (female) Longer/normal Longer/normal Longer Longer Longer Longer Shorter Longer inmales; Shorter Shorter -Unknown- Shorter/normal normal inwomen Downloaded fromBioscientifica.com at09/29/202110:18:07AM , 200 , 201 ). GHD mouse models 178 :5 200 ( ( ( References ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 3 327 102 200 28 249 200 12 351 200 200 15 26 228 335 200 200 200 328 347 343 342 338 332 , , , , 4 , , , 200 200 , ) ) , , , ) 200 211 , , , , , , 202 ) ) , ) , ) 9 108 350 348 345 341 336 334 333 203 329 344 339 al 2 Table , 200 ) ) , , R162 http:// , , ) , , 201 249 ) , ) ) , , ) , 203 200 349 346 337 331 330 340 , , , via freeaccess ) ) , , , ) ). ). ). ) . European Journal of Endocrinology 1. mouse intheworldincludefollowing– that lead to the GHRKO mice being the longest-lived maximum butnotmeanlifespan( mice asIGF-1deficiencyaloneisknowntoextend an important factor for increased lifespan of the GHRKO models ( responsible forlifespanextensioninhumansandmouse Reduction ofGH/IGF1actionhasbeenfoundtobe Factors forextendedlifespanofGHRKOmice diseases alongthecourseofstudy( factor shifting toward cancer rather thancardiovascular mortality rate,especiallyinfemales,withthemajorrisk orradiotherapy,surgery foundasignificantlyhigher 1980 and1999inFinland,87%ofwhomunderwent follow-up of 333 acromegaly patients diagnosed between often normalize lifespan ( pegvisomant treatment,tonormalizeserumIGF-1levels, like trans-sphenoidalsurgery, somatostatinanalogsor acromegaly patients( studies havereportedahigherthannormalmortalityin their wild-type counterparts ( other hand,giantbGHmicelivesignificantlyshorterthan and insulinlevelswithageinGHAmice( This may be ascribed to an increase in adiposity, leptin to thedwarfGHAmice,whichhaveanormallifespan( increased lifespanindwarfGHRKOmicedoesnotextend expression ( sexually dimorphic nature of GH-regulated hepatic genes modulation ofGHactioninliveralsohighlightsthe GHR-JAK2-STAT5 activation( of GHRexpressionandSOCS-mediateddownregulation estrogen-mediated antagonismofGHactionatthelevel are notcompletelyunderstood,butcouldbearesultof longer than the WT male mice. The underlying reasons similar lifespan,theWTfemalemicelivesignificantly mice. While both male and female GHRKO mice have from gender-specificdifferencesinthewild-typeC57BL/6J gender-specific differences in GHRKO mouse models stem longer thantheirWTcounterparts( background, they lived 38% (females) to 55% (males) mice weregeneratedandmaintainedinamixedgenetic C57BL/6J background ( than theirwild-typecounterparts,whenmaintainedina Review free-radical scavenging( systems ( activity ofglutaredoxinand thioredoxin detoxification redox homeostasis due to upregulated expression and increased stressresistance resulting fromsuperior 196 208 , 214 212 , , 209 ). Low serum IGF-1 levels is undoubtedly 215 , 210 108 , 216 204 ). Importantly, of theobservation ), although several interventions ), althoughseveralinterventions 200 , ). Interestingly, when GHRKO 218 217 205 ). In this regard, a 20-year 211 ), ) ratherthanchangesin R Basu,YQianandothers , 213 206 ). In humans, isolated 102 15 ). Additionalfactors , ). 207 ). These observed ). Theseobserved ). Theestrogen 15 ). Onthe 28 ). 4. 9. 8. 7. 6. 5. 3. 2. to exon-4oftheGHRprecursor resultsind3-GHRsplice and lifespanextension( (d3-GHR) providesanewperspective ofGHRisoforms with enrichmentofanexon-3-deleted isoformoftheGHR A recentreportofexceptional longevityinmalesassociated Lifespan ind3-GHRvariants ( mice holdsinGH-resistanthumansremainsunknown inGHRKO dysfunction andextendedlongevityobserved answer tothequestionwhetherlinkbetweenGHR GHR deficiencyinhumans( prominent factorsunderlyinglifespanextensiondue to LS patients( from cancerwasalsoconsistentintheIsraelicohortof but not cancer or diabetes ( and deathduetoaccidents,convulsionoralcohol-related Ecuadorian LS patients were high childhood mortality, relatives ( delayed aging, compared to their normal GH-responsive long butnotexceptionallifespan,yetseemtoundergo TheEcuadorianLSpatientshavea relevant observations. which canbeacriticaldeterminantinsubsequent these LSpatientsreceivedrecombinantIGF-1treatment, in lateryears( a normallifespanwithsomeinstancesofdiabetesmellitus In humans,theIsraelicohortofLSpatientsappeartohave Lifespan inhumanGHRdeficiency Lessons from 198 suppressed hypothalamicinflammation( improved insulinsensitivity( resistance to diabetogenic effects of aHFdiet ( regeneration ( stemcellpoolandimpairedtissue embryonic-like small and insulinwithconcomitantdepletionofvery lead to increased sensitivity to circulating GH, IGF1 age-related changes inDNAmethylationpatterns muscle andkidney( heart andincreasedeNOSPGC1 including higherlevelsofAMPK,SIRT1andSIRT3in increased markersofmitochondrialbiogenesis burden inWAT ( WAT lipiddistributionandreducedsenescentcell adipokineprofile,invertedliver- an anti-inflammatory end-goal ofanti-agingdrugs( resistance toneoplasticincidenceandgrowth( 221 reduced activityofTORC1kinasecomplex( , 201 ), ). 12 ). Primary causesofshortenedlifespaninthe ). Primary GHR 99 ) and,therefore,displayoneofthemost 3 -disrupted mice ). Itisimportanttonotethatmostof 225 62 , 226 , 224 68 228 Downloaded fromBioscientifica.com at09/29/202110:18:07AM ), , ), 70 ). In-framesplicingofexon-2 12 227 , 72 ). This marked protection 15 223 ). Fornow, aconclusive ), ). ), 178 α www.eje-online.org :5 levelsinskeletal 222 219 14 24 ) –an R163 ), and , , 220 97 via freeaccess ), , European Journal of Endocrinology www.eje-online.org 1. below: enriched setofqueriesrelatedtoaging.Somearelisted studiesinGHDmousemodels presentan Contemporary Future directions oflifespanstudiesonGHRKOmice GH/IGF axisindetermininglifespan. opportunity ofdissectingthenatureassociation its sexually dimorphic phenotypes provide an additional in acromegalypatients( to beadeterminantinresponsepegvisomanttreatment isoform. Interestingly, thed3-GHRisoformwasnotfound the only consistent difference due to this particular GHR BMIs ind3-GHRpolymorphicacromegalypatientsas from Korea( in the d3-GHR homozygous patients ( homozygous d3-GHRpolymorphismreportedalowerBMI 2010 with76acromegalypatientsincludingsevena d3-GHR inacromegalypatients.Aretrospectivestudy Multiple studieshavereportedtheeffectsofhomozygous in female offspring of Ashkenazi centenarians ( higher thannormalIGF-1levels,yetshorterstature variations of d3-GHR are highlighted by normal lifespan, GHR activity( signaling intermediates,canalsoallowforanextended polymorphisms, which increasethetone of GH-induced d3-GHR givingrisetoaGHBPanalog.Additionally, SOCS2 with a22-aminoaciddeletedextracellulardomainofthe a modifiedkineticsofinteractiontheGHmolecule of itlikeTIMP3( of theGHRhomodimergeneratingGHBPorregulators action incleavingtheGH-boundextracellulardomain a reducedactivityofmetalloproteaseTACE/ADAM17 GH–GHR signaling( a significantlyincreasedlifespanindicatingaugmented male offspringofcentenarianswererelativelytalland,had GH-, GHR-andGH-bindingprotein(GHBP).Thed3-GHR IGF-1and IGFBP1levelsyetsurprisinglyreducedof full-length GHR.Individualswithd3-GHRhavelowserum variant, with22aminoacidslessattheN-terminalthan

Review lived GHRKOmice. of proteostasisandareworth inquiringintothelong- transcription factorslike 240 ( synthesis withsex-andtissue-specificdifferences proteostasis with reduced protein aswell as DNA GH-deficient mousemodelshaveshownimproved 237 ) and , 238 ). Mostrecentagingresearch inyeast( 234 231 Caenorhabditis elegans ) andTurkey ( 229 ). Ontheotherhand,gender-specific 228 , 230 ). Itisworthinquiringwhether 236 ) arecausallinksorifthereis Gcn4 ). Thed3-GHRisoformand 235 R Basu,YQianandothers or ) havereportedhigher Atf4 ( 233 inmaintanance 241 ). Later studies ) implicate 232 239 ). ,

interventions inslowingaginghumans.Basedon interventions in agingstudiesdiscussedprospectsandfeasibilityof In 2013inErice,Italy, aworkshopwithleadingexperts 3. 2. remains unknown. inGH/IGFaxistowardincreasinglifespan,intervention what would bethelimiting adult age of meaningful sexspecificity,mechanisms oftheobserved aswell same extrapolates to humans, defining the underlying with congenitalGHresistance( inexperimentalmodels andhumansbenefits observed regulation oftheGH/IGF-1axismaytranslatehealth longevity andseveralhealthytraits.Thus,temporal of age)canresultinfemaleswithincreasedmaximal knocking outGHRexpressioninadultmice(at6 weeks serious adverseevents( for its‘reassuring’safetyprofileswithfewlong-term pegvisomant, useinhumanswasparticularlymentioned treating age-related pathologies. The GHR antagonist, towardextendinglongevityor adult lifeintervention and targetingtheGH/IGFaxiswasvotedastop toextendmouselifespan’ consistent geneticintervention somatotrophic axisisperhapsthemostvalidatedand approaches, ‘reducingtheactivityofGH/IGF-I and ( of sirtuinsorAMPK,( ( inhibition of the mTOR-S6Kpathwayor inflammation, pharmacological inhibition of theGH/IGFaxis,( as themostpromisingpro-longevitystrategies:( the panelofexpertslistedfollowingsixapproaches validated evidencesofsafetyandefficacyknowndrugs, Lessons from 3

) chronictreatmentwithmetformin,( cohorts ofLSpatientscanbevaluable. in GHRKO mice as well in Israeli and Ecuadorian systematic interrogationoftheepigeneticlandscape ( patterns inAmesmicecomparedtotheirWTlittermates described epigeneticsignaturesinDNAmethylation Extensive workbyBrown-Borgandcolleagueshave in onlyfemaleAmesmice( and GH combined treatment reduced maximal lifespan effect onlifespan( mice ( lifespan andcellularstressresistanceinAmesdwarf weeksage)reduced exposure toGH(startingat2 phaseofearly recently reportedthatashort(6 weeks) conditions ofGHdeficitsandaging( Bartke and colleagues have intensively studied various 247 Meanwhile, wehaverecentlyreportedthat 6 ) intermittentorprolongedfasting( , 248 243 GHR ). Thisindicatesthatatissue-andsex-specific ). A parallel thyroxine treatment had no -disrupted mice 243 92 5 Downloaded fromBioscientifica.com at09/29/202110:18:07AM ) useofepigeneticmodulators ). , 244 246 , 245 ). ), whereasthyroxine 249 178 :5 ). Whetherthe 198 4 92 ) activation , ). Ofthese 242 R164 ) and via freeaccess 2 1 ) ) European Journal of Endocrinology effects ofage-relatedchanges. Alongwithanextended GHRKO micehavebeen well studiedfordifferent was unchangedwhileastrocyte levelsdecreased( neuronpopulation were upregulated,parvalbumin calretinin andcalbindin-expressing corticalinterneurons in GHRKOmicebrainasstriatalcholinergicneuronsand stimulus todevelopingneurons.Thisisespeciallyrelevant in neuronalmigrationaseitheranaversiveorattractive normal brainmaturationbutalsosuggeststheroleofGH ( systemofGHRKOmiceandits WTcounterparts nervous central total cell number was reported in the embryonal proportionate variation( weight althoughtherestofbodypartsshowamore size inGHAandGHRKOanimalsrelativetototalbody decreased brainsizeinbGHmiceandincreased isreflectedinthe in affectingcognitionandmemory The apparentdichotomy in thepatterns of GH action Cognitive studieswithGHRKOmice splenic lymphocytes( leucocytes ( ( mediated crossingacrosstheblood-brain-barrier(BBB) in thebraintissues,asGHisknowntohaveareceptor- any othertissueinthebodyandnotnecessarilyoriginate at anypointoftimecanalsohaveaperipheralsource in system to notethattheGHaffectingcentralnervous ( as cognition and memory along withage-relateddeclineinGHproductionaswell binding inbraintissuedecreaseasafunctionofage( and hypothalamus( in thechoroidplexus,pituitary, hippocampus,thalamus Particularly highexpressionlevelsofGHRwasobserved as wellratsandmice(reviewedin( expression ofGHRthroughoutthebrainhumans immunohistochemical studiesconfirmedanearubiquitous in different brain regions. Later, quantitative PCR and cadavers within48 Early studiesinrabbits( GHR presence inbrain of theextendedlifespanmustbeevaluated. GH/IGF-1 action is fundamentally important, the quality and cognition.Asincreasedlongevitywithabsenceof Aging isassociatedwithaprogressivedeclineinmemory Cognition 262 259 Review ). Inthiscontext,additionalsources ofGHcouldbe ). ThisnotonlyimplicatesacriticalroleofGHin 260 ) andinincreasingamountsfromaging h ofdeath( 256 261 ). It was further observed thatGH ). Itwasfurtherobserved 250 253 ). 258 ), chickens( ). However, nodifference in ). However, itis important 252 R Basu,YQianandothers ), showedGHbinding 251 253 ) andhuman , 254 , 255 262 257 )). ). ) test for spatial learning and cognitive memory ( test forspatiallearningandcognitivememory well as2~3-month-oldWTmiceintheMorrisWater Maze outperformed same-aged WT littermates and scored as whenthey 15-month-old GHRKOmicewasobserved delayed aging-relatedcognitivedeclineinthe12-to display of the compared to WTcontrols. An exemplary mice ( littermates. SimilarstudiesinGHRKO( ( long-term andshort-termmemory receptors, whicharedirectlyinvolvedinpotentiating performance ( musculoskeletal deterioration( lifespan, theydisplayareducedspeedofneuronaland impairment comparedtotheir unaffectedrelatives( tasksandhadsignificantlylower cognitive in memory patients reportedthattheyperformedsignificantlybetter study with 12 members of the Ecuadorian cohort of LS mutation intheGHR( score, dependingonthetypeofinactivatingaminoacid cohort ofLSpatientsshowedanormaltosub-normalIQ In humanswithcongenitalGHresistance,theIsraeli Cognitive studiesinhumanswithGHRdeficiency to befullydescribed. and reductionofGHactioninmiceisvaluableremain reduced age-relateddeclineincognitiontheabsence explaininga mechanisms forthesesetofobservations 25-35 in Ames mice ( oftauproteinsinducedbyAbeta- hyperphosphorylation of hippocampaltissueadultmicereporteddecreased and coworkers using organotypic slice system culture as WTlittermatesofsameage( performed significantlypoorerthanbothGHAaswell than same-agedlittermatesinthestudywhilebGHmice search strategiesandcommitted significantlylesserrors WT littermates( GHA miceshowedsignificantlysuperiorresultsabove bGH mice in Barne’s Maze studies wherein the dwarf retentionof spatial learningandshort-termmemory memory retention( memory mice indicatinganaccelerateddeclineinlearningand mice performedtothesamelevelas25-month-oldWT avoidancetest,6-month-oldbGH In aninhibitory cognitive testsasreportedbyusandothers( and decreasedactivitiesinpre-frontal andmid-temporal long-term memory, anxiety and impaired decision making reported cognitiondeficits, decreasedshort-termand In humanacromegalypatients, severalstudieshave Lessons from In contrast,bGHmiceperformedpoorlyin 267 ) showed significantly better memory retention ) showedsignificantlybettermemory GHR 264 -disrupted mice 270 ) and increased expression of NMDAR ). TheGHAmiceusedmoredirect 3 269 , 271 9 Downloaded fromBioscientifica.com at09/29/202110:18:07AM , ). We recentlyshowedpoor 272 ). The underlying molecular ). However, recently, asmall 263 270 ), enhancedcognitive 265 ). AstudybySchrag 178 ) comparedtoWT www.eje-online.org :5 266 ) andAmes 269 268 R165 , ). 273 270 via freeaccess ). ). European Journal of Endocrinology www.eje-online.org paracrine manner. BBB inaffectingdifferentbrain regionsinanautocrine/ contribution oflocalGHor peripheralGHcrossingthe limited areasofneurogenesis;aswell(ii)thevery brain withactiveneurogenesis vsanadultbrainwith distinctions between(i)theroleofGHinadeveloping can beachievedbyanalysesinasex-specificmanner, the some casesofGHdeficiency. Furtherclarity inthisfield absence ofGHactionaswellwithtreatment in and cognition associated with congenitalmemory from humansandmiceindicateanimprovement in ( andanenlarged amygdalaa reducedspatialmemory preterm was associatedwithlevels inchildrenbornvery mice ( in liverandadiposetissueofthelong-livedGHDAmes profileslifespan andadverselyaffectstheinflammatory indicates, anearlylifeGHtreatmentinfactdecreases GH, priortodevelopmentofGHD.Asrecentresearch action, butratherhadaperi-orpost-natalexposureto GHD patientsdidnothaveacongenitalabsenceofGH GHD patients,animportantpointtoconsideristhat considering thedetrimentaleffectoflackGHin with Prader-Willi syndrome( were alsomadefollowingGHtreatmentinpatients 286 significant improvements in these variables ( GHreplacementtherapyshowedhave beenobserved. attention andsleepoverallqualityoflife(QoL) functionalities likecognition,memory, motivation, dysfunction,adeclineinneurocognitivepituitary ( treatment beginningafteraninitialacutephaseresolves (TBI) ( from traumatic brain injury isgrowthhormonedeficiency(GHD)resultingmemory marginally butsignificantlyimprovecognitionand which atransientGHtreatmenthasbeenfoundto scoliosis ( apnea, intracranialhypertension,pancreatitisand edema, carpal-tunnelsyndrome,obstructivesleep is knownto significantly increase theriskofdiabetes, decline innormalagingGHDpatients,andinstead, 280 in cognitivedevelopmentandmaintenance( (BD) furtherstimulatingthepleiotropyofGHaction in majordepressivedisorder(MDD)andbipolar higher thannormalserumIGF-1asadiseasetraitmarker reports and multiple meta-analyses directly implicate a cortices inbrain( 294 284 Review , , GH treatment doesnotappeartoaffect cognitive ). Together, thecurrentlyavailableinformation ). Inchildhoodoradult-onsetGHDbecauseof 281 287 243 ). , 288 112 , 244 , , 289 113 ). Additionally, highendogenousGH 274 , , 290 , 282 275 , 291 ). Oneparticularsituationin , 276 , 292 , 293 277 R Basu,YQianandothers ). Similarobservations ). Interestingly, while ). Interestingly, recent 283 ), especially 254 278 , , 285 279 , ,

promoter/enhancers intheCre-floxsystem( and conditionallyknockeddownusingtissue-specific the GHRindifferenttissueshavebeenspecifically To studythespecificeffectsofGHinvarioustissues, Tissue-specific GHR-knockoutmousemodels represented in mouse asdiscussedintheabovesectionshavebeen defects intheGHRhumanLSpatientsandGHRKO deficiency orGHresistancearisingduetomutational The variousadvantagesanddisadvantagesofGHR GHR deficiency Advantages anddisadvantagesof aging andlongevity( of GHactioningrowth,glucosehomeostasis,cancer, These studiesareofvaluetohelpunderstandtheimpact novo transgene ( globulin (TBG)promoter driving aCre-recombinase virus (AAV) bearing a liver-specific thyroxine-binding injection at 10- to 12-weeks-age with adeno-associated (aLivGHRkd) mousemodelwasdevelopedthrough the GHRLDmiceweremostlystudiedat16 weeksofage. Li-GHRKO micewasdoneinalongitudinalorderwhile and inflammation.Itisnoteworthythatthestudy of Li-GHRKOs. Also,GHRLDmicehaveincreasedfibrosis lines butonlyinfemaleGHRLDmice,notthe Second, liversteatosiswaspresentedinbothmalemouse no significant difference at body weight or composition. months ofage,while16-week-oldGHRLDshowed at 6 size, weight, and adiposity compared with control mice mouse lines.First,Li-GHRKOmicehavedecreasedbody inthesetwo phenotypic differenceshavebeenobserved weight comparedwithcontrolmice.However, several hyperinsulinemia, increased lipid accumulation and liver lines havehighGH,lowIGF-1levels,hyperglycemiaand mouse line,whichiscalledGHRLD( study alsogenerated an independent liver-specific GHRKO under thecontrolofalbuminpromoter( specific GHRKO mice (Li-GHRKO) using Cre-flox system produced intheliver. generatedliver- Thus,ourlaboratory almost alltissues,although~90%ofcirculating IGF-1is GH inducesIGF-1productionthroughbindingtoGHRon Liver-specific GHRKO Lessons from An adult-onsethepatocyte-specific GHRknockdown lipogenesissignificantlyincreased andhepatosteatosis 299 GHR ). Sevendaysaftertheinjection, hepatic Fig. 1 -disrupted mice . Fig. 2). Downloaded fromBioscientifica.com at09/29/202110:18:07AM 178 298 :5 ). Bothmouse 297 ). Another 295 R166 , 296 via freeaccess de ). European Journal of Endocrinology Global, tissue-specificandtime-dependent GHRKOmiceandtheircharacters. Figure 2 inhibit to suggesting thathepaticGHactionsnormallyserve developed inmalemiceandovariectomizedfemale Laron Syndrome(LS)patientsandtheglobalGHR-knockout(GHRKO)mouse. Advantages anddisadvantagesofgrowthhormone(GH)resistanceduetomutationsinGHreceptor(GHR),asobserved human Figure 1 Review de novo lipogenesisinthelivers.To dissectthe *U FD  $ UG ,QGXFLEOH *U *U $GXOW /IHPDOHV *OX  LR*+5 &1 /1 RZWK$$GLSRVLW\  *+5. *OX &1 *U  $  ' '     RQVHW    '  2 .2 R Basu,YQianandothers   PR   ZN V V  *OX * /LYH *U *OREDO $ & OXFRVHKRPHRVWDVLV    / *OX  U *OX *U *+5. $ &  /   *             +5    2 .2 $GLSRVH*+5. &&DQFHU *OX hepatic IGF-1transgenewasstudiedandresultssuggested induced liversteatosis,GHRLDmicethatexpresseda mechanisms ofGHresistanceandIGF-1deficiency- Lessons from *U &1 $ /     ' L   QFLGHQFH ƑFHOOV*+5. *OX 3D 2 *U $  &1 QFUH /1    RQ+)' / '  ' DWLF  / GHR LIHVSDQ  2 -disrupted mice 0XVFOH*+5 1 *U *OX '1RWGHWHUPLQHG /PDO &1 $  $  *U    *OX  0DFU '  H   Downloaded fromBioscientifica.com at09/29/202110:18:07AM     *+5.  &1  /1 .2  RSKDJH  RQ+)' RQ ' ' RQ+)' 2 +)'  178 www.eje-online.org :5 R167 via freeaccess European Journal of Endocrinology www.eje-online.org expressed inskeletalandcardiac muscleduringallstages adult muscleandfetalheart andbrain,whileMCKis enhancer ( the secondusedmusclecreatine kinase(MCK)promoter/ promoter/enhancer toknockout GHRinmuscle( different promoters/enhancers.ThefirstusedMef-2c-73k muscle-specific GHRKOmiceweregeneratedusing To study the GH action on muscle, two independent Another importantinsulin-sensitivetissueismuscle. Muscle-specific GHRKO homeostasis inextendedlongevityaswediscussedearlier. that thepotentialsignificanceofimprovedglucose the lifespanofFaGHRKOmicewasdecreasedsuggesting play different roles inglucose homeostasis. Interestingly, in FaGHRKO mice suggesting that different depots may glucose homeostasisfoundinGHRKOmicewasnotseen depot relativetocontrols.Moreimportantly, theimproved unique increaseintheproportionofsubcutaneous GHRKO micehavedepot-specificincrease,thatis,a due to the absence of GH’s lipolytic effects. In contrast, have generalincreaseinallfatdepotsandbodyweight knockdown GHR(FaGHRKO)( usedFabp4promoter/enhancertospecifically laboratory action on adipose tissues and its potential impacts, our to maintainglucosehomeostasis.To understandtheGH are responsibleforapartofwhole-bodyglucoseuptake Adipose tissuesareGHandinsulin-sensitivethat Adipose tissues-specificGHRKO sensitivity maybeoneofthekeyslongevity. earlier, improvedglucosehomeostasisandinsulin absence of hepatic GH action( of livercancerprobablyduetosteatosisinducedbythe to increaselifespan.GHRLDmicehaveincreasedincidence lifespan, suggestingthatloweredIGF-1itselfisinsufficient decreased number of cancers and do not have increased ( observed and females.However, nodifferencesintheliverswere control micewithdifferentpatternsofchangesinmale brains and kidneys in Li-GHRKO mice compared with biogenesis and apoptosis wassignificantly altered in oxidative stress( to inhibitsteatosis-inducedhepaticinflammationand against lipidaccumulationcompletelyandwasinsufficient and insulinsensitivity;however, itwasunabletoprotect that restoration of IGF-1 improved glucose homeostasis Review Gene expressionofkeyregulatorsmitochondrial 300 305 , , 301 61 306 ). ). TheLi-GHRKOmicedonothave , 307 ). Mef-2c-73kisexpressed in 303 R Basu,YQianandothers 302 ). TheFaGHRKOmice ). Also, as discussed 304 ); To furtherstudytheeffectsofGHon the GH promotes the proliferation of pancreatic Pancreatic adipose inflammation. intolerance andinsulinresistanceaswellincreased increased epididymaladiposedepotandimpairedglucose When on HF diet (45% fat), the MacGHRKO mice have tae65 months,thesemicehaddecreasedfatmass. at age6.5 was foundwhencomparedwithcontrols.However, or longitudinalsystolicbloodpressuremeasurements dobutamine stresstestechocardiographymeasurements months ( specific GHR-disrupted(iC-GHRKO)mouselineat4 generated a tamoxifen-inducible cardiac- our laboratory To clarifythedirecteffectsofGHRoncardiactissue, Inducible cardio-specific GHRKO induced metabolicdeterioration( ( maximum lifespanalongwithdecreasedinflammation 306 sensitivities wereoppositeinthesetwolines( the changesofgrowth,bodycompositionsandinsulin the differencesbetweenthesetwomouselines.Thatis, of development.Thisdifferencemaybeusedtoexplain direct effectonpromoting pancreatic not seeninnormalchowdiet, suggestingthatGHhasa they experiencedimpaired insulin response,whichwas have decreasednumberof knocked downinthemice ( glucose homeostasis,GHRinthe responses( effects ofGHontheinflammatory LysM promoter/enhancertobetterunderstandthedirect specific GHRKOmice(MacGHRKO)weregeneratedusing important rolesininflammation.Therefore,macrophage- markers( inflammatory GHRKO andGHRLDmicehavealteredlevelsof Macrophage-specific GHRKO adult mice,whileitdoesaffectmetabolicparameters. GH-induced signalingdoesnotaffectcardiacfunctionin study indicatesthatthedisruptionofcardiomyocyte by decreasedcirculating IGF-1. Surprisingly, this glucose intolerance and insulin resistance accompanied mice was the same as controls and the mice developed thefatmassofiC-GHRKO Furthermore, by12.5 months, Lessons from 305 , , 307 307 , 309 , 308 308 β GHR cells-specificGHRKO , 310 ). Importantly, theMCKmalesincreased ), andtheywereprotectedfromHFdiet- -disrupted mice ). Nodifferenceinbaselineorpost- Downloaded fromBioscientifica.com at09/29/202110:18:07AM 91 β , β GHRKO) ( cells.WhenonHFdiet, 61 306 ). Macrophagesplay β cellswasspecifically 178 ). β cellproliferation :5 312 ). Thesemice β β cells ( cellsand 304 R168 , 311 305 85 via freeaccess ). ). , European Journal of Endocrinology perceived asprejudicingtheimpartiality ofthisreview. The authorsdeclarethatthereis no conflictofinterestthatcouldbe Declaration ofinterest with atantalizingquestion– ‘Islessmore?’ numerous ofexistingandongoingstudiesonit,leavesus more cognizant, longest-lived GHRKO mouseand the disease. The dwarf, obese, cancer-free, diabetes-resistant, clarify the enigmatic role of GH–GHR in health and of globalGHRdisruption,itwouldbepossibletofurther organ-specific GHRknockoutsandadult-onsetmodels ( the mechanism(s)ofagingasafunctionGHaction continue tounderstand the intrinsicdifferences in to humansisbeingincreasinglyfine-tuned,as we lifespan extensionanddelayedaginginanimalmodels dwarf mouse models ( associated withstudiesintheGH-deficientandresistant possible reduction in reproductive fitness have been tradeoffs intheprocess.Areducedstature,obesityand differences ( and mitochondrialhealth.However, therearesex-specific been associated with increased cellular stress resistance as neuropathologies.AreductioninGHactionhasalso protection fromincidenceofdiabetes,cancer, aswell possibly alongerthannormallifespanandsubstantial improved glucosehomeostasis,cognition,bettermemory, and humans,theglobalabsenceofGHactionleadsto of GH/IGF-1inhumanaginganddisease( Decades of research has documented a pleiotropic role Closing comments infemales. lifespan extensionwasonlyobserved benefits foundinGHRKOmice.Surprisingly, maximal and improved insulin sensitivity, similar to several of the that these mice have delayed growth, increased adiposity ROSA26-Cre-ERT locus( tamoxifen-inducible Cre-floxsystememployingthe 6-week-old adult-onsetGHRKOmice(aGHRKO)using generated may have clinical implications, our laboratory effects oftemporalsuppressionGHinadults,which resistance tocancerandextendedlifespan.To studythe GHRKO mice have improved glucose homeostasis, Time-dependent GHRKO impaired glucosehomeostasis. to increaseinsulinsecretion,andtherefore,prevent 317 Review ). Throughintensivestudiesonsingleandmultiple 90 , 313 , 314 16 249 , , 315 ). Asstatedearlier, wefound 316 ) aswellunavoidable ). Further, extrapolating R Basu,YQianandothers 16 ). Inmice References Athens, Ohio. AMVETS, andbytheEdisonBiotechnologyInstituteatOhioUniversity, Program thatincludesagiftfromMiltonandLawrenceGoll,bythe This workwassupportedinpartbytheStateofOhio’s EminentScholar Funding

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