Hormonal Signaling in Biology and Medicine: Comprehensive Modern Endocrinology

712 Pages·2019·17.652 MB·English

by  Gerald Litwack (editor)

HORMONAL
SIGNALING IN
BIOLOGY AND
MEDICINE
COMPREHENSIVE MODERN
ENDOCRINOLOGY
Edited by
Gerald Litwack
Emeritus Professor and ChairofBasic Sciences, GeisingerCommonwealth School ofMedicine,
Scranton, PA,UnitedStates
Formerly Professor ofMolecular andCellular Medicine andAssociate Director, Institutefor Regenerative Medicine,
TexasA&M Health ScienceCenter,Temple, TX,United States
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Contributors
MarahArmouti DepartmentofPhysiologyandBiophysics, GiuliaCantini DepartmentofExperimentalandClinical
CollegeofMedicine, UniversityofIllinoisat Chicago, BiomedicalSciences “MarioSerio”,University ofFlorence,
Chicago,Illinois, USA Florence,Italy
JohnA.Arnott GeisingerCommonwealth Schoolof AyanoChiba DepartmentofCellBiology,NationalCerebral
Medicine,Scranton, PA, UnitedStates andCardiovascularCenterResearch Institute,Suita,Japan
KushalBakshi DepartmentofNeuroscienceand GeorgeP.Chrousos DivisionofEndocrinology,Metabolism
ExperimentalTherapeutics,CollegeofMedicine, Texas andDiabetes,FirstDepartmentofPediatrics,Nationaland
A&MUniversityHealthScienceCenter,Bryan,TX,United KapodistrianUniversity ofAthensMedicalSchool, ‘Aghia
States Sophia’Children’sHospital, Athens,Greece;Divisionof
NatalieJ.Bales Department ofBiomedicalSciences, EndocrinologyandMetabolism,CenterofClinical,
ColoradoStateUniversity,FortCollins, CO,UnitedStates ExperimentalSurgeryandTranslationalResearch,
BiomedicalResearchFoundationoftheAcademyofAthens,
MaryBethBauer DepartmentofBiomedicalSciences,
Athens,Greece
CooperMedicalSchoolofRowanUniversity,Camden,NJ,
SilaCocciolillo RoyalVictoria Hospital,McGill University
UnitedStates
HealthCenter,andDepartmentofMedicine, McGill
NathanA.Berger DepartmentofGeneticsandGenome
University,Montreal,QC,Canada
Sciences,CaseWesternReserveUniversity,Cleveland,OH,
R.Comaposada-Baro´ MolecularBasisofNeurodegeneration
UnitedStates;CaseComprehensiveCancerCenter,Case
Unit,Institutode BiomedicinadeValencia(IBV-CSIC),
WesternReserveUniversity,Cleveland,OH,UnitedStates;
DepartmentofMedicine,CaseWesternReserveUniversity, Valencia,Spain
Cleveland,OH,UnitedStates;DepartmentofBiochemistry, KevinP.M.Currie DepartmentofBiomedicalSciences,
CaseWesternReserveUniversity,Cleveland,OH,United CooperMedicalSchoolofRowanUniversity,Camden,NJ,
States UnitedStates
DanielJ.Bernard DepartmentsofPharmacologyand PierreDeMeyts DepartmentofCell Signalling,de Duve
Therapeutics,andAnatomyandCellBiology,McGill Institute,Brussels, Belgium;DepartmentofStemCell
University,Montreal,QC, Canada Research,NovoNordiskA/S,Ma˚løv,Denmark
MarkBlostein LadyDavisInstitute forMedicalResearch, IlariaDicembrini DepartmentofExperimentalandClinical
JewishGeneralHospitalandDepartmentofMedicine, BiomedicalSciences “MarioSerio”,University ofFlorence,
McGillUniversity,Montreal,QC,Canada Florence,Italy;CareggiUniversityHospital(AOUC),
M.LuisaBonet LaboratoryofMolecularBiology,Nutrition Florence,Italy
and Biotechnology (Nutrigenomics), University of the ClarkW.Distelhorst CaseComprehensiveCancerCenter,
Balearic Islands (UIB), CIBER Fisiopatolog´ıa de la CaseWesternReserveUniversity,Cleveland,OH,United
Obesidad y Nutricio´n (CIBEROBN), and Institut States;DepartmentofMedicine,CaseWesternReserve
d’Investigacio´ Sanita`ria Illes Balears (IdISBa), Palma de University,Cleveland,OH,UnitedStates
Mallorca, Spain NikolettaDobos DepartmentofBiopharmacy,Facultyof
AmandaP.Borrow Department ofBiomedicalSciences, Pharmacy,UniversityofDebrecen,Debrecen,Hungary
ColoradoStateUniversity,FortCollins, CO,UnitedStates DavidE.Fisher CutaneousBiology Research Center,
GregoryA.Brent Division ofEndocrinology,Diabetes,and DepartmentofDermatology,MassachusettsGeneral
Metabolism,DepartmentsofMedicineandPhysiology Hospital,HarvardMedicalSchool, Charlestown,MA,
DavidGeffenSchoolofMedicine atUCLADepartment of UnitedStates
Medicine,VAGreaterLosAngelesHealthcareSystem,Los M.L.Franco Molecular BasisofNeurodegenerationUnit,
Angeles,California,US InstitutodeBiomedicinade Valencia(IBV-CSIC),Valencia,
EmilieBruˆle´ Departments ofPharmacology and Spain
Therapeutics,andAnatomyandCellBiology,McGill GaborHalmos Department ofBiopharmacy,Facultyof
University,Montreal,QC, Canada
Pharmacy,UniversityofDebrecen,Debrecen,Hungary;
MaxH.Cake SchoolofVeterinary andLifeSciences, Endocrine,PolypeptideandCancerInstitute,Veterans
MurdochUniversity,Perth,WA, Australia AffairsMedicalCenter,Miami,FL,UnitedStates
xv
xvi
CONTRIBUTORS
RobertJ.Handa DepartmentofBiomedical Sciences, DavidJ.Lyons SchoolofPhysiology,Pharmacologyand
ColoradoStateUniversity,FortCollins,CO,United States Neuroscience,University ofBristol,Bristol,United
ElieHobeika DepartmentofPhysiologyandBiophysics, Kingdom
CollegeofMedicine, UniversityofIllinois atChicago, RongMa Department ofPhysiologyandAnatomy,
Chicago,Illinois,USA UniversityofNorthTexasHealth ScienceCenter,Fort
EvaJuhasz InstituteofPediatrics,ClinicalCenter,University Worth,TX,United States
ofDebrecen,Debrecen, Hungary RobertT.Mallet DepartmentofPhysiologyandAnatomy,
HamsiniSudheerKala DepartmentofPhysiologyand UniversityofNorthTexasHealth ScienceCenter,Fort
Biophysics, CollegeofMedicine, UniversityofIllinoisat Worth,TX,United States
Chicago,Chicago,Illinois,USA EdoardoMannucci DepartmentofExperimentaland
LajosV.Kemeny CutaneousBiology ResearchCenter, Clinical BiomedicalSciences “MarioSerio”,University of
Florence,Florence,Italy;CareggiUniversityHospital
DepartmentofDermatology,MassachusettsGeneral
Hospital,HarvardMedicalSchool, Charlestown, MA, (AOUC),Florence,Italy
UnitedStates MichaelJ.Shipston CentreforDiscovery BrainSciences,
RuthA.Keri DepartmentofPharmacology,CaseWestern UniversityofEdinburgh, Edinburgh,UK
ReserveUniversity,Cleveland,OH,UnitedStates; AnnaMilanesi Division ofEndocrinology,Diabetes,and
DepartmentofGeneticsandGenomeSciences,Case Metabolism,Departments ofMedicine andPhysiology
WesternReserveUniversity,Cleveland,OH,UnitedStates; DavidGeffenSchoolofMedicineatUCLADepartmentof
CaseComprehensiveCancerCenter,CaseWesternReserve Medicine, VAGreaterLosAngelesHealthcareSystem,Los
University,Cleveland,OH,UnitedStates Angeles,California,US
HarukaKobayashi InstituteofMolecular Medicine, NaokiMochizuki DepartmentofCellBiology,National
McGovernMedicalSchoolattheUniversityofTexasHealth Cerebral andCardiovascularCenterResearch Institute,
ScienceCenteratHouston,Houston,TX,United States; Suita,Japan;AMED-CREST
TokushimaUniversityFacultyofMedicine,Tokushima, J.F.Murray CentreforDiscovery Brain Sciences,University
Tokushima,Japan ofEdinburgh,Edinburgh,UnitedKingdom
ChristopherS.Kovacs Faculty ofMedicine, Memorial NicolasC.Nicolaides Division ofEndocrinology,
UniversityofNewfoundland,HealthSciences Centre,St. Metabolism andDiabetes, FirstDepartmentofPediatrics,
John’s,NL,Canada NationalandKapodistrian UniversityofAthensMedical
KalmanKovacs DepartmentofLaboratoryMedicine, School,‘AghiaSophia’Children’sHospital,Athens,Greece;
Division ofPathology,University ofToronto,Toronto,ON, DivisionofEndocrinologyandMetabolism,Centerof
Canada;TheKeenanResearchCentreforBiomedical Clinical,ExperimentalSurgeryandTranslationalResearch,
ScienceattheLiKaShingKnowledgeInstitute,St.Michael’s BiomedicalResearchFoundationoftheAcademyofAthens,
Hospital,UniversityofToronto,Toronto,ON,Canada Athens,Greece
PierreJ.Lefe`bvre Division ofDiabetes,Nutritionand KostasPantopoulos LadyDavisInstituteforMedical
MetabolicDiseases,DepartmentofMedicine, CHU,Lie`ge, Research,Jewish GeneralHospitalandDepartmentof
Belgium Medicine, McGillUniversity,Montreal,QC,Canada
CaroleLeHenaff Department ofBasicScienceand NicolaC.Partridge DepartmentofBasicScienceand
Craniofacial Biology,NewYorkUniversityCollegeof Craniofacial Biology,NewYorkUniversityCollegeof
Dentistry,NewYork, NY,UnitedStates Dentistry,NewYork, NY,UnitedStates
P.R.LeTissier CentreforDiscovery BrainSciences, DoodipalaSambaReddy Department ofNeuroscienceand
UniversityofEdinburgh, Edinburgh,UnitedKingdom ExperimentalTherapeutics,CollegeofMedicine, Texas
GeraldLitwack FormerlyInstitute forRegenerative A&MUniversityHealth ScienceCenter,Bryan, TX,United
Medicine,TexasA&M HealthScienceCenter,Temple,TX, States
UnitedStates LinaM.Restrepo DepartmentofEndocrinology,Clinica
Yan-YunLiu Division ofEndocrinology,Diabetes, and Medellin-GrupoQuiro´nsalud,Medellin,Colombia
Metabolism,Departments ofMedicineandPhysiology JoanRibot LaboratoryofMolecular Biology,Nutrition and
DavidGeffenSchoolofMedicineatUCLADepartmentof Biotechnology(Nutrigenomics), UniversityoftheBalearic
Medicine,VAGreaterLosAngelesHealthcareSystem,Los Islands(UIB),CIBERFisiopatolog´ıadelaObesidady
Angeles,California,US Nutricio´n(CIBEROBN),andInstitutd’Investigacio´
MichaelaLuconi DepartmentofExperimentalandClinical Sanita`riaIllesBalears (IdISBa),PalmadeMallorca,Spain
BiomedicalSciences “MarioSerio”,University ofFlorence, AllisonJ.Richard Pennington BiomedicalResearchCenter,
Florence,Italy;CareggiUniversityHospital(AOUC), BatonRouge, LA,UnitedStates
Florence,Italy
xvii
CONTRIBUTORS
AnaM.Rodrı´guez LaboratoryofMolecular Biology, CarlosStocco DepartmentofPhysiologyandBiophysics,
NutritionandBiotechnology(Nutrigenomics),University CollegeofMedicine, UniversityofIllinois atChicago,
oftheBalearicIslands(UIB),CIBERFisiopatolog´ıadela Chicago,Illinois,USA
ObesidadyNutricio´n(CIBEROBN),andInstitut SallyA.Stover Department ofBiomedicalSciences,
d’Investigacio´ Sanita`riaIllesBalears (IdISBa),Palmade ColoradoStateUniversity,FortCollins,CO,UnitedStates
Mallorca,Spain
LuisV.Syro DepartmentofNeurosurgery,HospitalPablo
NicolaRomano` CentreforDiscovery Brain Sciences, TobonUribe,andClinica Medellin-GrupoQuiro´nsalud,
UniversityofEdinburgh,Edinburgh,UK Medellin,Colombia
FabioRotondo DepartmentofLaboratory Medicine, ZsuzsannaSzabo DepartmentofBiopharmacy,Facultyof
DivisionofPathology,UniversityofToronto,Toronto, ON, Pharmacy,UniversityofDebrecen,Debrecen,Hungary
Canada;TheKeenanResearchCentreforBiomedical
MartinaTrabucco DepartmentofExperimentalandClinical
ScienceattheLiKaShingKnowledgeInstitute,St.Michael’s
BiomedicalSciences “MarioSerio”,University ofFlorence,
Hospital,UniversityofToronto,Toronto,ON,Canada
Florence,Italy
AndrewV.Schally Endocrine,Polypeptide andCancer
M.Vilar Molecular BasisofNeurodegenerationUnit,
Institute,VeteransAffairs MedicalCenter,Miami,FL,
InstitutodeBiomedicinade Valencia(IBV-CSIC),Valencia,
UnitedStates;DepartmentofPathology,Divisionsof
HematologyeOncologyandEndocrinology,MillerSchoolof Spain
Medicine,UniversityofMiami,Miami,FL,UnitedStates; DavidE.Volk InstituteofMolecular Medicine,McGovern
DepartmentofMedicine,DivisionsofHematology MedicalSchoolattheUniversity ofTexasHealth Science
eOncologyandEndocrinology,MillerSchoolofMedicine, Centerat Houston,Houston,TX,UnitedStates
UniversityofMiami,Miami,FL,UnitedStates;Sylvester HelgeWaldum Faculty ofMedicine, NorwegianUniversity
ComprehensiveCancerCenter,UniversityofMiami,Miami, ofScienceandTechnologyandSt.Olav’sUniversity
FL,UnitedStates Hospital,Trondheim,Norway
GiadaSebastiani RoyalVictoriaHospital,McGillUniversity RichardJ.Wurtman MassachusettsInstituteofTechnology,
HealthCenter,andDepartmentofMedicine,McGill Cambridge,MA,UnitedStates
University,Montreal,QC, Canada
GeorgeC.T.Yeoh HarryPerkins InstituteofMedical
CarlosA.Serna LaboratoriodePatologiayCitologia Research,QEIIMedicalCentre,Perth,WA,Australia
RodrigoRestrepo,DepartmentofPathology,Clinica Las
YueYu InstituteofMolecularMedicine,McGovernMedical
Ame´ricas,UniversidadCES,Medellin,Colombia
SchoolattheUniversity ofTexasHealthScienceCenterat
NimaSharifi CaseComprehensiveCancerCenter,Case Houston,Houston,TX,UnitedStates;ShanghaiJiaoTong
Western ReserveUniversity,Cleveland,OH,UnitedStates; UniversitySchoolofMedicine,Shanghai,China
GenitourinaryMalignanciesResearchCenter,Department
EleonoraZakharian DepartmentofCancerBiology and
ofCancerBiology,LernerResearchInstitute,Cleveland
Pharmacology,University ofIllinois CollegeofMedicine,
Clinic,Cleveland,OH,UnitedStates
Peoria,IL,UnitedStates
SoniaLobo GeisingerCommonwealth SchoolofMedicine,
Scranton,PA,UnitedStates
JacquelineM.Stephens PenningtonBiomedical Research
Center,Baton Rouge,LA,UnitedStates;Departmentof
BiologicalSciences,LouisianaStateUniversity,Baton
Rouge,LA,UnitedStates
Preface
Hormonesarethemessengersfromspecializedtissuestoothertissues,nearandfar,ofthebody,sothecomplex
organismcanfunctionefficiently.Modernresearchnotonlyinformsofthespecificreceptorsforhormones,located
distally,intheneighborhood,oreveninthecellproducingthehormone,butofthepathwaysthatarestimulatedor
depressedinsidethetargetcellasaresultofreceptoractivationbythehormonalligand.Emphasisinthisvolumeis
placed upon the physiologic effects of hormones, their interactions with specific receptors, and the consequent
metabolicpathwayswithinthetargetcellsthatareaffected.Inshort,muchisnowknownabouttheexactmechanisms
by which hormones function, either upon local or upon distant cells within the organism. In addition, there is
emphasisonthemolecularstructuresofhormonesandtheirreceptors,somanychapterswillillustrateX-raycrystal
structuresofthehormoneunderdiscussion,itsreceptor,andinsomecasesthecomplexofthereceptorwithitsligand.
Inbrief,suchanapproachfulfillstheunderstandingofcomprehensivemodernendocrinology.
Inthisbook,theclassificationofhormonesisorganizedbythetissuecellsthatsynthesizethem.Nowadays,itis
recognized that, occasionally, different types of cells may be the sites of synthesis of the same hormone, and this
diversityisdealtwith.
Theorganizationextendsfromtheupperpartofthebodytothelower,thebrain,andthendownward.However,
there are exceptions. First, there are two introductory chapters that survey hormones and perinatal development,
followed by a chapter on hormones of programmed cell death, a phenomenon critical to the homeostasis of cell
number.
Theeffectiveorganizationoftopicsfollows,firstwiththebrain,asexemplifiedby successivechaptersonhypo-
thalamicreleasinghormones,neurosteroids,neurotrophins,thepinealgland,andtheanteriorandposteriorpituitary.
Thehormonalregulationofionchannelsisthenconsideredintwochapters,thefirstdealingwithneuralionchannels
and the second dealing with epithelial nonneural ion channels. The thymosins are considered next. Originally,
thymosinwasconsideredtobeahormoneofthethymus,andwhileoneofthekeythymosinsissynthesizedinthe
thymus,otherkeythymosinsaresynthesizedinothertissues,however,notdetractingfromtheirpotentialimportance.
Thesequenceofthesubsequentchaptersreturnstotheoriginalclassification.Thenextchapterfocusesonhormones
producedintheheartandtheiractions.Similarapproachesareilluminatedinthefollowingchapters,startingwiththe
stomach,theintestine,pancreas,liver,kidney,adiposetissue(nowcertainlyconsideredtobeahormone-producing
gland),thyroid,parathyroid,skin,testes,ovaries,muscle,andadrenalgland(consistingofachapterontheadrenal
cortex and another chapter on the adrenal medulla). Finally, there are two chapters that emphasize clinical obser-
vations, thefirstdealing withpituitarytumorsproducing (ectopic)hormonesandthesecondrelatingtheeffectsof
hormonesupontumors.
Selecting 30 corresponding authors and approaching them to prepare manuscripts that emphasized the aspects
envisionedwasaheftyproposition.Fortunately,Ihadsomehelp.Initially,Ithoughtthattheanteriorpituitaryhor-
monescouldbecoveredbyasingleauthor.Thatprovedtobeunrealistic.Here,ImustrecognizethefactthatDr.Daniel
Bernard of McGill University suggested that the topic be divided into three portions, one of which he would un-
dertake,andthenherecommendedtwootherauthorsfortheremainingsections.Thankfully,theybothagreed.Iam
mostgratefultoDanforhishelp.Dr.NathanBergerhelpedwiththetitle,soitwouldbesuitablyrepresentativeof
clinical interest as well as that of the basic sciences. Nate is an old friend and I was very open to his suggestion.
Narmatha Mohanof Elsevieragreedto take ontheawesomeresponsibilityforobtainingpermissionstoreproduce
figuresandothermaterialsexistingintheliteratureforalloftheauthors.Ifrequiredoftheauthors,themselves,this
couldhavebeenadrainingtask.IammostgratefultoNarmathaforshoulderingthisresponsibility.Aswithmyearlier
experiencesspanningmorethan30years,TariBroderickofElsevierwasalwaysavailabletosmoothoutanywrinkles.
It has ever been a great pleasure to collaborate with her. Finally, perhaps the greatest burden for mounting manu-
scripts on the electronic submission system (EMSS) and for keeping myself and all of the information we have
gatheredonthestraightandnarrow,TimothyBennettofElseviertookupthereinsand,obviously,wasakeyplayerin
theproductionofthisbook.Iextendmythanksforhisefforts.
xix
xx
PREFACE
Thebookcoveris,inmyview,acriticalitem.Searchingforanimpressivefigurefromtheliteraturetogracethe
coverpresentedanumberofproblems.First,onewouldhavetoknowwhethersuchafigurehadeverbeenusedonthe
coverofsomeotherbook.Toevadethisproblem,wedecidedtouseafigurefromoneofthechaptersinthisbook,andI
hadtomaketheselection.Withthisaccomplished,thebookcoverdesigneratElsevierwouldrenderthreeversionsofa
cover,afterwhichIcouldswitchelementsofanyofthethreearoundtocomeupwithacoverthat,tome,wouldbe
strikingandattractive.Fig.15ofChapter18wasselectedasasuitablefigure.Thisisacrystalstructureofthereceptor-
bindingdomainofthrombopoietincomplexedtoaneutralizingantibody(TnFab),astructurefromtheProteinData
Bank (PDB ID: 1V7N) that is in the public domain. Chapter 18 is entitled “Liver Hormones” by S. Cocciodillo, G.
Sebastiani,M.Blostein,andK.Pantopoulos.
Consideringthecoverageofvirtuallyalloftheknownhormones,theirreceptors,themechanismsofsignalingfrom
theactivatedreceptoronwardwithinthetargetcelltogetherwithstructuralaspectsrepresentedthebestofwhatwe
knowaboutmodernendocrinology.Inaddition,virtuallyeverychapterconsidersdiseasesevolvingfromhormone
insufficiencyorhormoneexcessandalsotherolesofparticipantsinagivenhormonalpathwaythatleadtodisease.
Therefore,itcametomindthatthesubtitle“ComprehensiveModernEndocrinology”wouldbebeneficial.Ihaveto
thankTariforagreeingwiththisproposition.
Asaresultofthisconsiderableeffort,myhopeisthatthisbookwillbeinstrumentalinteaching,where,asasource,
aninstructorcouldminethematerialneededforaspecificlectureand,aswell,makeuseoftheextensiveillustrative
materials.Inadditiontoitspotentialvalueforinstructorswhoareresponsibleforvariouscoursesorspecificlectures,I
anticipatethatbothresearchersandclinicianswillfindthistobeavitalresourceforreference.
GeraldLitwack
NorthHollywood,CA
June10,2019
C H A P T E R
1
Hormones and Perinatal Development
1 2
Max H. Cake , George C.T. Yeoh
1SchoolofVeterinaryandLifeSciences,MurdochUniversity,Perth,WA,Australia;2HarryPerkinsInstituteofMedical
Research, QEII Medical Centre, Perth,WA,Australia
1. INTRODUCTION
regulatory proteins with transcriptional response se-
quences. This causes activation or inhibition of expres-
Celldivisionisoneofthemostfundamentalactivities sion of specific genes, resulting in an altered level of
of multicellular existence. It is obviously important the protein product. Although there are numerous ex-
during embryological development, during which the amplesthatcouldbechosentohighlighttheimportance
single, fertilized ovum undergoes a complex, pro- of hormones in activating specific developmental
grammedsequenceofcelldivisionstogenerateamature events,thischapterwillfocusonthepostnataldevelop-
organismconsistingofmanymillionsofcells.Evenafter ment of key processes in the liver (gluconeogenesis,
a higher animal has reached maturity, cell division is amino acid catabolism, and urea cycle function), the
required to replenish those tissues that have suffered lung (surfactant production), and the intestine (diges-
cell losses due to wear and tear. For instance, based on tion) of eukaryotes and especially address the impact
a blood volume of 4.7L, human erythrocytes having a ofglucocorticoids,glucagon,epinephrine,andtheinhib-
lifespanof120daysandbeingpresentinbloodatacon- itoryeffectsofinsulinandandrogens.Theprocessesdis-
centrationof5(cid:1)1012cells/L(Albertsetal.,2002),itwas cussed are vital to postnatal survival, and if they are
calculatedthat,justtomaintaintheerythrocytepopula- impaired, at a minimum, the health status of the post-
tion, an adult human must produce >2.3 million new natalorganismiscompromised.
erythrocytes per second, which confirms the value pre-
viously published (Sackmann, 1995). In this context,
erythropoietin is the principal mediator that regulates
2. DEVELOPMENT OF HEPATIC
the erythron (Adamson, 1996). There are a host of
METABOLIC PROCESSES
tissue-specific growth factors and hormones that deter-
mine the size of different organs of the body (Hafen
2.1 Neonatal Development of Hepatic
andStocker,2003).
Gluconeogenesis
Numerous studies have shown, however, that hor-
monesareessentialformanyeukaryoticdevelopmental
Theprocessofbirth,uponcompletionofmammalian
processesaswellasforcellularhomeostasis.Workfrom
gestation, interrupts the continuous maternal supply of
thelaboratoriesofO’Malley(Tsaietal.,1978)andCham-
fuelsthatareprovidedviatransplacentaltransfer,lead-
bon(Wasylyketal.,1980;Chambon,2004)showedthat,
ingtoanalteredmetabolicenvironmentinthenewborn.
through an interaction with specific receptor proteins,
Although suckling provides an alternative fuel supply,
the hormone estrogen regulates the rate of expression
thereisadelaybetweenbirthandtheonsetofsuckling.
ofthegenesfortheeggwhiteproteins,ovalbumin,con-
During this period, there is a reduction in the blood
albumin,ovomucoid,andlysozymebyinteractingwith
glucoseconcentration(hypoglycemia),whichisquickly
andactivatingitscognatereceptorsoitbindstospecific,
returned to normal levels as a result of phosphorylase
upstreamenhancersequences.Subsequently,ithasbeen
activation (Dawkins, 1963; Cake and Oliver, 1969) that
shown that the majority of developmental events
initiatesglycogenolysisandthedevelopmentofhepatic
orchestrated by hormones are the result of transcrip-
gluconeogenesis (Dawkins, 1963; Cake et al., 1971; Gir-
tional events initiated by interaction of specific nuclear
ardet al., 1973; Marsacet al., 1976).
HormonalSignalinginBiologyandMedicine 1
https://doi.org/10.1016/B978-0-12-813814-4.00001-8 Copyright©2020ElsevierInc.Allrightsreserved.
2
1. HORMONESANDPERINATALDEVELOPMENT
Invertebrates,gluconeogenesis,whichcanbedefined postnatal rats, which possess PEP carboxykinase activ-
as the synthesis of glucose from noncarbohydrate pre- ity, triamcinolone administration elicits a two- to three-
cursors such as pyruvate, lactate, glycerol, and glyco- fold increase in enzyme activity. This increase was
genic amino acids, takes place mainly in the liver and shown to be the result of increased synthesis of the
in the cortex of the kidney(Gerich et al., 2001).Hepatic enzyme, accompanied by enhanced PEP carboxykinase
gluconeogenesis is virtually absent in the fetus and mRNA(MencherandReshef,1979).RenalPEPcarboxy-
only becomes evident postnatally (Ballard and Oliver, kinase, unlike that of the liver, was detectable prior to
1963, 1965; Warnes et al., 1977; Platt and Deshpande, birth and was elevated in both fetal and postnatal ani-
2005). In rats, the inability to synthesize glucose from mals when exposed to triamcinolone. Conflicting re-
noncarbohydrate precursors prior to birth is due to the ports on the effect of glucocorticoids on PEP
absenceoftheenzymephosphoenolpyruvatecarboxyki- carboxykinase activity (Gunn et al., 1975; Mencher and
nase(EC4.1.1.32;PEPcarboxykinase),despitethepres- Reshef, 1979) question the role played by glucocorti-
ence of the other three enzymes essential for coids in thedevelopmental regulation ofthis enzyme.
gluconeogenesis, namely pyruvate carboxylase (EC The postnatal accumulation of PEP carboxykinase
6.4.1.1), fructose 1,6-bisphosphatase (EC 3.1.3.11), and mRNA, and as a consequence the enhanced enzymatic
glucose6-phosphatase(EC3.1.3.9)(BallardandHanson, activity,isnowrecognizedasbeingpromotedbythedra-
1967;Yeungetal.,1967;Fig.1.1).Naturalbirthorprema- maticchangeinthecirculatinglevelofthepancreatichor-
turedeliverybyuterinesectionoffetalratsresultsinthe mones that occurs at birth (Girard et al., 1973; Pegorier
appearance of PEP carboxykinase, which is linearly etal.,1992) togetherwith a riseinepinephrine, released
correlatedwithpostnatalgluconeogenicactivity(Yeung from the adrenalmedulla asa consequence ofthestress
andOliver,1967).Theappearanceoftheenzymeatthis associated with birth. Within an hour of the birth of
time is the result of a transcriptional event, which is rats, the plasma glucagon concentration rose by more
apparentfromtherapidaccumulationofPEPcarboxyki- thanthreefold,whereastheinsulinconcentration,which
nasemRNAfromanundetectablelevelintheliverofthe was high in the fetal circulation, fell to less than 30% of
fetal rat late in gestation to a peak level 24h after birth thatrecordedforlatefetalratsandremainedatthislow
(Lyonnet et al., 1988). level over the first 2 postnatal weeks (Girard et al.,
The administration of the synthetic glucocorticoid, 1972, 1973; Fig. 1.2). As a result, there was a greater
triamcinolone, does not precociously induce hepatic than10-folddeclineintheinsulin/glucagonmolarratio,
PEP carboxykinase activity in the fetal rat (Yeung implyingthat,soonafterbirth,therewouldbeadramatic
et al., 1967; Mencher and Reshef, 1979). In contrast, in increase in the hepatic concentration of cyclic AMP
(cAMP). The in utero administration of either glucagon
or dibutyryl cAMP precociously induced both PEP
100
m) 80 6 1000
u
m
xi
% of ma 60 g/mL) 4 800 pg/mL)
nzyme activity ( 2400 Insulin conc. (n 2 460000 Glucagon conc. (
E 200
0 0 0
-5 0 5 10 15 20 0 5 10 15
Postnatal age (days) Postnatal age (h)
FIGURE 1.1 FIGURE 1.2
Developmental changes in the activities of the glu- Postnatal changes in the circulatory levels of the
coneogenicenzymespyruvatecarboxylase(black),PEPcarboxykinase pancreatichormonesinsulin(black)andglucagon(red)intherat. Data
(red), fructose 1,6-bisphosphatase (green), and glucose 6-phosphatase was taken from Girard, J.R., Cuendet, G.S., Marliss, E.B., Kervran, A.,
(blue) in the rat. Data was taken from Yeung, D., Stanley, R.S., Oliver, Rieutort,M.,Assan,R.,1973.Fuels,hormonesandlivermetabolismatterm
I.T., 1967. Development of gluconeogenesis in neonatal rat liver. Effect of and during the early postnatal period in the rat. J. Clin. Investig. 52,
triamcinolone.Biochem.J.105,1219e1227. 3190e3200.