生物化学英文版课件：chapter 23 Integration and Hormonal regulation of mammalian metablism

Chap23

HormonalRegulation&IntegrationofMammalianMetabolismAccordingtoRobert,thestudyofendocrinologybeganinChina:isolationofsex(steroid)andpituitary(peptide)hormonesfromhumanurineandusingthemformedicinalpurposes2200yearsago.Metabolicprocessesinsinglecellsareregulatedatthelevelofenzymes

Substrateavailability;Allostericregulation;Covalentmodification;Compartmentalization.Metabolismatthewholeorganismlevel:

SpecializationofeachorganHormonalcoordinationofallManymetaboliceventsmightoccurinasinglecell.Mutuallybeneficialdivisionoflaboramongtheorgansalloweachperformfunctionstoservetheshort-andlong-terminterestsofthebody.Monitorsandregulatesbloodcomposition;Reducesnutrientfluctuation;Detoxification,etc.HighmetabolicflexibilityDivisionoflaborandcooperationamongorgansmaintainhomeostasisinthefeeding-fastingcycleBloodProcessCenterofmetabolismATPconsumer(butcontributesduringfastingandprolongedstarvation)ATPconsumerATPconsumerStore&supplyfattyacidsNutrientabsorptionRichinmitochondriaControlcenterofmetabolismMajoreventsinthestorage,retrieval,anduseoffuelsinthefedandunfedstatesandinearlystarvationMetabolismisadjustedtoprovidefirstglucoseandthenketonebodiesforthebrain

duringstarvation.Changesofplasmaconcentrationsoffattyacids,glucose,andketonebodiesduringthefirstweekofstarvationnormal(<0.5mM)hyperketonemia(1-3mM)ketoacidosis(>3mM)8Hormones("Iexiteorarouse"):chemicalmessengersthatconveymessagefromonecelltoanotherFunctioninsmallamountandtobeactivated(secreted)byaparticularstimulus;Involvesahierarchicalsignalamplification&triggersacascadeofsecondaryeffects;Differenttissuesoftenresponddifferentlytothesamehormone;Oftenformnegativefeedbackloopstomaintainthehomeostaticstatus.

Effectiveconcentrationofhormone-receptorcomplexesdeterminessignalinginitiation.Threemajortypes:peptides;lipids,monoaminesErnestStarling(1905onsecretin)(WilliamBaylissThehomeostaticnegative(orpositive)feedbackloopsnotshownhere!CoordinationCenterHypothalamuscontrolsbodytemperature,hunger,thirst,fatigue,sleep,andcircadiancycles.

‘Master'endocrineglandSecondaryendocrineglandsTargettissuesNeronalconnectionsThehierarchyofhormonalsignalingstartsfromtheCNSandintegratemetabolismofdifferentorganstoachievehomeostasisinthebody.Guillemin,Schally(Nobel,1977)Allhormonessecretedbythepituitaryglandarepeptidehormones!Hormonalcascadesresultsinlargeamplificationsofsignalsalongtheway.

Thecascadeisalsoregulatedbyfeedbackinhibition(noticedearlierthanthoseinthesyntheticpathwaysofaminoacidsandnucleotides).CoordinationCenter

‘Master'endocrineglandSecondaryendocrineglandTargettissues41aminoacids39AminoacidsFeedbackinhibitionAradioimmunoassay(RIA)wasdevelopedtomeasureextremelylowconcentrationsofpeptidehormonesbyuseofantibodies(1960,Yalow)

(measuredbeforebasedonthebiologicaleffecttheygenerateinanimals,thusveryunreliable)RosalynYalow(1921-Shared1977NobelPrizeinPhysiologyorMedicine

Coldantigencompeteswiththehotantigensinbindingtotheantibodies.

(10−12g)10−12gNoblePrize,1977(Knownquantity)(Knownquantity)(Unknownquantity)ThestandardcurveYalowRS,BersonSA(1960)."Immunoassayofendogenousplasmainsulininman".J.Clin.Invest.39:1157–75.Precisemeasurementofminuteamountsofpeptidehormonesrevolutionizedthefieldofendocrinology!SeparatingboundfromunboundantigeniscrucialPeptidehormonesareoftenproducedasinactiveprecursorsprocessedbyproteolyticcleavage(1970s)

TheinsulinAandBchainsproposedtobemadeasasinglepolypeptidechainandconfirmedinhumanisletcelladenoma(1967)★HighmolecularweightimmunoreactiveACTH(1971);★

Immunoprecipitationbyantibodiesofmultiplehormones(1978);★

IsolationcDNAcloning(1979)Inpituitary(285residues)

44residues

FuelmetabolismofdifferentorgansiscoordinatedthroughafewmajorhormonesInsulin,glucagon,andepinepherinehavebeenfoundtointerplayincoordinatingfuelmetabolisminmuscle,liver,andadiposetissue,thuskeepingthebloodglucoselevelnear4.5mM.Insulinsignalshighbloodglucose(actsmainlyonliver,muscleandadiposetissues).Glucagonsignalslowbloodglucose(actsmainlyonliverandadiposetissues).Epinepherine(adrenalineinUK)signalsimpendingactivity(actsonmuscle,liverandadiposetissues).Insulinstimulatesglucoseuptakeandstorageinliver,muscleandadiposecells.Thewell-fedstate:Storedasglycogenortriacyglycerol.Secretionstimulatedbyanincreaseinbloodglucoselevel.

bcellsFrederickBanting

JohnMacleodNobelprize,1923CharlesBest

JamesCollip

Insulinbindstoitsreceptor(1),whichstartsmanyproteinactivationcascades(2)leadingto:★TranslocationofGlut-4toplasma membrane;★

Influxofglucose(3),★

Glycogensynthesis(4),★

Glycolysis(5)★

Fattyacidsynthesis(6).Well-fedstateGlucagonstimulatesglucoseproductionandreleaseinliver.Thefastingstate:Alsomobilizesthefattyacids(sparingglucoseforthebrain)acells29-residuepeptideGPCRDiscoveredasanadditionalsubstanceininsulinpreparationofpancreaticextractsthatraisedbloodsugar(hyperglycemic,inteadofhypoglycemic)indepancreatizeddogs.(KimballandMurlin,1923)Epinephrinepreparesanimalforactionandexhibitssimilareffectasglucagon

AmonoaminederivedfromTyrGPCRInsuliniseithernotproduced(TypeI)ornotrecognizedbythetissues(TypeII),anduptakeofbloodglucosecompromised.

Highlevelofglucoseinbloodandurine;productionandexcretionofketonebodies.Theadiposetissuewasfoundtoproduceaproteinhormone,leptin(16kDa),thatactonthehypothalamustoregulatethefeedingbehaviorandenergyexpenditureofamammaltomaintainaconstantbodymass(1994).JeffreyM.FriedmanGenescloned(1994)frommassivelyobesehomozygous“ob/ob”mice(reportedin1950).ZhangY,ProencaR,MaffeiM,BaroneM,LeopoldL,FriedmanJM(1994)."Positionalcloningofthemouseobesegeneanditshumanhomologue".Nature372:425–432.“ob/ob”“ob/ob”(4Xweighter)Leptin(1994)Aset-pointmodelformaintainingaconstantbodymassLeptin:a“satietyhormone”producedindirectproportiontofatmass(adipocytes)Other"satietyhormones"-cholecystokinin,nesfatin-1,obestatin."hungerhormones"-ghrelin,orexin,andPYY3-36.NeurosecretorycellsHormonesandneuropeptidecontroleatingbehaviorsHypothalamusAppetite-inhibitingAppetite-stimulatin