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FGF21 A Missing Link in the Biology of Fasting

CellMetabolism

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FGF21:AMissingLinkintheBiologyofFasting

MarcL.Reitman1,*

1

DepartmentofMetabolicDisorders,MerckResearchLaboratories,Rahway,NJ07065,USA*Correspondence:marc_reitman@http://www.wenkuxiazai.comDOI10.1016/j.cmet.2007.05.010

Asuf cientenergysupplyisessentialforlife;consequently,multiplemechanismshaveevolvedtoensurebothenergyavailabilityandconservationduringfastingandstarvation.TworeportsinthisissueofCellMetabolism(Badmanetal.,2007;Inagakietal.,2007)demonstratethatFGF21,acircu-latingproteinproducedintheliverinresponsetothePPARatranscriptionfactor,isa‘‘missinglink’’inthebiologyoffasting,inducingadiposetissuelipolysis,liverketogenesis,andmetabolicadaptationtothefastingstate.

BiologyofFasting

Theadaptationfromthefedtofasted(totallackoffoodintake,usuallyacute)orstarved(chronicundernutrition)statehasbeenasubjectoffascination,andinvestigation,forcenturies(Cahill,2006;Keysetal.,1950;seealsoTucker,2006).Inthefedstate,glucoseful llsthebody’sacute,immediateen-ergyneeds.Thebodysensesadropinglucoseconcentrationatsitessuchasthepancreaticislets,brain,andportalvein.Itrespondsbyreducinginsulinsecretionfromisletbcellsandbyin-creasingglucagonsecretionfromisletacells.Anotherresponseissympa-theticadrenalstimulationcausingin-creasedepinephrinelevels;thisarmisofsecondaryimportancebuthasalargerroleinpatientswithtype2diabetes(Cryeretal.,2003).

Duringfasting,liverglycogen,aglucose-storagepolymer,isinitiallymobilizedtoreplenishbloodglucose(glycogenolysis).Majorchangesinmetabolismoccurastheglycogensupplydwindles.Storedadiposetis-suetriglyceridesarereleasedintothecirculationasglycerolandfattyacids.Theglycerolisconvertedbytheliverintoglucose(gluconeogenesis).Thefattyacidsaredirectlyoxidizedasanenergysourcebysometissues(liverandmuscle);theliveralsometabolizesthefattyacidstob-hydroxybutyrateandacetoacetate(‘‘ketonebodies’’).Ketonebodiesarereleasedintothecirculationforusebytissues,notablythebrain,whichcannotusefattyacids.Theliveralsousesketonesforgluconeogenesis.Whenfastingisprolonged,muscleproteinbreakdownoccurs,sendingalaninetotheliverasanothersubstrateforgluconeogenesis(Cahill,2006).

Themajorcontrollersofenergyho-meostasisareinsulin,glucagon,andthesympatheticnervoussystem,butotherregulatorhormonesplayaroletoo.Leptinissecretedbyadiposetissueinproportiontoadiposetriglyc-eridecontent(thedeterminantofhowlongthebodycansurvivestarvation);thisinformationontriglyceridelevelscontrolschronicenergyhomeostasisandrelatedevents,including,forex-ample,theabilitytoreproduce.Otherphysiologicalsignalsofenergystatusincludetheguthormonesthatcom-municatenutritionalstatus(examplesincludeghrelin,cholecystokinin,pancreaticpolypeptide,glucagon-likepeptide-1,polypeptideYY,gas-trin-releasingpeptide,andneurome-dinU).Noneoftheseguthormones,however,hasthedramatic,nonredun-dantimportanceofinsulin,glucagon,orleptin,asevidencedbythede -ciencyphenotypesoftherespectiveknockoutmice.Hypotheticalrolesforasyetundiscoveredhormonesmightincludehormonessecretedbytheliverreportingitsglycogenortriglyceridecontent,orbymusclebroadcastingthatitsglycogenstoresareloworthatitslactateproductionishigh.

Overthepastfewyears,ithasbecomeclearthatthereisanothersourceof‘‘hormonal’’informationonfuelhomeostasis.Therearenowanumberofexamplesofthemetabolicfuelsthemselvesservingashormones(i.e.,asligandswithoutundergoing

furthermetabolism).Metabolicsub-strateGprotein-coupledreceptorsincludeGPR109Aforb-hydroxybuty-rate,GPR91forsuccinate,GPR99fora-ketoglutarate,andGPR41andGPR43forshort-chainfattyacids.In-tracellulartranscriptionfactorsthatappeartobefuelsensorsareHNF4andPPARsforfattyacids(amongothers;seeLazarandWillson,2007).FGF21

FGF21burstintothepicturewhenKharitonenkovetal.(2005)showedthatitimprovedglucose,insulin,andtriglyceridelevelsindiabeticmiceandthattransgenicoverexpressionre-sultedinalean,insulin-sensitivephe-notype.Afollow-upstudyof6weeks’treatmentofdiabeticrhesusmonkeyssigni cantlyexpandedtheseresults:FGF21reducedglucose,insulin,andglucagonlevels;improvedlipidpro- les;andslightlyreducedbodyweight(Kharitonenkovetal.,2007).Ofsigni -cantinterestforidentifyingpossiblepharmaceuticaltargets,nosignalsofhypoglycemiaorcellproliferationweredetected.

Thetwopapersinthisissue(Badmanetal.,2007;Inagakietal.,2007)establishFGF21asahormoneimportantintheintermediatetimepe-riod(hours)inthebody’sadaptationtofasting.Thepaperscomplementeachotherwell,withInagakietal.con-centratingonFGF21excess,showingthatitissuf cient,whileBadmanetal.focusonFGF21de ciency(liverknockdown),showingthatitisnec-essary,foradaptationtofasting(Figure1).

CellMetabolism5,June2007ª2007ElsevierInc.405

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