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1、REVIEWSGprotein-coupledreceptorsforenergymetabolitesasnewtherapeutictargetsClaraC. Blad1,CongTang1andStefanOffermanns1,2Abstract
2、SeveralGprotein-coupledreceptors(GPCRs)thatareactivatedbyintermediatesofenergymetabolism—suchasfattyacids,saccharides,lactateandketonebod
3、ies—haverecentlybeendiscovered.Thesereceptorsareabletosensemetabolicactivityorlevelsofenergysubstratesandusethisinformationtocontrolthesecretionofmetabolichormonesortoregulatethemetabolicactivityofparticularcells.Moreover,mostofthesereceptorsappeartobeinvolvedinthep
4、athophysiologyofmetabolicdiseasessuchasdiabetes,dyslipidaemiaandobesity.ThisReviewsummarizesthefunctionsofthesemetabolite-sensingGPCRsinphysiologyanddisease,anddiscussestheemergingpharmacologicalagentsthatarebeingdevelopedtotargettheseGPCRsforthetreatmentofmetabolic
5、disorders.Gprotein-coupledreceptors(GPCRs)constitutebyfargluconeogenesis,orfattyacidoxidationandsynthesisEnteroendocrinecellsSpecializedendocrinecellsofthelargestreceptorfamilyinmammalsandareinvolved—whichisoftendisturbedinmetabolicdiseasessuchthegastrointestinaltra
6、ctthatintheregulationofvirtuallyallcellularandphysiologi-asobesity,type 2diabetesanddyslipidaemia.Giventheirareincontactwiththegutcalfunctionsinthebody.Owingtotheirabilitytobindcentralroleinthecoordinationofmetabolicprocesses,lumenandsecretevarioustoligandswithahigh
7、specificityandaffinity,GPCRsmetabolite-sensingGPCRsarepossibletargetsfordrugshormonessuchastheincretinsarepreferentiallytargetedforthedevelopmentofnewthatmodulatemetabolicfluxesandconsequentlyinflu-glucagon-likepeptide 1andgastricinhibitorypeptide.therapeuticsandacc
8、ountforabout20%ofthecurrentlyencetheoutcomeofmetabolicdisorders.Forexample,exploiteddrugtargets1.Onceactivatedbyaligand,metabolite-sensingGPCRsthatarehighlyexpressedbyGPCRscanbecoupledtofourdifferentfamiliesofhet-adipocytescanbetargetedtoregulatelipolyticactiv-erotr
9、imericGproteins(G,G/G,G/GandG/G),ity,withtheaimofloweringplasmalipidlevelsorlipidsioq111213whichinturnthenregulatetheactivityofoneorsevera
