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ThursdayNovember8,2018OlympicMuseum-Quaid'Ouchy1,1006Lausanne……………………………………………………………………………………………………………………………………LIMNASymposium:CentralRegulationofMetabolismandFeeding…………………………………………………………………………………………………………………………………OrganizingCommittee:Prof.BartDeplancke,Prof.BéatriceDesvergne,Prof.LluisFajas,Prof.NellyPitteloud,Prof.BernardThorens,Prof.KeiSakamoto,Prof.KristinaSchoonjansandDr.LaurenceDescamps.

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InvitedSpeakers

• DanielaCota,INSERMNeurocentreMagendie,BordeauxUniversity,France• SabrinaDiano,YaleUniversitySchoolofMedicine,USA• TedDinan,UniversityCollegeCork,Ireland• AnaI.Domingos,UniversityofOxford,UK• MiguelLopez,CiMUS,UniversityofSantiagodeCompostela,Spain• SergeLuquet,UniversityParisDiderot,France• MartinG.Myers,UniversityofMichiganMedicalschool,AnnArbor,USA• SophieSteculorum,MaxPlanckInstituteforMetabolism

Research,Cologne,Germany

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Agenda8h30-9h00WelcomeanddistributionofbadgesOpening9h00BernardThorensWelcomeMorningsessionChairman:TBD9h10MartinG.Myers"TheCNScontrolofbloodglucose-rolesforVMNsubpopulations"9h45SabrinaDiano"Centralmitochondriadynamicsandmetabolism"10h20CoffeeBreakChairman:TBD10h40MiguelLopez"TargetinghypothalamicAMPKforthetreatmentofobesity"11h15DanielaCota"Bileacidsignalingasnovelmechanisminthecentralcontrolofenergybalance"11h50Selectedspeaker1basedonabstractsubmission12h05Selectedspeaker2basedonabstractsubmission12h20Lunch

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AfternoonsessionChairman:TBD13h05Postersession14h05TedDinan“Gutmicrobetobraincommunication:implicationsforpsychopharmacology"14h40AnaI.Domingos“SympatheticNeuroimmunityinObesity"15h15Selectedspeaker3basedonabstractsubmission15h30CoffeeBreak15h50Selectedspeaker4basedonabstractsubmission16h05SophieSteculorum"Novelregulatorsofthecentralcontroloffeedingandsystemicinsulinsensitivity"16h40SergeLuquet"Triglyceridesensinginthemesolimbicsystemandthecontroloffoodreward"17h15Concludingremarksandposterprizedistribution

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ABSTRACTSTheCNScontrolofbloodglucose-rolesforVMNsubpopulationsMartinG.MyersUniversityofMichiganMedicalschool,AnnArbor,USAWhile the ventromedial hypothalamic nucleus (VMN) plays an essential role in thecontrolofglucosehomeostasis,includingbymediatingthecounter-regulatoryresponse(CRR)tohypoglycemia,theVMNcontainsmultiplesubpopulationsofneuronsthatplaydistinct roles in the control of hypoglycemia, and the neurons that control hepaticglucoseoutput,includingduringtheCRRhavenotpreviouslybeenmolecularlydefined.Since we previously showed that cholecystokinin (CCK) neurotransmission plays animportantroleintheVMN-mediatedCRR,wegeneratedCCKreceptorb(Cckbr)-cremicetostudythepotentialroleofVMNCckbrneuronsinthecontrolofbloodglucose.CckbrCrereportermiceidentifiedasubstantialpopulationofVMNCckbrneuronsinthedorsomedialVMN. The optogenetic activation of VMNCckbr neurons increased blood glucose,consistentwitharoleinthecontrolofglucoseproduction.Furthermore,whiletetanustoxin-mediated silencing of the entire VMN (using SF1cre) promoted obesity andhyperglycemia,silencingVMNCckbrneuronsdidnotalterbodyweight,butreducedbloodglucose at baseline and impaired the CRR (as well as the hyperglycemic response toother stimuli). Thus, VMNCckbr neurons play a crucial role in the control of glucoseproduction,includingduringtheCRR.

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CentralmitochondriadynamicsandmetabolismSabrinaDiano1,2,3,4,51ProgramofIntegrativeCellSignalingandNeurobiologyofMetabolism,2DepartmentsofObstetrics,Gynecology,andReproductiveSciences,3ofNeuroscienceand4ofComparativeMedicine,YaleUniversitySchoolofMedicineandGraduateSchool,NewHaven,Connecticut,06520USA;Dept.ClinicalMedicineandSurgery,UniversityofNaples“FedericoII”,Naples,Italy.Our research has been focusing on deciphering intracellular mechanisms that enablecellsintheCentralNervousSystem(CNS)tosenseandrespondtochangesincirculatingnutrientandhormonelevelsinthecontrolofsystemicenergyandglucosemetabolism.OurrecentfindingshaveunmaskedCNSmitochondriaascriticalintracellularorganelleindetectingchangesinperipheralmetabolism.Byalteringtheirsize,shapeandfunction,mitochondria enable cells to adjust their activity, which in turn alter behavior andperipheral tissue functions to fine tune systemic metabolism. This presentation willhighlight these cellularbiologicalprocess in theCNS regulationof energyandglucosehomeostasis.

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TargetinghypothalamicAMPKforthetreatmentofobesityMiguelLópez.E-mail:m.lopez@us.esNeurObesityGroup,DepartmentofPhysiology,CIMUS,UniversityofSantiagodeCompostela-InstitutodeInvestigaciónSanitaria,SantiagodeCompostela,15782,SpainBesides the classicalneuropeptideandneurotransmitter-based theory for feedingandenergy expenditure regulation, recent data demonstrate that AMP-activated proteinkinase(AMPK)playsamajorroleinthemodulationofenergybalance.Atcentrallevel,theAMPKpathway is a canonical route regulating energyhomeostasis, by integratingperipheralsignals,suchashormonesandmetaboliteswithneuronalnetworks.Currentevidence has linked hypothalamic AMPK with feeding brown adipose tissue (BAT)thermogenesisandbrowningofwhiteadiposetissue(WAT),boththroughmodulationofthesympatheticnervoussystem,aswellasmusclemetabolism,hepaticfunctionandglucose homeostasis a process in with hindbrain AMPK has been also involved. Therelevance of these data is interesting from a therapeutic point of view since severalagentswithpotentialanti-obesityand/orantidiabeticeffects,currentlybeingclinicallyused, such as nicotine,metformin and liraglutide are known to act throughAMPK, atperipheral or central level. Furthermore, the orexigenic and weight-gain effect ofworldwideusedantipsychoticdrugs,likeolanzapine,arealsomediatedbyhypothalamicAMPK.Overall,thisevidencemakeshypothalamicAMPKsignalinganinterestingtargetfor drug development. This talk will summarize the role of hypothalamic AMPK onwholebodyenergymetabolismanditspotentialastargetforobesitytreatment.

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BileacidsignalingasnovelmechanisminthecentralcontrolofenergybalanceDanielaCota,MD1,21.Teamleader,TeamEnergyBalanceandObesity,INSERMU1215,NeurocentreMagendie,Bordeaux,France2.UniversityofBordeaux,FrancePreviousstudieshaveshownthatbileacidsarecriticalregulatorofmetabolicresponsesin peripheral organs. However, no investigation has so far evaluated the role of bileacidsanditsreceptorTGR5inthehypothalamiccontrolofenergybalance.Datathatwehave generated support the existence of a hypothalamic bile acids-TGR5 signalingsystem,which isrelevant forthemaintenanceofenergyhomeostasis.Pharmacologicalstimulation of central TGR5 reduces food intake and body weight, while decreasingadiposity and improving insulin sensitivity in diet-induced obese mice. Conversely,hypothalamic deletion of TGR5 in adult mice causes hyperphagia and obesity.Investigationscurrentlyongoingwillhelpdefinethecellularandmolecularmechanismsinvolved, thusproviding furtherevidence supportingabeneficial role forbile acids inobesityandtype2diabetes.Acknowledgements:INSERM,AquitaineRegion,ANR,FFRD,MexicanConaCyt.

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Gutmicrobetobrainsignalling:implicationsfordepressionandco-morbidobesityTedDinanMD,PhDDepartmentofPsychiatryandAPCMicrobiomeInstitute,UniversityCollegeCork,IrelandEvidence is accumulating to suggest that gut microbes may be involved in neuraldevelopmentandfunction,bothperipherallyintheentericnervoussystemandcentrallyin the brain. There is an increasing and intense current interest in the role that gutbacteria play in maintaining the health of the host. Altogether the mass of intestinalbacteria represents a virtual inner organ with 100 times the total genetic materialcontainedinallthecellsinthehumanbody.However,adisorderedbalanceamongstgutmicrobes is now thought to be an associated or even causal factor formany chronicmedical conditions as varied as obesity and inflammatory bowel diseases. Whileevidence isstill limited inpsychiatric illnesses, therearerapidlycoalescingclustersofevidence which point to the possibility that variations in the composition of gutmicrobes may be associated with changes in the normal functioning of the nervoussystem, especially in patients with major depression. Studies in germ-free animalsindicate aberrant development of the brain monoaminergic system together withmemory deficits and autistic patterns of behaviour. These deficits can be partiallynormalised if there is early gut colonisation. Recent pre-clinical studies suggest thatcertainBifidobacteriamayhaveanxiolyticorantidepressant.Major depression is associated with an increased risk of metabolic disturbance. Ourstudies have demonstrated that depressed patients have increases in visceral fatcontent,which isa risk factor forheartdisease. Suchpatientsalsohave increases incirculating pro-inflammatory cytokines, notably IL-6 and TNF-alpha. Furthermore,there are now three separate studies showing that the gut microbiota is altered indepression. When rodents undergo a microbiota transplant from patients withdepression they show behavioural and immune changes consistent with depression.Theseobservationshaveledtotheconclusionthatdepressionisadisorderofthebrain-gut-microbiotaaxis.MetchnikoffwasthefirsttoobservethefactthatthoselivinginaregionofBulgariawhoconsumed fermented food in their diet tended to live longer. He first published hisobservationsin1908andthisgaverisetotheconceptofaprobioticorbacteriawithahealth benefit. That bacteriamight have a positivemental health aswell as physicalbenefit is nowbecoming clear. Suchbacteriamay influence the capacity todealwithstress, reducing anxiety, perhaps positively impacting on mood and are now calledpsychobiotics.Somestrainsofprobiotics/psychobioticsmayhavethecapacitynotjustto treat stress related disorders but also the ability to impact co-morbid obesity.Prebiotics, which are indigestible fibres, have been shown to positively impact themetabolic syndrome and our recent studies indicate that the prebiotics FOS and GOSalsoimpactstressresponses.

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Themechanismsthroughwhichgutmicrobesinfluencemoodandco-morbidmetabolicdisturbance are not entirely clear. The production of short chain fatty acids such asbutyrate,propionateandacetatemaybeimportant.Lacobacillusrhamnosushaspotentanti-anxiety effects in animals and does so by producing major changes in theexpression of GABA receptors in the brain. GABA is the most important inhibitorytransmitter in the human brain and these are the receptors through whichbenzodiazepinessuchasdiazepamandvariousanaestheticagentsact. Thechangesinthesereceptorsaremediatedbythevagusnervewhichconnectsthebrainandgut.Thevagusnervehasbeenshowntohavepotentanti-inflammatorypotentialwhichmaybeimportant in counteracting the pro-inflammatory effects of co-morbid obesityfrequentlyobservedindepression.Communication between the brain and gut is bidirectional and complex. Increasedunderstandingofthisaxisandtheroleofthegutmicrobiotamayaidthedevelopmentoftherapiesnotjustformooddisordersbutrelatedmetabolicdisturbance.

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SympatheticNeuroimmunityforObesity AnaDomingos,PhD1,21.AssociateProfessorofNeuroscience,Dept.Physiology,Anatomy,GeneticsatUniversityofOxford.2.HowardHughesMedicalInstitute,IRS,ObesityLaboratory,GulbenkianScienceInstituteRuaDaQuintaGrande,6,2780-156,OeirasThe brain controls adiposity via central and peripheral neural circuits. We usedmoleculargenetictoolssuchasoptogeneticstoprobetheconnectionbetweenperipheralsympatheticneuronsandadipocytes.Further,wefoundthisneuro-adipose junctiontodrivelipolysisvianorepinephrine(NE)signaling(1)andthattheSNSisnecessaryandsufficientforfatmassreduction(1,2).Asobesityisachronicinflammatorystate,wesetto define neuroimmune mechanisms that link inflammation to SNS neurons (3). Wereport the discovery of Sympathetic neuron-Associated Macrophages (SAMs) thatdirectlyregulatetheextracellularavailabilityofnorepinephrine(NE).Weidentifiedthemolecular mechanism by which SAMs import and metabolize norepinephrine (NE).Abrogationof themechanism for theuptakeofNEby SAMs increasesNE availability,which in turn promotes thermogenesis and browning, and long-term amelioration ofobesity independentlyof food intake(3).TheroleofSAMsatsteadystateandobesitywillbediscussed.Acknowledgements: Howard Hughes Medical Institute, The Welcome Trust, HumanFrontiers Science Fund, European Molecular Biology Organization, Fundação paraCiênciaeTecnologia,MaratonadaSaúde,FundaçãoCalousteGulbenkian.References:1.ZengW*, PirzgalskaRM*; PereiraMMA;KubasovaN;BarateiroA;SeixasE;LuYH;Kozlova A; Voss H; Martins GG; Friedman JM, Domingos AIψ (2015). SympatheticNeuro-AdiposeConnectionsMediateLeptin-DrivenLipolysis.Cell.163(1):84–94,2. Pereira MMA, Mahú I, Seixas E, Martinéz-Sánchez N, Kubasova N, Pirzgalska RM,Cohen P, Dietrich MO, López M, Bernardes GJL, Domingos, AIψ A brain-sparingdiphtheriatoxinforchemicalgeneticablationofperipheralcelllineages.(2017)NatureCommunications.8:15673.3.RoksanaMPirzgalska*,ElsaSeixas*,JasonSSeidman,VerenaMLink,NoeliaMartínezSánchez,Inês Mahú,Raquel Mendes,Vitka Gres,Nadiya Kubasova,ImogenMorris,BernardoAArús,ChelseaMLarabee,MiguelVasques,FranciscoTortosa,AnaLSousa,Sathyavathy Anandan,Erin Tranfield,Maureen K Hahn,MatteoIannacone,Nathanael J Spann,Christopher K Glass&Ana IDomingosψ(2017).Sympathetic neuron–associated macrophages contribute toobesity by importing and metabolizing norepinephrine.Nature Medicine.Feature: Conor A. Bradley (2017).Specialized macrophages contribute toobesity.NatureReviewsEndocrinology.

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NovelregulatorsofthecentralcontroloffeedingandsystemicinsulinsensitivitySophieM.SteculorumMaxPlanckInstituteforMetabolismResearchOver the last decades, our understanding of the fundamental processes governingenergy balance and glucose homeostasis has largely evolved andpinpointed a pivotalroleof thecentralnervoussystemandmoreparticularlyof thearcuatenucleusof thehypothalamus(ARH).Notably,activationoforexigenicAgRP-expressingneuronslocatedintheARHpotentlypromotesfeeding.Wedemonstratethatinadditiontoitsorexigeniceffects, chronically altering AgRP-neurons activity also affects peripheral glucosehomeostasis. Acute activation of AgRP-neurons causes insulin resistance throughimpairmentof insulin-stimulatedglucoseuptake intobrownadipose tissue (BAT)anddecreased sympathetic nerve activity. Optogenetic circuitry mapping reveals thatfeeding and insulin sensitivity are controlled by both distinct and overlapping AgRP-projections.WenotablyfindthatactivationofAgRP→aBNSTvl(ventrolateralpartoftheanterior bed nucleus of the stria terminalis) projectionsmediates the effect of AgRP-neuron activation on insulin sensitivity and BAT gene expression. Our results thusreveal a mechanism by which these neurons rapidly coordinate hunger states withglucosehomeostasis.Alongthisline,wediscoveredanovelAgRP-neurons’stimulatorypathway able to modulate both feeding and insulin sensitivity. We show that AgRP-neurons express the purinergic receptor 6 (P2Y6) and that activation of P2Y6 by itsendogenousliganduridine-diphosphateincreasesAgRP-neuron’sactionpotentialfiringandpromotes feeding.Further, selectivelyabrogatingP2Y6-signaling inAgRP-neuronsalleviates obesity-associated adiposity, hyperphagia, and insulin resistance. Our workthereforerevealsthatmodulatingAgRP-neuronsbytargetingP2Y6-signalingimprovesobesity-associatedmetabolicoutcomes.

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TriglyceridesensinginthemesolimbicsystemandthecontroloffoodrewardChloéBerland1,2,CelineCansell1,YukoNakamuraY3,4,GiuseppeGangarossa1,MohammadAliShenasa5,JulienCastel1,MartineCador6.7,StephanieCaille6.7,StefaniaTolu8,FabioMarti8,PhilippeFaure8,JacobHecksher-Sørensen9.10,CasperBoJensen9,10,C.MaryBurke3.4,XueSun3,4,MatthiasH.Tschöp2,11,12,ThomasS.Hnasko5,DanaMSmall3.4,andSergeLuquet11UnivParisDiderot,SorbonneParisCité,UnitédeBiologieFonctionnelleetAdaptative,CNRSUMR8251,F-75205Paris,France.2HelmholtzDiabetesCenter,HelmholtzZentrumMünchen,GermanResearchCenterforEnvironmentalHealth,München/Neuherberg,Germany.3TheJohnBPierceLaboratory,290CongressAve,NewHavenCT,USA4YaleUniversity,333Cedar,NewHavenCT,USA5DepartmentofNeurosciences,UniversityofCalifornia,SanDiego,LaJollaCA,USA.6Univ.Bordeaux,InstitutdeNeurosciencesCognitivesetIntégrativesd’Aquitaine,UMR5287,33076Bordeaux,France7CNRS,InstitutdeNeurosciencesCognitivesetIntégrativesd’Aquitaine,UMR5287,33076Bordeaux,France8NeuroscienceParis-Seine–IBPS-UPMCUMCR18–CNRSUMR8246–INSERMU1130.EquipeNeurophysiologieetComportement(NPC),UniversiteP.etM.Curie,Paris,FRANCE8GlobalResearch,NovoNordiskA/S,Måløv,Denmark;9ImageAnalysis&ComputerGraphics,DepartmentofAppliedMathematicsandComputerScience,TechnicalUniversityofDenmark,Kgs.Lyngby,Denmark;10GubraApS,HørsholmKongevej11B,2970Hørsholm,Denmark11DivisionofMetabolicDiseases,TUM,Munich,Germany;12InstituteforAdvancedStudy,TUM,Munich,GermanyCirculating triglycerides (TGs) normally increase after a meal but are altered inpathophysiological conditions, such as obesity in both human and rodent. TG-hydrolyzingenzymesareexpressedinthemesolimbicdopaminergicsystemsuggestingthat central TG-sensing might regulate dopamine neurons activity and ultimatelyreward-drivenbehaviour.Using brain-specific TG delivery (BTGD), we show nutritional TG accessmesocorticolimbic (MCL) structures where they modulate dopamine (DA) neuronsactivityandsignalling.CentralTGsensingismediated,atleastinpart,bythelipoproteinlipase(LPL)whosetranscript isspecifically foundontoDAandmediumSpinyNeuron(MSN) neurons. TG detected centrally create positive reinforcement in a conditionedplacepreferenceparadigm(liking)but leadtoreducedmotivationtowork forreward(wanting)asassessedbybothoperantconditioningandself-administration.Finally,wefind that TG action on reward seeking behaviour primarily rely on the indirectDopaminereceptorDRD2pathway.Usingfunctionalmagneticresonance(fMRI)wefoundthat inhuman,post-prandialTGexcursionsmodulatebrainresponsetofoodversusnon-foodcues.Theresponseoftheventromedial prefrontal cortex (vmPFC)was specific to TG and independent of otherenergy-relatedsignals.Finally, theactionofTGontobrainresponsewasdrivenbythe

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genetic polymorphism TaqAI, a mutation known to affect D2DR signaling andsusceptibilitytoaddiction.Collectively, these findings reveal new mechanisms by which dietary TG altermesolimbic circuit function and reward seeking behaviour, and provide a novelhypothesisbywhichenergy-richdietmight leadtodopaminecircuitryadaptationandultimatelyaddictivebehaviour.

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