2021
Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis
Gómez-Valadés AG, Pozo M, Varela L, Boudjadja MB, Ramírez S, Chivite I, Eyre E, Haddad-Tóvolli R, Obri A, Milà-Guasch M, Altirriba J, Schneeberger M, Imbernón M, Garcia-Rendueles AR, Gama-Perez P, Rojo-Ruiz J, Rácz B, Alonso MT, Gomis R, Zorzano A, D’Agostino G, Alvarez CV, Nogueiras R, Garcia-Roves PM, Horvath TL, Claret M. Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis. Cell Metabolism 2021, 33: 1820-1835.e9. PMID: 34343501, PMCID: PMC8432968, DOI: 10.1016/j.cmet.2021.07.008.Peer-Reviewed Original ResearchConceptsProtein OPA1Mitochondrial CaMitochondrial cristae architectureAdipose tissue lipolysisKey metabolic sensorPOMC neuronsCellular metabolic adaptationTissue lipolysisCristae architectureMetabolic sensorNutrient availabilityWhite adipose tissue lipolysisAlpha-melanocyte stimulating hormoneGenetic inactivationNovel axisMitochondrial functionOPA1Metabolic adaptationMitochondrial cristaeDramatic alterationsMutant miceProopiomelanocortin neuronsLipolysis controlWAT lipolysisPharmacological blockade
2017
Endothelial HIF-1α Enables Hypothalamic Glucose Uptake to Drive POMC Neurons
Varela L, Suyama S, Huang Y, Shanabrough M, Tschöp M, Gao XB, Giordano FJ, Horvath TL. Endothelial HIF-1α Enables Hypothalamic Glucose Uptake to Drive POMC Neurons. Diabetes 2017, 66: db161106. PMID: 28292966, PMCID: PMC5440016, DOI: 10.2337/db16-1106.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBehavior, AnimalBlotting, WesternEndotheliumEnergy MetabolismFood DeprivationGene Knockdown TechniquesGlucoseHyperphagiaHypothalamusHypoxia-Inducible Factor 1, alpha SubunitImmunohistochemistryMiceMicroscopy, ElectronMitochondriaNeuronsPatch-Clamp TechniquesPro-OpiomelanocortinReal-Time Polymerase Chain ReactionConceptsPOMC neuronsGlucose uptakePOMC neuronal activityHypothalamic proopiomelanocortin (POMC) neuronsHypoxia-inducible factor-1αProopiomelanocortin neuronsVascular impairmentGlucose administrationMetabolic disordersNeuronal activityMetabolic environmentFactor-1αImpaired functioningEndothelial cellsNeuronsFood deprivationVivoCentral controlHypothalamusMiceAdministrationUptakeImpairment
2016
Hypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis
Jin S, Kim JG, Park JW, Koch M, Horvath TL, Lee BJ. Hypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis. Scientific Reports 2016, 6: 29424. PMID: 27405276, PMCID: PMC4942617, DOI: 10.1038/srep29424.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnorexiaArcuate Nucleus of HypothalamusCyclooxygenase InhibitorsEnergy MetabolismFeverInflammationLipopeptidesMaleMiceMice, KnockoutMicrogliaMyeloid Differentiation Factor 88NF-kappa BPro-OpiomelanocortinRatsReceptor, Melanocortin, Type 3Receptor, Melanocortin, Type 4Toll-Like Receptor 2Weight LossConceptsSickness behaviorHypothalamic inflammationToll-like receptor 2 (TLR2) activationSickness behavior symptomsNuclear factor kappa BBody weight lossReceptor 2 activationFactor kappa BNeuronal circuit functionHypothalamic microgliaProopiomelanocortin neuronsInflammatory mechanismsIntracerebroventricular injectionPathophysiologic mechanismsTLR2 activationInflammatory processCyclooxygenase pathwayNeuronal activationKappa BBehavior symptomsWeight lossInput organizationMicrogliaTLR2Inflammation
2014
Mitochondrial dynamics in the central regulation of metabolism
Nasrallah CM, Horvath TL. Mitochondrial dynamics in the central regulation of metabolism. Nature Reviews Endocrinology 2014, 10: 650-658. PMID: 25200564, DOI: 10.1038/nrendo.2014.160.Peer-Reviewed Original ResearchConceptsPOMC neuronsMetabolic disordersPeripheral tissue functionsCentral melanocortin systemMitochondrial dynamicsProopiomelanocortin neuronsAnorexigenic responseOrexigenic responseHypothalamic neuronsCentral regulationMelanocortin systemNeuronsDistinct signaling pathwaysSignaling pathwaysMitochondrial fusionMolecular regulatorsTissue functionDistinct functionsDisordersFatty acidsMetabolismActivationObesityAppetiteResponsePPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding
Long L, Toda C, Jeong JK, Horvath TL, Diano S. PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding. Journal Of Clinical Investigation 2014, 124: 4017-4027. PMID: 25083994, PMCID: PMC4151211, DOI: 10.1172/jci76220.Peer-Reviewed Original ResearchConceptsHigh-fat dietPOMC neuronsFood intakeImproved glucose metabolismHigh-fat feedingWhole-body energy balanceBody weight gainProopiomelanocortin neuronsPeripheral administrationFat massLeptin sensitivityControl animalsGlucose metabolismBody weightPPARγ activatorsLocomotor activityEnergy homeostasisPPARγWeight gainNeuronsSelective ablationEnergy expenditureIntakeNuclear receptorsMice
2012
Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes
Fuente-Martín E, García-Cáceres C, Granado M, de Ceballos ML, Sánchez-Garrido MÁ, Sarman B, Liu ZW, Dietrich MO, Tena-Sempere M, Argente-Arizón P, Díaz F, Argente J, Horvath TL, Chowen JA. Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes. Journal Of Clinical Investigation 2012, 122: 3900-3913. PMID: 23064363, PMCID: PMC3484452, DOI: 10.1172/jci64102.Peer-Reviewed Original ResearchConceptsGlial structural proteinsPathology of obesityHypothalamic proopiomelanocortin (POMC) neuronsGlial cell activityOffspring of mothersHigh-fat dietActivity of neuronsExpression of glucoseProopiomelanocortin neuronsHypothalamic astrocytesGlial cellsBody weightSynaptic efficacyGlutamate transportersNeuronal functionCell activityLeptinGlucose uptakeMetabolic statusElectrical activityMetabolic signalsNeuronsAppetiteGlucose transporterKey regulator
2011
Effects of chronic weight perturbation on energy homeostasis and brain structure in mice
Ravussin Y, Gutman R, Diano S, Shanabrough M, Borok E, Sarman B, Lehmann A, LeDuc CA, Rosenbaum M, Horvath TL, Leibel RL. Effects of chronic weight perturbation on energy homeostasis and brain structure in mice. AJP Regulatory Integrative And Comparative Physiology 2011, 300: r1352-r1362. PMID: 21411766, PMCID: PMC3119157, DOI: 10.1152/ajpregu.00429.2010.Peer-Reviewed Original ResearchConceptsDiet-induced obeseEnergy expenditureArcuate nucleus proopiomelanocortin neuronsWeight lossWeight-reduced individualsSustained weight lossReduced body weightObese human subjectsCentral nervous systemHuman subjectsSustained weight gainProopiomelanocortin neuronsBody massUpward resettingMale miceExcitatory synapsesBody fatMouse modelBody weightNervous systemSynaptic changesPersistent decreaseEnergy homeostasisWeight gainBrain structures
2009
Divergent Regulation of Energy Expenditure and Hepatic Glucose Production by Insulin Receptor in Agouti-Related Protein and POMC Neurons
Lin HV, Plum L, Ono H, Gutiérrez-Juárez R, Shanabrough M, Borok E, Horvath TL, Rossetti L, Accili D. Divergent Regulation of Energy Expenditure and Hepatic Glucose Production by Insulin Receptor in Agouti-Related Protein and POMC Neurons. Diabetes 2009, 59: 337-346. PMID: 19933998, PMCID: PMC2809966, DOI: 10.2337/db09-1303.Peer-Reviewed Original ResearchConceptsHepatic glucose productionAgRP neuronsPOMC neuronsInsulin receptorEnergy expenditureInsulin actionGlucose productionInhibitory synaptic contactsSulfonylurea receptor 1 (SUR1) subunitsCentral nervous systemL1 miceProopiomelanocortin neuronsHypothalamic insulinDivergent regulationInsulin resistanceSynaptic contactsInsulin suppressionGlucose metabolismHypothalamic deficiencyNervous systemLocomotor activityDecreased expressionEnergy homeostasisINSRNeurons
2006
Synaptic Plasticity in Energy Balance Regulation
Horvath TL. Synaptic Plasticity in Energy Balance Regulation. Obesity 2006, 14: 228s-233s. PMID: 17021372, DOI: 10.1038/oby.2006.314.Peer-Reviewed Original ResearchConceptsOb/ob miceNumber of excitatoryNeuropeptide YSynaptic plasticityPOMC neuronsOb miceFood intakeBehavioral effectsLeptin receptor-deficient miceRearrangement of synapsesLeptin-deficient miceReceptor-deficient miceHypothalamic arcuate nucleusOb/obEnergy balance regulationWild-type miceInfluences brain functionObserved synaptic plasticityWild-type animalsProopiomelanocortin neuronsAnorexigenic hormonesOrexigenic hormonePost-synaptic densityGlutamate inputsExtrahypothalamic sitesgp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor
Janoschek R, Plum L, Koch L, Münzberg H, Diano S, Shanabrough M, Müller W, Horvath TL, Brüning JC. gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor. Proceedings Of The National Academy Of Sciences Of The United States Of America 2006, 103: 10707-10712. PMID: 16818888, PMCID: PMC1502296, DOI: 10.1073/pnas.0600425103.Peer-Reviewed Original ResearchConceptsCiliary neurotrophic factorAnorectic effectPOMC neuronsNeurotrophic factorCNTF actionAcute anorectic responseNormal energy homeostasisHigh-fat dietStress-induced anorexiaC-fos expressionProopiomelanocortin neuronsAnorectic responseHypothalamic neuronsLeptin resistanceFat dietParaventricular nucleusUnaltered numberKnockout micePOMC cellsCommon cytokinesEnergy homeostasisNeuronsSTAT3 phosphorylationExact siteCre-loxPEnhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity
Plum L, Ma X, Hampel B, Balthasar N, Coppari R, Münzberg H, Shanabrough M, Burdakov D, Rother E, Janoschek R, Alber J, Belgardt BF, Koch L, Seibler J, Schwenk F, Fekete C, Suzuki A, Mak TW, Krone W, Horvath TL, Ashcroft FM, Brüning JC. Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. Journal Of Clinical Investigation 2006, 116: 1886-1901. PMID: 16794735, PMCID: PMC1481658, DOI: 10.1172/jci27123.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsChromonesDietEatingFemaleHypoglycemic AgentsHypothalamusInsulinLeptinMaleMembrane PotentialsMiceMice, KnockoutMorpholinesNeuronsObesityPhosphatidylinositol 3-KinasesPhosphatidylinositol PhosphatesPhosphoinositide-3 Kinase InhibitorsPotassium ChannelsPro-OpiomelanocortinPTEN PhosphohydrolaseSecond Messenger SystemsTolbutamideConceptsPOMC neuronsATP-sensitive potassium channel activityBasal firing rateHypothalamic proopiomelanocortin (POMC) neuronsElectrical activityKATP channel activationPI3K inhibitor LY294002PTEN knockout micePotassium channel activityK inhibitor LY294002PI3K pathwayProopiomelanocortin neuronsHypothalamic receptorsICV administrationFood intakeKATP channelsKnockout miceMelanocortin systemLeptinFiring rateNeuronsMiceSTAT3 phosphorylationK pathwayInhibitor LY294002
2004
Rapid Rewiring of Arcuate Nucleus Feeding Circuits by Leptin
Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X, Friedman JM, Horvath TL. Rapid Rewiring of Arcuate Nucleus Feeding Circuits by Leptin. Science 2004, 304: 110-115. PMID: 15064421, DOI: 10.1126/science.1089459.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArcuate Nucleus of HypothalamusBody WeightEatingEvoked PotentialsExcitatory Postsynaptic PotentialsFeeding BehaviorGamma-Aminobutyric AcidGhrelinGlutamic AcidGreen Fluorescent ProteinsIn Vitro TechniquesLeptinLuminescent ProteinsMiceMice, ObeseMice, TransgenicNeuronal PlasticityNeuronsNeuropeptide YPatch-Clamp TechniquesPeptide HormonesPro-OpiomelanocortinRecombinant Fusion ProteinsSynapsesTetrodotoxinTransgenesConceptsProopiomelanocortin neuronsNeuropeptide YFat-derived hormone leptinBehavioral effectsOb/ob miceLeptin-deficient miceOb/obHypothalamic arcuate nucleusWild-type miceNumber of excitatoryArcuate nucleusLeptin effectsPostsynaptic currentsOb miceHormone leptinSynaptic densityInhibitory synapsesFood intakeNeuronal typesLeptinMiceNeuronsFeeding circuitRapid rewiringHours