2015
AgRP Neurons Regulate Bone Mass
Kim JG, Sun BH, Dietrich MO, Koch M, Yao GQ, Diano S, Insogna K, Horvath TL. AgRP Neurons Regulate Bone Mass. Cell Reports 2015, 13: 8-14. PMID: 26411686, PMCID: PMC5868421, DOI: 10.1016/j.celrep.2015.08.070.Peer-Reviewed Original ResearchMeSH KeywordsAgouti-Related ProteinAnimalsArcuate Nucleus of HypothalamusBone DensityBone Diseases, MetabolicFemurGene Expression RegulationHomeostasisHypothalamusIon ChannelsLeptinMaleMiceMice, KnockoutMitochondrial ProteinsNeuronsNorepinephrinePhenotypePropranololReceptors, Adrenergic, betaReceptors, LeptinSignal TransductionSirtuin 1TibiaUncoupling Protein 2ConceptsAgRP neuronsCell-autonomous deletionSignificant regulatory roleAgRP neuronal functionBone massLeptin receptor deletionSkeletal bone metabolismTransgenic animalsRegulatory roleGene deletionBone homeostasisDeletionNeuronal functionPostnatal deletionSympathetic toneReceptor deletionArcuate nucleusLeptin actionBone metabolismSkeletal metabolismMultiple linesNeuronsMiceMetabolismCircuit integrityHypothalamic POMC neurons promote cannabinoid-induced feeding
Koch M, Varela L, Kim JG, Kim JD, Hernández-Nuño F, Simonds SE, Castorena CM, Vianna CR, Elmquist JK, Morozov YM, Rakic P, Bechmann I, Cowley MA, Szigeti-Buck K, Dietrich MO, Gao XB, Diano S, Horvath TL. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 2015, 519: 45-50. PMID: 25707796, PMCID: PMC4496586, DOI: 10.1038/nature14260.Peer-Reviewed Original ResearchConceptsPOMC neuronsΒ-endorphinHypothalamic pro-opiomelanocortin (POMC) neuronsOpioid peptide β-endorphinHypothalamic POMC neuronsPromotion of feedingPro-opiomelanocortin (POMC) neuronsCannabinoid receptor 1CB1R activityPOMC activitySated miceHormone releaseHypothalamic administrationFood intakeCentral regulationNeuronal activityParadoxical increaseCB1RReceptor 1POMC cellsNeuronsMitochondrial adaptationsDecreased activityPOMC geneUnsuspected role
2013
UCP2 overexpression worsens mitochondrial dysfunction and accelerates disease progression in a mouse model of amyotrophic lateral sclerosis
Peixoto PM, Kim HJ, Sider B, Starkov A, Horvath TL, Manfredi G. UCP2 overexpression worsens mitochondrial dysfunction and accelerates disease progression in a mouse model of amyotrophic lateral sclerosis. Molecular And Cellular Neuroscience 2013, 57: 104-110. PMID: 24141050, PMCID: PMC3891658, DOI: 10.1016/j.mcn.2013.10.002.Peer-Reviewed Original ResearchConceptsAmyotrophic lateral sclerosisDouble transgenic miceFamilial amyotrophic lateral sclerosisMouse modelLateral sclerosisMitochondrial dysfunctionTransgenic miceMutant SOD1 mouse modelHuman UCP2Brain mitochondriaSOD1 mutant miceUCP2 overexpressionPotential neuroprotective effectsProtection of neuronsSOD1 mouse modelCentral nervous systemReactive oxygen species productionDisease courseG93A miceNeuroprotective effectsNeuroprotective roleFree radical generationDisease progressionOxygen species productionInjury paradigmsNatural birth-induced UCP2 in brain development
Seli E, Horvath TL. Natural birth-induced UCP2 in brain development. Reviews In Endocrine And Metabolic Disorders 2013, 14: 347-350. PMID: 23979530, DOI: 10.1007/s11154-013-9262-8.Peer-Reviewed Original ResearchConceptsVaginal birthPost-operative surgical careLong-term outcomesEarly postnatal periodWild-type littermatesAdult brain structureUCP2 mRNA expressionTerm outcomesSurgical techniqueSurgical carePostnatal periodSurgical meansHippocampal formationMore deliveriesSynapse formationAxonal outgrowthC-sectionKnockout animalsMRNA expressionUCP2 expressionBrain developmentBrain structuresNeuronal differentiationBirthHippocampusRole of uncoupling protein 3 in ischemia-reperfusion injury, arrhythmias, and preconditioning
Ozcan C, Palmeri M, Horvath TL, Russell KS, Russell RR. Role of uncoupling protein 3 in ischemia-reperfusion injury, arrhythmias, and preconditioning. AJP Heart And Circulatory Physiology 2013, 304: h1192-h1200. PMID: 23457013, PMCID: PMC3652089, DOI: 10.1152/ajpheart.00592.2012.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsArrhythmias, CardiacCarbonyl Cyanide p-TrifluoromethoxyphenylhydrazoneCoronary OcclusionIn Vitro TechniquesIon ChannelsIschemic Preconditioning, MyocardialMaleMiceMice, Inbred C57BLMitochondrial ProteinsMyocardial InfarctionMyocardial Reperfusion InjuryMyocytes, CardiacReactive Oxygen SpeciesUncoupling Protein 2Uncoupling Protein 3Ventricular DysfunctionConceptsIschemia-reperfusion injuryR injuryIschemic preconditioningWT heartsMyocardial energeticsMouse heartsReactive oxygen speciesLeft coronary arteryLeft ventricular functionPostischemic functional recoveryWild-type mouse heartsUncoupling proteinDecreased ATP contentR arrhythmiasLarge infarctsVentricular functionFunctional recoveryWT miceCoronary arteryProtective efficacyCardioprotective efficacyMyocardial vulnerabilityVivo modelInjuryRole of UCPs
2012
Ucp2 Induced by Natural Birth Regulates Neuronal Differentiation of the Hippocampus and Related Adult Behavior
Simon-Areces J, Dietrich MO, Hermes G, Garcia-Segura LM, Arevalo MA, Horvath TL. Ucp2 Induced by Natural Birth Regulates Neuronal Differentiation of the Hippocampus and Related Adult Behavior. PLOS ONE 2012, 7: e42911. PMID: 22905184, PMCID: PMC3414493, DOI: 10.1371/journal.pone.0042911.Peer-Reviewed Original ResearchConceptsUCP2 expressionCellular stressHippocampal neuronsChemical inhibitionMitochondrial bioenergeticsNeuronal differentiationGenetic ablationNatural birthProtein 2Adult behaviorCell proliferationCritical roleAdult brainNeuronal numberExpressionBioenergeticsNeuronsBirthDifferentiationRegulationProliferationSynaptogenesisVitroNeuroprotectionHippocampus
2011
Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism
Diano S, Horvath TL. Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism. Trends In Molecular Medicine 2011, 18: 52-58. PMID: 21917523, DOI: 10.1016/j.molmed.2011.08.003.Peer-Reviewed Original ResearchConceptsProtein 2Lipid metabolismExcess of nutrientsHypothalamic neuronal circuitsNutrient availabilityPeripheral tissue functionsPhysiological functionsMetabolism regulationChronic diseasesMetabolism-related chronic diseasesTissue functionFuture therapeutic strategiesPathological processesPeripheral mechanismsLipid levelsNeuronal circuitsTherapeutic strategiesMetabolismImpairs healthMitochondriaDiseaseUCP2GlucoseRegulationNutrients
2010
Uncoupling Protein-2 Decreases the Lipogenic Actions of Ghrelin
Andrews ZB, Erion DM, Beiler R, Choi CS, Shulman GI, Horvath TL. Uncoupling Protein-2 Decreases the Lipogenic Actions of Ghrelin. Endocrinology 2010, 151: 2078-2086. PMID: 20189996, PMCID: PMC2869261, DOI: 10.1210/en.2009-0850.Peer-Reviewed Original ResearchConceptsBody weight gainGhrelin treatmentWeight gainLipogenic actionsBody weightFat oxidationFat metabolismChronic ghrelin treatmentDaily ip injectionsWhite adipose tissueNegative energy balanceCalorie restriction modelOsmotic minipumpsIP injectionBody fatGhrelinAdipose tissueMiceReactive oxygen speciesExact mechanismUCP2 mRNALipogenesisProtein 2Oxygen speciesTreatment
2009
Ghrelin Promotes and Protects Nigrostriatal Dopamine Function via a UCP2-Dependent Mitochondrial Mechanism
Andrews ZB, Erion D, Beiler R, Liu ZW, Abizaid A, Zigman J, Elsworth JD, Savitt JM, DiMarchi R, Tschöp M, Roth RH, Gao XB, Horvath TL. Ghrelin Promotes and Protects Nigrostriatal Dopamine Function via a UCP2-Dependent Mitochondrial Mechanism. Journal Of Neuroscience 2009, 29: 14057-14065. PMID: 19906954, PMCID: PMC2845822, DOI: 10.1523/jneurosci.3890-09.2009.Peer-Reviewed Original ResearchConceptsDA cell lossNigrostriatal dopamine functionParkinson's diseaseDopamine functionCell lossSubstantia nigra pars compactaSNpc DA neuronsStriatal dopamine levelsStriatal dopamine lossExogenous ghrelin administrationLoss of appetiteDopamine cell degenerationNovel therapeutic strategiesMitochondrial mechanismsTyrosine hydroxylase mRNAReactive oxygen species productionMPTP treatmentPeripheral ghrelinSNpc cellsTetrahydropyridine (MPTP) treatmentDA neuronsDopamine lossGhrelin administrationPars compactaCatecholaminergic neuronsThe role of mitochondrial uncoupling proteins in lifespan
Dietrich MO, Horvath TL. The role of mitochondrial uncoupling proteins in lifespan. Pflügers Archiv - European Journal Of Physiology 2009, 459: 269-275. PMID: 19760284, PMCID: PMC2809791, DOI: 10.1007/s00424-009-0729-0.Peer-Reviewed Original ResearchConceptsMitochondrial inner membraneCellular biochemical reactionsMitochondrial uncoupling proteinProduction of ATPCellular functionsInner membraneSpecialized proteinsBreakdown of lipidsMain organellesExcess of ROSPhysiological uncouplingOxidative phosphorylationUncoupling proteinAdenosine triphosphateOxygen reactive speciesROS productionProteinEnergetic substratesBiochemical reactionsCellular damageMitochondriaROSIntermediate substrateUCPShed lightUncoupling protein-2 regulates lifespan in mice
Andrews ZB, Horvath TL. Uncoupling protein-2 regulates lifespan in mice. AJP Endocrinology And Metabolism 2009, 296: e621-e627. PMID: 19141680, PMCID: PMC2670629, DOI: 10.1152/ajpendo.90903.2008.Peer-Reviewed Original ResearchConceptsDifferent tissuesProtein 2Uncoupled mitochondrial respirationReactive oxygen species productionMammalian physiologyMutant animalsOxygen species productionMitochondrial respirationLevels of UCP2Species productionTissue functionLong lifespanUCP2Oxidative stressLifespanPostnatal survivalWild-type miceMiceTissuePhysiologyRespirationCells
2008
Exercise-Induced Synaptogenesis in the Hippocampus Is Dependent on UCP2-Regulated Mitochondrial Adaptation
Dietrich MO, Andrews ZB, Horvath TL. Exercise-Induced Synaptogenesis in the Hippocampus Is Dependent on UCP2-Regulated Mitochondrial Adaptation. Journal Of Neuroscience 2008, 28: 10766-10771. PMID: 18923051, PMCID: PMC3865437, DOI: 10.1523/jneurosci.2744-08.2008.Peer-Reviewed Original ResearchConceptsSynaptic plasticityVoluntary exerciseEssential organellesUCP2 functionProtein-2 mRNA expressionDendritic spine synapsesBioenergetic adaptationMitochondrial metabolismMitochondrial oxygen consumptionMitochondrial numberEnergetic needsMitochondrial adaptationsMitochondrial mechanismsExercise inducesDentate gyrusStratum radiatumSpine synapsesCA1 regionGlial morphologyHippocampal formationNeuronal activityGranule cellsAction potentialsNeuronal morphologyMRNA expressionUCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals
Andrews ZB, Liu ZW, Walllingford N, Erion DM, Borok E, Friedman JM, Tschöp MH, Shanabrough M, Cline G, Shulman GI, Coppola A, Gao XB, Horvath TL, Diano S. UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals. Nature 2008, 454: 846-851. PMID: 18668043, PMCID: PMC4101536, DOI: 10.1038/nature07181.Peer-Reviewed Original ResearchMeSH KeywordsAgouti-Related ProteinAnimalsCarnitine O-PalmitoyltransferaseFatty AcidsFeeding BehaviorGene Expression RegulationGhrelinHypothalamusIon ChannelsMembrane Potential, MitochondrialMiceMitochondriaMitochondrial ProteinsNeuronsNeuropeptide YPhosphorylationReactive Oxygen SpeciesSynapsesUncoupling Protein 2ConceptsNPY/AgRP neuronsAgRP neuronsNeuronal activityCo-express neuropeptide YGut-derived hormone ghrelinAgRP neuronal activityArcuate nucleus neuronsFatty acid oxidation pathwayHypothalamic mitochondrial respirationG protein-coupled receptorsGhrelin actionNeuropeptide YNucleus neuronsHormone ghrelinFood intakeGhrelinFree radicalsSynaptic plasticityNeuronal functionIntracellular mechanismsNeuronsMitochondrial mechanismsProtein 2Mitochondrial proliferationRobust changesOverexpression of UCP2 Protects Thalamic Neurons following Global Ischemia in the Mouse
Olsson T, Wieloch T, Diano S, Warden CH, Horvath TL, Mattiasson G. Overexpression of UCP2 Protects Thalamic Neurons following Global Ischemia in the Mouse. Cerebrovascular And Brain Metabolism Reviews 2008, 28: 1186-1195. PMID: 18301432, PMCID: PMC2642535, DOI: 10.1038/jcbfm.2008.8.Peer-Reviewed Original ResearchConceptsGlobal ischemiaHistologic damageNeurodegenerative diseasesDentate gyrus hippocampal subfieldGlobal brain ischemiaSelective neuronal deathWild-type littermatesDays of recoveryCell deathNeuronal damageOverexpression of UCP2Brain ischemiaHistopathological outcomeSublethal ischemiaThalamic neuronsNeuronal deathThalamic nucleiWT animalsThalamic regionsHippocampal subfieldsIschemiaExtensive cell deathUCP2 expressionThalamusLevels of UCP2
2007
A Central Thermogenic-like Mechanism in Feeding Regulation: An Interplay between Arcuate Nucleus T3 and UCP2
Coppola A, Liu ZW, Andrews ZB, Paradis E, Roy MC, Friedman JM, Ricquier D, Richard D, Horvath TL, Gao XB, Diano S. A Central Thermogenic-like Mechanism in Feeding Regulation: An Interplay between Arcuate Nucleus T3 and UCP2. Cell Metabolism 2007, 5: 21-33. PMID: 17189204, PMCID: PMC1783766, DOI: 10.1016/j.cmet.2006.12.002.Peer-Reviewed Original ResearchMeSH KeywordsAgouti-Related ProteinAnimalsArcuate Nucleus of HypothalamusEatingFastingFeeding BehaviorGreen Fluorescent ProteinsGuanosine DiphosphateHypothalamusIntercellular Signaling Peptides and ProteinsIodide PeroxidaseIon ChannelsMiceMice, Inbred C57BLMice, KnockoutMitochondriaMitochondrial ProteinsNeurogliaNeuronsNeuropeptide YProto-Oncogene Proteins c-fosThermogenesisTriiodothyronineUncoupling Protein 2ConceptsUncoupling protein 2Mitochondrial uncoupling protein 2Thyroid hormone productionProtein activityType 2 deiodinaseMitochondrial proliferationNeuropeptide YArcuate nucleusPhysiological roleMitochondrial uncouplingUCP2 activationProtein 2Hormone productionNPY/AgRP neuronsPhysiological significanceActive thyroid hormoneHypothalamic arcuate nucleusHypothalamic neuronal networksGlial cellsRebound feedingAgRP neuronsOrexigenic neuronsDeiodinaseDII activityPeripheral tissues
2006
Uncoupling protein‐2 promotes nigrostriatal dopamine neuronal function
Andrews ZB, Rivera A, Elsworth JD, Roth RH, Agnati L, Gago B, Abizaid A, Schwartz M, Fuxe K, Horvath TL. Uncoupling protein‐2 promotes nigrostriatal dopamine neuronal function. European Journal Of Neuroscience 2006, 24: 32-36. PMID: 16882005, DOI: 10.1111/j.1460-9568.2006.04906.x.Peer-Reviewed Original ResearchMeSH Keywords3,4-Dihydroxyphenylacetic AcidAnimalsCorpus StriatumDopamineDopamine Plasma Membrane Transport ProteinsImmunohistochemistryIon ChannelsMaleMembrane Transport ProteinsMiceMice, KnockoutMitochondrial ProteinsMotor ActivityNeuronsSubstantia NigraTyrosine 3-MonooxygenaseUncoupling Protein 2ConceptsSubstantia nigra pars compactaDopamine neuronal functionUCP2-KO miceParkinson's diseaseNeuronal functionNigrostriatal dopamine functionTyrosine hydroxylase immunoreactivityUCP2 knockout miceDopamine transporter immunoreactivityProtein 2Wild-type controlsHydroxylase immunoreactivityPars compactaDopamine turnoverTransporter immunoreactivityDopamine ratioBehavioral deficitsLocomotor functionNucleus accumbensBiochemical deficitsDopamine functionBrain regionsNeurological pathologiesDiseaseMiceUncoupling protein 2/3 immunoreactivity and the ascending dopaminergic and noradrenergic neuronal systems: Relevance for volume transmission
Rivera A, Agnati LF, Horvath TL, Valderrama JJ, de La Calle A, Fuxe K. Uncoupling protein 2/3 immunoreactivity and the ascending dopaminergic and noradrenergic neuronal systems: Relevance for volume transmission. Neuroscience 2006, 137: 1447-1461. PMID: 16387447, DOI: 10.1016/j.neuroscience.2005.05.051.Peer-Reviewed Original ResearchConceptsConfocal laser microscopy analysisReactive oxygen species productionLaser microscopy analysisProtein 2/3Oxygen species productionUncouple oxidative phosphorylationOxidative phosphorylationATP synthesisProteinSpecies productionDouble immunolabelingImportant roleMicroscopy analysisPhosphorylationMitochondriaRegulationCell groupsPlastic changesLocalizationIslandsAnimal modelsMagnaTyrosine hydroxylaseNeuronal systems
2005
Mitochondrial uncoupling proteins in the cns: in support of function and survival
Andrews ZB, Diano S, Horvath TL. Mitochondrial uncoupling proteins in the cns: in support of function and survival. Nature Reviews Neuroscience 2005, 6: 829-840. PMID: 16224498, DOI: 10.1038/nrn1767.Peer-Reviewed Original ResearchConceptsNeuronal functionNeurological disordersTraumatic brain injuryAmyotrophic lateral sclerosisClinical treatment strategiesMitochondrial calcium influxModels of neurodegenerationMitochondrial uncouplingFree radical productionReactive oxygen species productionNeuronal deteriorationNeuronal deathSubstantia nigraBrain injurySpinal cordVentral tegmentumTreatment strategiesOxygen species productionNeuronal microenvironmentSynaptic transmissionCalcium influxLimbic systemNeurological conditionsLateral sclerosisParkinson's diseaseUncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6‐methyl‐phenyl‐tetrahydropyridine toxicity
Conti B, Sugama S, Lucero J, Winsky‐Sommerer R, Wirz SA, Maher P, Andrews Z, Barr AM, Morale MC, Paneda C, Pemberton J, Gaidarova S, Behrens MM, Beal F, Sanna PP, Horvath T, Bartfai T. Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6‐methyl‐phenyl‐tetrahydropyridine toxicity. Journal Of Neurochemistry 2005, 93: 493-501. PMID: 15816872, DOI: 10.1111/j.1471-4159.2005.03052.x.Peer-Reviewed Original ResearchConceptsDopaminergic neuronsParkinson's diseaseOxidative stressSpecific neuronal expressionTyrosine hydroxylase promoterTetrahydropyridine (MPTP) toxicityCatecholaminergic neuronsSubstantia nigraHydroxylase promoterLocomotor functionMouse modelNeuronal expressionAcute exposureTransgenic miceSporadic formsTwofold elevationUCP2 expressionDiseaseMarked reductionNeuronsMiceNeuroprotectionProtein 2UCP familyDrug targetsUncoupling Protein-2 Is Critical for Nigral Dopamine Cell Survival in a Mouse Model of Parkinson's Disease
Andrews ZB, Horvath B, Barnstable CJ, Elseworth J, Yang L, Beal MF, Roth RH, Matthews RT, Horvath TL. Uncoupling Protein-2 Is Critical for Nigral Dopamine Cell Survival in a Mouse Model of Parkinson's Disease. Journal Of Neuroscience 2005, 25: 184-191. PMID: 15634780, PMCID: PMC6725213, DOI: 10.1523/jneurosci.4269-04.2005.Peer-Reviewed Original ResearchMeSH Keywords1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine1-Methyl-4-phenylpyridiniumAnimalsCell SurvivalCorpus StriatumDisease Models, AnimalDopamineHumansImmunohistochemistryIon ChannelsMaleMembrane Transport ProteinsMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicMitochondriaMitochondrial ProteinsOxygen ConsumptionParkinsonian DisordersReactive Oxygen SpeciesSubstantia NigraUncoupling Protein 2ConceptsProtein 2Mitochondrial ROS productionLack of UCP2Reactive oxygen species productionGenetic manipulationOxygen species productionMitochondria numberCell metabolismATP synthesisCell survivalOverexpression of UCP2Wild-type controlsMitochondrial uncouplingNovel therapeutic targetROS productionUCP2Species productionElectron microscopic analysisOverexpressionCell functionUCP2 overexpressionDopamine cell survivalTherapeutic targetFluorescent ethidiumDopamine cell function