2024
microRNA-33 controls hunger signaling in hypothalamic AgRP neurons
Price N, Fernández-Tussy P, Varela L, Cardelo M, Shanabrough M, Aryal B, de Cabo R, Suárez Y, Horvath T, Fernández-Hernando C. microRNA-33 controls hunger signaling in hypothalamic AgRP neurons. Nature Communications 2024, 15: 2131. PMID: 38459068, PMCID: PMC10923783, DOI: 10.1038/s41467-024-46427-0.Peer-Reviewed Original ResearchConceptsAgRP neuronsFeeding behaviorFatty acid metabolismNon-coding RNAsMitochondrial biogenesisRegulatory pathwaysTarget genesHypothalamic AgRP neuronsExcessive nutrient intakeCentral regulatorBioenergetic processesAcid metabolismActivation of AgRP neuronsModulate feeding behaviorCentral regulation of feeding behaviorRegulation of feeding behaviorMiR-33Hunger signalsMicroRNA-33Metabolic diseasesAlternative therapeutic approachLoss of miR-33Mouse modelMetabolic dysfunctionRegulation
2023
A small-molecule degrader of TET3 as treatment for anorexia nervosa in an animal model
Lv H, Catarino J, Li D, Liu B, Gao X, Horvath T, Huang Y. A small-molecule degrader of TET3 as treatment for anorexia nervosa in an animal model. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2300015120. PMID: 37036983, PMCID: PMC10120042, DOI: 10.1073/pnas.2300015120.Peer-Reviewed Original ResearchConceptsVesicular GABA transporterActivity-based anorexiaExpression of AgRPNeuropeptide YAgRP neuronsAnorexia nervosaAnxiety/depressive-like behaviorsHypothalamic AgRP neuronsDepressive-like behaviorCurrent treatment optionsHigh relapse rateStress-related disordersHuman neuronal cellsNutritional supportRelapse rateTreatment optionsAnxiolytic effectsPsychiatric illnessMouse modelAnimal modelsHigh mortalityGABA transporterGenetic ablationNeuronal cellsNeurons
2022
TET3 epigenetically controls feeding and stress response behaviors via AGRP neurons
Xie D, Stutz B, Li F, Chen F, Lv H, Sestan-Pesa M, Catarino J, Gu J, Zhao H, Stoddard CE, Carmichael GG, Shanabrough M, Taylor HS, Liu ZW, Gao XB, Horvath TL, Huang Y. TET3 epigenetically controls feeding and stress response behaviors via AGRP neurons. Journal Of Clinical Investigation 2022, 132: e162365. PMID: 36189793, PMCID: PMC9525119, DOI: 10.1172/jci162365.Peer-Reviewed Original ResearchConceptsAgRP neuronsNeuropeptide YExpression of AgRPControl of feedingHypothalamic agoutiAnxiolytic effectsNeurotransmitter GABAMouse modelLeptin signalingStress-like behaviorsGenetic ablationNeuronsAgRPCritical central regulatorsEnergy expenditureGABAEnergy metabolismAppetiteFeedingCentral regulatorMetabolismCentral controlHuman cellsTET3Obesity
2021
Adiponectin preserves metabolic fitness during aging
Li N, Zhao S, Zhang Z, Zhu Y, Gliniak CM, Vishvanath L, An YA, Wang MY, Deng Y, Zhu Q, Shan B, Sherwood A, Onodera T, Oz OK, Gordillo R, Gupta RK, Liu M, Horvath TL, Dixit VD, Scherer PE. Adiponectin preserves metabolic fitness during aging. ELife 2021, 10: e65108. PMID: 33904399, PMCID: PMC8099426, DOI: 10.7554/elife.65108.Peer-Reviewed Original ResearchConceptsAdiponectin null miceSystemic insulin sensitivityInsulin sensitivityNull miceAge-related glucoseRole of adiponectinLipid metabolism disordersHigh-fat dietTransgenic mouse modelAdiponectin levelsTissue inflammationMetabolism disordersClinical studiesMouse modelAdiponectinMice displayMetabolic fitnessOverexpression modelPositive associationMiceMedian lifespanHealthspanDirect effectEssential regulatorAging process
2020
AgRP neurons control compulsive exercise and survival in an activity-based anorexia model
Miletta MC, Iyilikci O, Shanabrough M, Šestan-Peša M, Cammisa A, Zeiss CJ, Dietrich MO, Horvath TL. AgRP neurons control compulsive exercise and survival in an activity-based anorexia model. Nature Metabolism 2020, 2: 1204-1211. PMID: 33106687, DOI: 10.1038/s42255-020-00300-8.Peer-Reviewed Original ResearchConceptsAgRP neuronsActivity-based anorexia modelAgRP neuronal activityVivo fiber photometryFood-restricted miceFood-restricted animalsCompulsive exerciseAnorexia modelHypothalamic agoutiNeuropeptide YExercise volumeFood intakeMouse modelNeuronal activityFiber photometryDaily activationNeuronal circuitsPsychiatric conditionsAnorexia nervosaChemogenetic toolsNeuronsLong-term behavioral impactElevated fat contentVoluntary cessationFat content
2018
Brown adipose tissue derived ANGPTL4 controls glucose and lipid metabolism and regulates thermogenesis
Singh AK, Aryal B, Chaube B, Rotllan N, Varela L, Horvath TL, Suárez Y, Fernández-Hernando C. Brown adipose tissue derived ANGPTL4 controls glucose and lipid metabolism and regulates thermogenesis. Molecular Metabolism 2018, 11: 59-69. PMID: 29627378, PMCID: PMC6001401, DOI: 10.1016/j.molmet.2018.03.011.Peer-Reviewed Original ResearchConceptsBrown adipose tissueAdipose tissueAbsence of ANGPTL4Lipoprotein metabolismLPL activityShort-term HFD feedingTriglyceride-rich lipoprotein catabolismLipoprotein lipaseRole of ANGPTL4Novel mouse modelAcute cold exposureGlucose toleranceHFD feedingFatty acidsLipoprotein catabolismWhole body lipidGlucose homeostasisMouse modelGlucose metabolismTAG clearanceBAT resultsLipid metabolismANGPTL4Cold exposureFA oxidation
2016
Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection
Yockey LJ, Varela L, Rakib T, Khoury-Hanold W, Fink SL, Stutz B, Szigeti-Buck K, Van den Pol A, Lindenbach BD, Horvath TL, Iwasaki A. Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection. Cell 2016, 166: 1247-1256.e4. PMID: 27565347, PMCID: PMC5006689, DOI: 10.1016/j.cell.2016.08.004.Peer-Reviewed Original ResearchMeSH KeywordsAbortion, HabitualAnimalsBrainBrain DiseasesDisease Models, AnimalFemaleFetal Growth RetardationInterferon Regulatory Factor-3MiceMice, Inbred C57BLMice, Mutant StrainsPregnancyPregnancy Complications, InfectiousReceptor, Interferon alpha-betaVaginaVirus ReplicationZika VirusZika Virus InfectionConceptsZika virusFetal brain infectionFetal growth restrictionLocal viral replicationWild-type miceType I interferon receptorZIKV challengeTranscription factor IRF3Vaginal exposureGenital mucosaBrain infectionWT miceEarly pregnancyZIKV infectionGrowth restrictionPregnant damsVaginal infectionsZIKV replicationFetal brainMouse modelIFN pathwayVaginal tractUnborn fetusViral replicationDisease consequencesViral Spread to Enteric Neurons Links Genital HSV-1 Infection to Toxic Megacolon and Lethality
Khoury-Hanold W, Yordy B, Kong P, Kong Y, Ge W, Szigeti-Buck K, Ralevski A, Horvath TL, Iwasaki A. Viral Spread to Enteric Neurons Links Genital HSV-1 Infection to Toxic Megacolon and Lethality. Cell Host & Microbe 2016, 19: 788-799. PMID: 27281569, PMCID: PMC4902295, DOI: 10.1016/j.chom.2016.05.008.Peer-Reviewed Original ResearchConceptsGenital HSV-1 infectionEnteric nervous systemHSV-1 infectionSensory nervous systemNervous systemGenital herpesToxic megacolonHSV-1Genital mucosal epithelial cellsPeripheral sensory nervous systemDorsal root gangliaPathological inflammatory responsesMucosal epithelial cellsHerpes simplex virus 1Simplex virus 1Urinary retentionEnteric neuronsLaxative treatmentAutonomic gangliaRoot gangliaInflammatory responseViral gene transcriptionMouse modelInfectionEpithelial cellsRole of mitochondrial uncoupling protein-2 (UCP2) in higher brain functions, neuronal plasticity and network oscillation
Hermes G, Nagy D, Waterson M, Zsarnovszky A, Varela L, Hajos M, Horvath TL. Role of mitochondrial uncoupling protein-2 (UCP2) in higher brain functions, neuronal plasticity and network oscillation. Molecular Metabolism 2016, 5: 415-421. PMID: 27257601, PMCID: PMC4877662, DOI: 10.1016/j.molmet.2016.04.002.Peer-Reviewed Original ResearchMouse modelSynaptic plasticityMental illnessUCP2 knockout miceNMDA receptor blockadeHigher brain regionsKO mouse modelMajor psychiatric illnessProtein 2 expressionHigher brain functionsReceptor blockadePsychiatric illnessNeuronal plasticityKnockout miceNeural transmissionCellular resilienceCortical activityBrain regionsProfound disorderBrain functionMitochondrial impairmentIllnessNetwork oscillationsMitochondrial functionProtein 2
2013
Intranasal epidermal growth factor treatment rescues neonatal brain injury
Scafidi J, Hammond TR, Scafidi S, Ritter J, Jablonska B, Roncal M, Szigeti-Buck K, Coman D, Huang Y, McCarter RJ, Hyder F, Horvath TL, Gallo V. Intranasal epidermal growth factor treatment rescues neonatal brain injury. Nature 2013, 506: 230-234. PMID: 24390343, PMCID: PMC4106485, DOI: 10.1038/nature12880.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, IntranasalAnimalsAnimals, NewbornBrain InjuriesCell DifferentiationCell DivisionCell LineageCell SurvivalDemyelinating DiseasesDisease Models, AnimalEpidermal Growth FactorErbB ReceptorsHumansHypoxiaInfant, Premature, DiseasesMaleMiceMolecular Targeted TherapyOligodendrogliaRegenerationSignal TransductionStem CellsTime FactorsConceptsDiffuse white matter injuryNeonatal brain injuryVery preterm infantsWhite matter injuryOligodendrocyte precursor cellsEpidermal growth factor receptorGrowth factor treatmentGrowth factor receptorPreterm infantsFunctional recoveryBrain injurySuch injuriesEpidermal growth factor treatmentMouse modelFactor treatmentInjuryFactor receptorPrecursor cellsInfantsReceptorsUCP2 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 paradigms
2012
Oligodendrocyte Regeneration after Neonatal Hypoxia Requires FoxO1-Mediated p27Kip1 Expression
Jablonska B, Scafidi J, Aguirre A, Vaccarino F, Nguyen V, Borok E, Horvath TL, Rowitch DH, Gallo V. Oligodendrocyte Regeneration after Neonatal Hypoxia Requires FoxO1-Mediated p27Kip1 Expression. Journal Of Neuroscience 2012, 32: 14775-14793. PMID: 23077062, PMCID: PMC3517297, DOI: 10.1523/jneurosci.2060-12.2012.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornCell DifferentiationCells, CulturedCyclin-Dependent Kinase Inhibitor p27Forkhead Box Protein O1Forkhead Transcription FactorsGene Expression Regulation, DevelopmentalHumansHypoxia, BrainInfantInfant, NewbornMiceMice, 129 StrainMice, Inbred C57BLMice, KnockoutMice, TransgenicNerve RegenerationOligodendrogliaConceptsDiffuse white matter injuryNeonatal hypoxiaOligodendrocyte regenerationOligodendrocyte progenitor cell proliferationWhite matter injuryWhite matter lesionsPermanent neurodevelopmental disabilityCritical developmental time windowWhite matter developmentOverexpression of FoxO1Preterm infantsProgenitor cell proliferationDevelopmental time windowMatter lesionsOligodendrocyte deathAbnormal myelinationNeurodevelopmental disabilitiesMouse modelBiphasic effectP27Kip1 expressionNull miceOligodendrogenesisHypoxiaOligodendrocyte differentiationOligodendrocyte development
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 structuresGPA protects the nigrostriatal dopamine system by enhancing mitochondrial function
Horvath TL, Erion DM, Elsworth JD, Roth RH, Shulman GI, Andrews ZB. GPA protects the nigrostriatal dopamine system by enhancing mitochondrial function. Neurobiology Of Disease 2011, 43: 152-162. PMID: 21406233, PMCID: PMC3623269, DOI: 10.1016/j.nbd.2011.03.005.Peer-Reviewed Original ResearchConceptsNormal chow-fed miceNigrostriatal dopamine systemChow-fed miceTH neuronsGuanidinopropionic acidNormal chowParkinson's diseaseDopamine systemMitochondrial functionMitochondrial dysfunctionModels of neurodegenerationMitochondrial numberAMPK activityMPTP treatmentMPTP intoxicationNigrostriatal functionNeuroprotective effectsMitochondrial respirationNeuroprotective propertiesStriatal dopamineAMPK-dependent increaseDisease progressionMouse modelMiceMPTP
2010
Direct inhibition of hypocretin/orexin neurons in the lateral hypothalamus by nociceptin/orphanin FQ blocks stress-induced analgesia in rats
Gerashchenko D, Horvath TL, Xie X. Direct inhibition of hypocretin/orexin neurons in the lateral hypothalamus by nociceptin/orphanin FQ blocks stress-induced analgesia in rats. Neuropharmacology 2010, 60: 543-549. PMID: 21195099, PMCID: PMC3031765, DOI: 10.1016/j.neuropharm.2010.12.026.Peer-Reviewed Original ResearchMeSH KeywordsAnalgesiaAnalysis of VarianceAnimalsCell CountHypothalamic Area, LateralImmunohistochemistryIntracellular Signaling Peptides and ProteinsMaleMicroinjectionsMicroscopy, ElectronNeuronsNeuropeptidesOpioid PeptidesOrexinsPain MeasurementPain PerceptionProto-Oncogene Proteins c-fosRatsRats, Sprague-DawleyReceptors, OpioidRestraint, PhysicalStatistics, NonparametricStress, PhysiologicalConceptsStress-induced analgesiaHcrt neuronsLateral hypothalamusPerifornical areaNociceptin/orphanin FQ systemHypocretin/orexin neuronsNociceptin/orphanin FQHcrt neuronal activityDirect inhibitionThermal pain thresholdThermal nociceptive testsHypocretin/orexinFos immunohistochemistryOrexin neuronsBilateral microinjectionIntracerebroventricular injectionPain thresholdNociceptive testsOrphanin FQOFQ receptorMouse modelNeuronal activityBrain areasHypothalamusNeurons
2008
Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia
Xie X, Wisor JP, Hara J, Crowder TL, LeWinter R, Khroyan TV, Yamanaka A, Diano S, Horvath TL, Sakurai T, Toll L, Kilduff TS. Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia. Journal Of Clinical Investigation 2008, 118: 2471-2481. PMID: 18551194, PMCID: PMC2423866, DOI: 10.1172/jci35115.Peer-Reviewed Original ResearchMeSH KeywordsAnalgesiaAnimalsAtaxin-3Behavior, AnimalBrainCalciumCytoplasmElectrophysiologyFemaleHypothalamus, PosteriorImmunohistochemistryIntracellular Signaling Peptides and ProteinsMaleMembrane PotentialsMiceMice, Inbred C57BLMice, TransgenicNarcotic AntagonistsNeuronsNeuropeptidesNociceptin ReceptorNuclear ProteinsOpioid PeptidesOrexinsPain ThresholdPresynaptic TerminalsReaction TimeReceptors, OpioidStress, PhysiologicalTetrodotoxinTranscription FactorsConceptsStress-induced analgesiaHcrt neuronsWild-type miceHypocretin/orexinNociceptin/orphanin FQMouse hypothalamic slicesCorticotropin-releasing factorPatch-clamp recordingsOrexin/ataxinPostsynaptic effectsPresynaptic releaseOrphanin FQElectron microscopic levelHypothalamic slicesSynaptic contactsHcrt-1Hcrt systemMouse modelAnalgesiaClamp recordingsPeptidergic systemsAction potentialsBrain tissueNeuronsInput resistance
2005
Uncoupling 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 targets