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
A hypothalamic dopamine locus for psychostimulant-induced hyperlocomotion in mice
Korchynska S, Rebernik P, Pende M, Boi L, Alpár A, Tasan R, Becker K, Balueva K, Saghafi S, Wulff P, Horvath TL, Fisone G, Dodt HU, Hökfelt T, Harkany T, Romanov RA. A hypothalamic dopamine locus for psychostimulant-induced hyperlocomotion in mice. Nature Communications 2022, 13: 5944. PMID: 36209152, PMCID: PMC9547883, DOI: 10.1038/s41467-022-33584-3.Peer-Reviewed Original ResearchConceptsLateral septumDopamine neuronsSuprachiasmatic nucleusSomatostatin-containing neuronsStimulation ex vivoAmphetamine-induced hyperlocomotionRegulation of locomotionDopamine outputChemogenetic inhibitionNeuropeptidergic innervationPeriventricular nucleusChemogenetic manipulationHypothalamic lociSynaptic targetsAnterior subdivisionEx vivoBrain clockNeuronsSedentary periodL activityHyperlocomotionCellular targetsMicePeVNInnervationTET3 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 cellsTET3ObesityVentromedial hypothalamic OGT drives adipose tissue lipolysis and curbs obesity
Wang Q, Zhang B, Stutz B, Liu ZW, Horvath TL, Yang X. Ventromedial hypothalamic OGT drives adipose tissue lipolysis and curbs obesity. Science Advances 2022, 8: eabn8092. PMID: 36044565, PMCID: PMC9432828, DOI: 10.1126/sciadv.abn8092.Peer-Reviewed Original ResearchConceptsVentromedial hypothalamusWhite adipose tissueVMH neuronsAdipose tissueBody weightLipid metabolismRapid weight gainCounterregulatory responsesSympathetic activitySympathetic innervationAdipocyte hypertrophyTissue lipolysisNeuronal excitabilityFood intakePhysical activityObesity phenotypesGenetic ablationWeight gainHomeostatic set pointEnergy expenditureNeuronsInnervationLipolysisSignificant changesCellular sensorsAgRP neurons control structure and function of the medial prefrontal cortex
Stutz B, Waterson MJ, Šestan-Peša M, Dietrich MO, Škarica M, Sestan N, Racz B, Magyar A, Sotonyi P, Liu ZW, Gao XB, Matyas F, Stoiljkovic M, Horvath TL. AgRP neurons control structure and function of the medial prefrontal cortex. Molecular Psychiatry 2022, 27: 3951-3960. PMID: 35906488, PMCID: PMC9891653, DOI: 10.1038/s41380-022-01691-8.Peer-Reviewed Original ResearchConceptsMedial prefrontal cortexAgRP neuronsNon-selective dopamine receptor antagonistBrain functionPrefrontal cortexHypothalamic AgRP neuronsMedial thalamic neuronsAdministration of clozapineDopamine receptor antagonistVentral tegmental areaOscillatory network activityHigher-order brain functionsHypothalamic agoutiThalamic neuronsChemogenetic inhibitionDopaminergic neuronsReceptor antagonistTegmental areaNeuronal pathwaysSensorimotor gatingAdult miceModulatory impactAmbulatory behaviorConstitutive impairmentNeurons
2021
Hunger-promoting AgRP neurons trigger an astrocyte-mediated feed-forward auto-activation loop in mice
Varela L, Stutz B, Song JE, Kim JG, Liu ZW, Gao XB, Horvath TL. Hunger-promoting AgRP neurons trigger an astrocyte-mediated feed-forward auto-activation loop in mice. Journal Of Clinical Investigation 2021, 131 PMID: 33848272, PMCID: PMC8121506, DOI: 10.1172/jci144239.Peer-Reviewed Original ResearchConceptsAgRP neuronsHypothalamic feeding circuitsInhibitory neurotransmitter GABAGhrelin administrationInhibitory toneAstrocytic responseMetabolic milieuProstaglandin E2Neurotransmitter GABANeuronal controlSynaptic plasticityGlial processesNeuronsNeural excitationMitochondrial adaptationsFood deprivationAstrocytesPerikaryaFeeding circuitRegion crucialFeedingObesityGABAExcitabilityChemogeneticsDrp1 is required for AgRP neuronal activity and feeding
Jin S, Yoon NA, Liu ZW, Song JE, Horvath TL, Kim JD, Diano S. Drp1 is required for AgRP neuronal activity and feeding. ELife 2021, 10: e64351. PMID: 33689681, PMCID: PMC7946429, DOI: 10.7554/elife.64351.Peer-Reviewed Original ResearchConceptsAgRP neuronal activityFatty acid oxidationAgRP neuronsNeuronal activityAgRP neuronal functionHypothalamic AgRP neuronsBody weight regulationMitochondrial fatty acid utilizationWhole-body energy homeostasisHypothalamic orexigenic agoutiFatty acid utilizationAcid oxidationFat massCKO miceNeuronal activationPeptide-1Body weightNeuronal functionOrexigenic agoutiEnergy homeostasisMitochondrial fissionSignificant decreaseEnergy expenditureNeuronsAcid utilization
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 contentImpaired hypocretin/orexin system alters responses to salient stimuli in obese male mice
Tan Y, Hang F, Liu ZW, Stoiljkovic M, Wu M, Tu Y, Han W, Lee AM, Kelley C, Hajos M, Lu L, de Lecea L, de Araujo I, Picciotto M, Horvath TL, Gao XB. Impaired hypocretin/orexin system alters responses to salient stimuli in obese male mice. Journal Of Clinical Investigation 2020, 130: 4985-4998. PMID: 32516139, PMCID: PMC7456212, DOI: 10.1172/jci130889.Peer-Reviewed Original ResearchConceptsHcrt cellsObese miceDiet-induced obese miceObese male miceExcessive energy intakeNeuropeptide hypocretin/orexinHypocretin/orexinHcrt neuronsMale miceHcrt systemClinical studiesCommon causeSynaptic transmissionObese animalsEnergy intakeAcute stressCognitive functionSalient stimuliAlters responsesExact mechanismMiceHomeostatic regulationNeuronal networksBehavioral changesNeuronsCrosstalk between maternal perinatal obesity and offspring dopaminergic circuitry
Yasumoto Y, Horvath TL. Crosstalk between maternal perinatal obesity and offspring dopaminergic circuitry. Journal Of Clinical Investigation 2020, 130: 3416-3418. PMID: 32510474, PMCID: PMC7324168, DOI: 10.1172/jci138123.Peer-Reviewed Original ResearchConceptsMedium spiny neuronsHigh-fat dietMaternal obesityD1 medium spiny neuronsD2 medium spiny neuronsFetal brain developmentDopamine midbrain neuronsBehavioral phenotypesAltered excitatoryPerinatal obesityMaternal miceInhibitory balanceSpiny neuronsDopaminergic circuitryMidbrain neuronsBrain developmentObesityAdult HealthOffspring developmentNeuronsPhenotypeExcitatoryMice
2019
Parallel Paths in PVH Control of Feeding
Varela L, Horvath TL. Parallel Paths in PVH Control of Feeding. Neuron 2019, 102: 514-516. PMID: 31071283, DOI: 10.1016/j.neuron.2019.04.026.Peer-Reviewed Original Research
2018
Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity
Timper K, Paeger L, Sánchez-Lasheras C, Varela L, Jais A, Nolte H, Vogt MC, Hausen AC, Heilinger C, Evers N, Pospisilik JA, Penninger JM, Taylor EB, Horvath TL, Kloppenburg P, Brüning JC. Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity. Cell Reports 2018, 25: 383-397.e10. PMID: 30304679, PMCID: PMC6349418, DOI: 10.1016/j.celrep.2018.09.034.Peer-Reviewed Original ResearchConceptsPOMC neuronsApoptosis-inducing factorImproved glucose metabolismFatty acid utilizationDecrease firingPomc-CreFatty acid metabolismHFD feedingReactive oxygen species formationSystemic glucoseHypothalamic proopiomelanocortinLean miceMitochondrial respirationObese miceObese conditionsInsulin sensitivityGlucose homeostasisGlucose metabolismMild impairmentOxygen species formationFiring propertiesNeuronsOxidative phosphorylationMicePartial impairmentInsulin regulates POMC neuronal plasticity to control glucose metabolism
Dodd GT, Michael NJ, Lee-Young RS, Mangiafico SP, Pryor JT, Munder AC, Simonds SE, Brüning JC, Zhang ZY, Cowley MA, Andrikopoulos S, Horvath TL, Spanswick D, Tiganis T. Insulin regulates POMC neuronal plasticity to control glucose metabolism. ELife 2018, 7: e38704. PMID: 30230471, PMCID: PMC6170188, DOI: 10.7554/elife.38704.Peer-Reviewed Original ResearchConceptsHepatic glucose productionPOMC neuronsSuch adaptive processesNutritional cuesGene expressionMolecular mechanismsGlucose metabolismInsulin receptorDiet-induced obesityTCPTPNeuronal plasticityAdaptive processHypothalamic neuronsNeuronal excitabilityGlucose productionMetabolismInsulinNeuronsRepressionNeural responsesObesityRegulationMechanismPlasticityExpressionHypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress
Alpár A, Zahola P, Hanics J, Hevesi Z, Korchynska S, Benevento M, Pifl C, Zachar G, Perugini J, Severi I, Leitgeb P, Bakker J, Miklosi AG, Tretiakov E, Keimpema E, Arque G, Tasan RO, Sperk G, Malenczyk K, Máté Z, Erdélyi F, Szabó G, Lubec G, Palkovits M, Giordano A, Hökfelt TG, Romanov RA, Horvath TL, Harkany T. Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress. The EMBO Journal 2018, 37: embj2018100087. PMID: 30209240, PMCID: PMC6213283, DOI: 10.15252/embj.2018100087.Peer-Reviewed Original ResearchConceptsHypothalamic activationVolume transmissionAcute stressNeurotrophic factor releaseNorepinephrinergic neuronsNoradrenergic neuronsCortical excitabilityMultimodal pathwaysNoradrenaline synthesisLocus coeruleusNeuronal excitationExtracellular signal-regulated kinases 1Norepinephrine synthesisTyrosine hydroxylaseEpendymal cellsSignal-regulated kinases 1ExcitabilityPrefrontal cortexFactor releaseCognate receptorsNeuronsHuman brainKinase 1CNTFActivationFrom white to beige: a new hypothalamic pathway
Miletta MC, Horvath TL. From white to beige: a new hypothalamic pathway. EMBO Reports 2018, 19: embr201845928. PMID: 29581171, PMCID: PMC5891399, DOI: 10.15252/embr.201845928.Peer-Reviewed Original ResearchConceptsVentromedial hypothalamusSympathetic nervous system outflowSubcutaneous white adipose tissueWhite adipose tissueSympathetic outflowHypothalamic pathwaysHomeostatic signalsAdipose tissueBeige fatBeige adipocytesNeuronal circuitsEnergy homeostasisFat tissueSystem outflowNeuronsMetabolic roleTissueActivationCross talkRegulatory pathwaysBeigingObesityHypothalamusVMHPathwayNeuronal Cilia: Another Player in the Melanocortin System
Varela L, Horvath TL. Neuronal Cilia: Another Player in the Melanocortin System. Trends In Molecular Medicine 2018, 24: 333-334. PMID: 29501261, DOI: 10.1016/j.molmed.2018.02.004.Peer-Reviewed Original Research
2017
Thyroid hormone- and estrogen receptor interactions with natural ligands and endocrine disruptors in the cerebellum
Zsarnovszky A, Kiss D, Jocsak G, Nemeth G, Toth I, Horvath TL. Thyroid hormone- and estrogen receptor interactions with natural ligands and endocrine disruptors in the cerebellum. Frontiers In Neuroendocrinology 2017, 48: 23-36. PMID: 28987779, DOI: 10.1016/j.yfrne.2017.10.001.Peer-Reviewed Original ResearchConceptsEffects of phytoestrogensThyroid hormonesBrain functionNormal physiological settingsMetabolic parametersMature brainEstrogen receptor interactionSteroid hormonesBrain developmentHormoneHomeostatic parametersIntercellular actionsHormonal mechanismsReceptor interactionNatural ligandEnergy metabolismCerebellumEndocrine disruptorsPhytoestrogensPivotal rolePhysiological settingsMetabolismGliaEstrogenNeuronsEndothelial 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
Molecular interrogation of hypothalamic organization reveals distinct dopamine neuronal subtypes
Romanov RA, Zeisel A, Bakker J, Girach F, Hellysaz A, Tomer R, Alpár A, Mulder J, Clotman F, Keimpema E, Hsueh B, Crow AK, Martens H, Schwindling C, Calvigioni D, Bains JS, Máté Z, Szabó G, Yanagawa Y, Zhang MD, Rendeiro A, Farlik M, Uhlén M, Wulff P, Bock C, Broberger C, Deisseroth K, Hökfelt T, Linnarsson S, Horvath TL, Harkany T. Molecular interrogation of hypothalamic organization reveals distinct dopamine neuronal subtypes. Nature Neuroscience 2016, 20: 176-188. PMID: 27991900, PMCID: PMC7615022, DOI: 10.1038/nn.4462.Peer-Reviewed Original ResearchMitochondria controlled by UCP2 determine hypoxia-induced synaptic remodeling in the cortex and hippocampus
Varela L, Schwartz ML, Horvath TL. Mitochondria controlled by UCP2 determine hypoxia-induced synaptic remodeling in the cortex and hippocampus. Neurobiology Of Disease 2016, 90: 68-74. PMID: 26777666, DOI: 10.1016/j.nbd.2016.01.004.Peer-Reviewed Original ResearchConceptsHippocampal neuronsMitochondria-endoplasmic reticulum interactionUCP2-KO miceEarly postnatal exposureLoss of synapsesOxygen tensionHigher brain regionsAdaptive mitochondrial responsesProtein 2 expressionHypothalamic circuitsPostnatal exposureKO miceSynaptic remodelingSystemic metabolismSynaptic inputsBrain cellsMetabolic controlNeuronal mitochondriaBrain regionsAdaptive responseNeuronsHippocampusMitochondrial dynamicsMetabolic challengesCortex