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 cellsTET3ObesityAgRP 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 ResearchMeSH KeywordsAgouti-Related ProteinAnimalsDopaminergic NeuronsHypothalamusMiceNeuropeptide YPrefrontal CortexConceptsMedial 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
2017
Cannabinoid type 1 receptor-containing axons innervate NPY/AgRP neurons in the mouse arcuate nucleus
Morozov YM, Koch M, Rakic P, Horvath TL. Cannabinoid type 1 receptor-containing axons innervate NPY/AgRP neurons in the mouse arcuate nucleus. Molecular Metabolism 2017, 6: 374-381. PMID: 28377876, PMCID: PMC5369208, DOI: 10.1016/j.molmet.2017.01.004.Peer-Reviewed Original Research
2014
Molecular and cellular regulation of hypothalamic melanocortin neurons controlling food intake and energy metabolism
Koch M, Horvath TL. Molecular and cellular regulation of hypothalamic melanocortin neurons controlling food intake and energy metabolism. Molecular Psychiatry 2014, 19: 752-761. PMID: 24732669, DOI: 10.1038/mp.2014.30.Peer-Reviewed Original ResearchConceptsHypothalamic melanocortin neuronsEnergy metabolismFood intakePotential functional interactionsMelanocortin neuronsCellular regulationCellular processesFunctional interactionNeuronal circuit activityCellular mechanismsPhysiological behaviorEnergy homeostasisMetabolic eventsRegulationHypothalamic neuronsMetabolic healthObese individualsChronic overloadGlial cellsPhysical activityMetabolic disordersMelanocortin systemNeuronal circuitryCentral connectionsPsychiatric diseases
2011
Peroxisome proliferation–associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity
Diano S, Liu ZW, Jeong JK, Dietrich MO, Ruan HB, Kim E, Suyama S, Kelly K, Gyengesi E, Arbiser JL, Belsham DD, Sarruf DA, Schwartz MW, Bennett AM, Shanabrough M, Mobbs CV, Yang X, Gao XB, Horvath TL. Peroxisome proliferation–associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nature Medicine 2011, 17: 1121-1127. PMID: 21873987, PMCID: PMC3388795, DOI: 10.1038/nm.2421.Peer-Reviewed Original Research
2010
Corticosterone Regulates Synaptic Input Organization of POMC and NPY/AgRP Neurons in Adult Mice
Gyengesi E, Liu ZW, D'Agostino G, Gan G, Horvath TL, Gao XB, Diano S. Corticosterone Regulates Synaptic Input Organization of POMC and NPY/AgRP Neurons in Adult Mice. Endocrinology 2010, 151: 5395-5402. PMID: 20843996, PMCID: PMC2954711, DOI: 10.1210/en.2010-0681.Peer-Reviewed Original ResearchConceptsNPY/AgRP neuronsSynaptic input organizationSham-operated controlsAgRP neuronsADX miceCorticosterone replacementNeuropeptide YArcuate nucleusSynaptic arrangementsInput organizationPair-fed control animalsPutative excitatory synapsesPutative inhibitory synapsesHypothalamic arcuate nucleusEffects of adrenalectomySham-operated animalsNumber of synapsesPOMC neuronsProtein (AgRP) neuronsOrexigenic actionMembrane potentialSynaptic analysisInhibitory synapsesExcitatory synapsesFood intakeEnhanced anorexigenic signaling in lean obesity resistant syndecan-3 null mice
Zheng Q, Zhu J, Shanabrough M, Borok E, Benoit SC, Horvath TL, Clegg DJ, Reizes O. Enhanced anorexigenic signaling in lean obesity resistant syndecan-3 null mice. Neuroscience 2010, 171: 1032-1040. PMID: 20923696, PMCID: PMC2991621, DOI: 10.1016/j.neuroscience.2010.09.060.Peer-Reviewed Original ResearchMeSH KeywordsAgouti-Related ProteinAlpha-MSHAnalysis of VarianceAnimalsBody WeightDose-Response Relationship, DrugEatingFeeding BehaviorFood DeprivationGene Expression RegulationMaleMiceMice, KnockoutNeuronsNeuropeptide YParaventricular Hypothalamic NucleusProto-Oncogene Proteins c-fosSignal TransductionSyndecan-3Time FactorsConceptsMelanocortin agonist melanotan IISyndecan-3 null miceParaventricular nucleusBody weightNull miceHypothalamic target neuronsNeuropeptide α-MSHRisk of diabetesC-Fos immunoreactivityHypothalamic paraventricular nucleusBody weight regulationWild-type miceTypes of cancerAnorexigenic αAgRP neuronsHormone neuronsHypothalamic circuitsNeuropeptide YAnorexigenic signalingNeuropeptide responsesCardiovascular diseaseFood intakeTarget neuronsMelanotan IIType miceSynaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity
Horvath TL, Sarman B, García-Cáceres C, Enriori PJ, Sotonyi P, Shanabrough M, Borok E, Argente J, Chowen JA, Perez-Tilve D, Pfluger PT, Brönneke HS, Levin BE, Diano S, Cowley MA, Tschöp MH. Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 14875-14880. PMID: 20679202, PMCID: PMC2930476, DOI: 10.1073/pnas.1004282107.Peer-Reviewed Original ResearchConceptsHigh-fat dietSynaptic input organizationReactive gliosisPOMC neuronsDIO ratsDR ratsArcuate nucleusMelanocortin systemPOMC cellsNeuropeptide Y cellsInput organizationLoss of synapsesDiet-induced obesityBlood-brain barrierHFD-fed animalsDIO animalsAnorexigenic proopiomelanocortinGlial ensheathmentSynaptic organizationInhibitory inputsLean ratsDR animalsNeuronal circuitsCell bodiesGliosis
2008
UCP2 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 changes
2007
Neuronal control of energy homeostasis
Gao Q, Horvath TL. Neuronal control of energy homeostasis. FEBS Letters 2007, 582: 132-141. PMID: 18061579, PMCID: PMC4113225, DOI: 10.1016/j.febslet.2007.11.063.Peer-Reviewed Original ResearchConceptsEnergy homeostasisNeuronal controlMolecular genetic toolsPeripheral metabolic hormonesHypothalamic neuronal circuitsLong-term energy balanceBody energy homeostasisGenetic toolsHomeostatic machineryMetabolic hormonesNeuronal activityNeuronal circuitryBody weightEnergy intakeNeuronal circuitsCellular mechanismsHomeostasisBehavioral techniquesLife spanKey mechanismMachineryIntakeHormoneA 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
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 sites
2005
Agouti-related peptide–expressing neurons are mandatory for feeding
Gropp E, Shanabrough M, Borok E, Xu AW, Janoschek R, Buch T, Plum L, Balthasar N, Hampel B, Waisman A, Barsh GS, Horvath TL, Brüning JC. Agouti-related peptide–expressing neurons are mandatory for feeding. Nature Neuroscience 2005, 8: 1289-1291. PMID: 16158063, DOI: 10.1038/nn1548.Peer-Reviewed Original ResearchMeSH KeywordsAgouti-Related ProteinAnimalsAnorexiaArcuate Nucleus of HypothalamusBeta-GalactosidaseBody WeightCell CountDiphtheria ToxinEatingFeeding BehaviorGene Expression RegulationIntercellular Signaling Peptides and ProteinsMiceMice, KnockoutNeuronsNeuropeptide YPro-OpiomelanocortinProteinsTime Factors
2004
Sex differences in adult suprachiasmatic nucleus neurons emerging late prenatally in rats
Abizaid A, Mezei G, Sotonyi P, Horvath TL. Sex differences in adult suprachiasmatic nucleus neurons emerging late prenatally in rats. European Journal Of Neuroscience 2004, 19: 2488-2496. PMID: 15128402, DOI: 10.1111/j.0953-816x.2004.03359.x.Peer-Reviewed Original ResearchMeSH KeywordsAgingAnalysis of VarianceAnimalsAnimals, NewbornArginine VasopressinBromodeoxyuridineCalbindin 1CalbindinsCell CountEmbryo, MammalianFemaleGeniculate BodiesGlial Fibrillary Acidic ProteinImmunohistochemistryMaleNeuronsNeuropeptide YPregnancyPrenatal Exposure Delayed EffectsRatsRats, Sprague-DawleyS100 Calcium Binding Protein GSex CharacteristicsSuprachiasmatic NucleusTestosterone PropionateConceptsSuprachiasmatic nucleusGonadal steroidsFemale ratsLate gestationSex differencesPregnant female ratsVasoactive intestinal peptideGestational day 18Postnatal day 60BrdU-labeled cellsCalbindin-D28KSuprachiasmatic nucleus neuronsCircadian rhythmIntestinal peptideNucleus neuronsDouble immunocytochemistryGonadal functionTestosterone propionateBrain sectionsRat fetusesDay 18Day 60Cell groupsRatsSCN cellsRapid 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
2003
The Distribution and Mechanism of Action of Ghrelin in the CNS Demonstrates a Novel Hypothalamic Circuit Regulating Energy Homeostasis
Cowley MA, Smith RG, Diano S, Tschöp M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, Horvath TL. The Distribution and Mechanism of Action of Ghrelin in the CNS Demonstrates a Novel Hypothalamic Circuit Regulating Energy Homeostasis. Neuron 2003, 37: 649-661. PMID: 12597862, DOI: 10.1016/s0896-6273(03)00063-1.Peer-Reviewed Original ResearchMeSH KeywordsAgouti-Related ProteinAnimalsCentral Nervous SystemCorticotropin-Releasing HormoneEnergy MetabolismFemaleGhrelinHomeostasisHypothalamusIn Vitro TechniquesIntercellular Signaling Peptides and ProteinsLuminescent ProteinsMiceMice, KnockoutMice, TransgenicNerve NetNeuronsNeuropeptide YOrgan SpecificityParaventricular Hypothalamic NucleusPatch-Clamp TechniquesPeptide HormonesPresynaptic TerminalsPro-OpiomelanocortinProtein BindingProtein BiosynthesisProteinsRatsConceptsCorticotropin-releasing hormoneNeuropeptide YNPY neuronsHypothalamic circuitsGastrointestinal peptide hormone ghrelinEffects of NPYEnergy homeostasisArcuate NPY neuronsRelease of ghrelinExpression of ghrelinMechanism of actionPeptide hormone ghrelinHypothalamic actionOrexigenic peptideHypothalamic nucleiHormone ghrelinParaventricular nucleusProopiomelanocortin (POMC) productsThird ventricleGhrelinPresynaptic terminalsElectrophysiological recordingsNeuronsHypothalamusHomeostasis
2001
Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus
Cowley M, Smart J, Rubinstein M, Cerdán M, Diano S, Horvath T, Cone R, Low M. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 2001, 411: 480-484. PMID: 11373681, DOI: 10.1038/35078085.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsAnimals, Genetically ModifiedAnorexiaArcuate Nucleus of HypothalamusElectrophysiologyEvoked PotentialsGamma-Aminobutyric AcidGreen Fluorescent ProteinsLeptinLuminescent ProteinsMaleMiceMice, Inbred C57BLNerve NetNeural InhibitionNeuronsNeuropeptide YPro-OpiomelanocortinConceptsAnorexigenic POMC neuronsPOMC neuronsArcuate nucleusLeptin actionLeptin-deficient humansLepob/Lepob miceLeptin receptor expressionLong-term energy balanceNonspecific cation channelGABA neuronsOrexigenic neuropeptidesObese humansAdipocyte hormoneNeuropeptide YLeptin resistanceElevated leptinReceptor expressionLepob miceMelanocortin peptidesTransgenic miceLeptinAction potentialsNeuropeptide modulatorsCommon obesityElectrophysiological recordingsA GABA-neuropeptide Y (NPY) interplay in LH release
Horvath T, Pu S, Dube M, Diano S, Kalra S. A GABA-neuropeptide Y (NPY) interplay in LH release. Peptides 2001, 22: 473-481. PMID: 11287104, DOI: 10.1016/s0196-9781(01)00343-6.Peer-Reviewed Original ResearchConceptsGamma-amino butyric acidLH releaseNeurotransmitter/neuromodulatorExcitatory effectsArcuate nucleusReceptor agonistInhibitory gamma-amino butyric acidY4 receptor agonistRelease of LHImmunoreactive axon terminalsRat brain sectionsDose-dependent mannerOvarian steroidsOvariectomized ratsAxon terminalsBrain sectionsPrimary siteNPYMorphological findingsCyclic releaseAgonistsLHNeuromodulatorsRatsAdministration
2000
Mitochondrial Uncoupling Protein 2 (UCP2) in the Nonhuman Primate Brain and Pituitary*This work was supported by NSF Grant IBN-9728581, NIH Grants NS-36111, MH-59847, RR-00163, HD-29186, and HD-37186.
Diano S, Urbanski H, Horvath B, Bechmann I, Kagiya A, Nemeth G, Naftolin F, Warden C, Horvath T. Mitochondrial Uncoupling Protein 2 (UCP2) in the Nonhuman Primate Brain and Pituitary*This work was supported by NSF Grant IBN-9728581, NIH Grants NS-36111, MH-59847, RR-00163, HD-29186, and HD-37186. Endocrinology 2000, 141: 4226-4238. PMID: 11089557, DOI: 10.1210/endo.141.11.7740.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrain ChemistryChlorocebus aethiopsCorticotropin-Releasing HormoneGene ExpressionHypothalamusImmunohistochemistryIn Situ HybridizationIon ChannelsLimbic SystemMacaca fascicularisMacaca mulattaMembrane Transport ProteinsMicroscopy, FluorescenceMitochondrial ProteinsNeuropeptide YOxytocinPituitary GlandPituitary Gland, AnteriorPituitary Gland, PosteriorProteinsRNA, MessengerUncoupling Protein 2VasopressinsConceptsUncoupling protein 2Pituitary glandAnterior lobePrimate brainAxonal processesBrain stem regionsNonhuman primate brainSitu hybridization histochemistryMessenger RNACentral autonomicRR-00163Mitochondrial uncoupling protein 2Neuropeptide YPrimate hypothalamusAnterior pituitaryMetabolic disordersRodent brainPosterior lobeHybridization histochemistryPOMC cellsCell bodiesUCP2 expressionRodent dataNovel targetBrainAMPA receptors colocalize with neuropeptide-Y- and galanin-containing, but not with dopamine, neurons of the female rat arcuate nucleus: a semiquantitative immunohistochemical colocalization study
Zsarnovszky A, Horvath T, Naftolin F, Leranth C. AMPA receptors colocalize with neuropeptide-Y- and galanin-containing, but not with dopamine, neurons of the female rat arcuate nucleus: a semiquantitative immunohistochemical colocalization study. Experimental Brain Research 2000, 133: 532-537. PMID: 10985687, DOI: 10.1007/s002210000425.Peer-Reviewed Original ResearchConceptsArcuate nucleusAMPA receptorsFemale rat arcuate nucleusExcitatory amino acid neurotransmissionIsoxazole propionic acid (AMPA) receptorsAmino acid neurotransmissionTH-ir cellsMajor neuronal populationsRat arcuate nucleusPropionic acid receptorsHormone delivery systemsImmunohistochemical colocalization studiesGlutamatergic innervationGlutamatergic inputsFemale ratsNeuronal populationsGalaninAcid receptorsNeuronsReceptorsNPYNeuropeptidesColocalization studiesPresent studyDelivery system