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 cellsTET3ObesityLINE-1 activation in the cerebellum drives ataxia
Takahashi T, Stoiljkovic M, Song E, Gao XB, Yasumoto Y, Kudo E, Carvalho F, Kong Y, Park A, Shanabrough M, Szigeti-Buck K, Liu ZW, Kristant A, Zhang Y, Sulkowski P, Glazer PM, Kaczmarek LK, Horvath TL, Iwasaki A. LINE-1 activation in the cerebellum drives ataxia. Neuron 2022, 110: 3278-3287.e8. PMID: 36070749, PMCID: PMC9588660, DOI: 10.1016/j.neuron.2022.08.011.Peer-Reviewed Original ResearchConceptsLINE-1 activationL1 activationAtaxia telangiectasia patientsNuclear element-1Transposable elementsEpigenetic silencersHuman genomeL1 promoterMolecular regulatorsDNA damagePurkinje cell dysfunctionElement 1First direct evidenceTelangiectasia patientsDirect targetingCerebellar expressionNeurodegenerative diseasesDisease etiologyCalcium homeostasisVentromedial 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 impairmentNeuronsAgRP neurons control feeding behaviour at cortical synapses via peripherally derived lysophospholipids
Endle H, Horta G, Stutz B, Muthuraman M, Tegeder I, Schreiber Y, Snodgrass IF, Gurke R, Liu ZW, Sestan-Pesa M, Radyushkin K, Streu N, Fan W, Baumgart J, Li Y, Kloss F, Groppa S, Opel N, Dannlowski U, Grabe HJ, Zipp F, Rácz B, Horvath TL, Nitsch R, Vogt J. AgRP neurons control feeding behaviour at cortical synapses via peripherally derived lysophospholipids. Nature Metabolism 2022, 4: 683-692. PMID: 35760867, PMCID: PMC9940119, DOI: 10.1038/s42255-022-00589-7.Peer-Reviewed Original ResearchConceptsFasting-induced hyperphagiaCortical excitabilityAgRP neuronsLysophosphatidic acidPeripheral metabolismHigher body mass indexFasting-induced elevationHypothalamic AgRP neuronsEffects of LPABody mass indexHigher cortical excitabilityBrain lipid levelsCentral nervous systemPrevalence of typeGlutamatergic transmissionHypothalamic agoutiMass indexOvernight fastingPeptide neuronsCortical synapsesLipid levelsFood intakeCerebrospinal fluidNervous systemPhospholipid levels
2021
Drp1 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
MC4R Signaling in Dorsal Raphe Nucleus Controls Feeding, Anxiety, and Depression
Bruschetta G, Jin S, Liu ZW, Kim JD, Diano S. MC4R Signaling in Dorsal Raphe Nucleus Controls Feeding, Anxiety, and Depression. Cell Reports 2020, 33: 108267. PMID: 33053350, DOI: 10.1016/j.celrep.2020.108267.Peer-Reviewed Original ResearchConceptsDorsal raphe nucleusNeuronal activationR neuronsDepressive-like behaviorMajor depressive disorderChemogenetic activationR miceChemogenetic inhibitionRaphe nucleusSerotonin levelsDepressive disorderMood behaviorΑ-MSHDRN infusionsControl feedingMiceWeight lossNeuronsSelective knockdownDepressionBehavioral phenotypesAnxietyActivationFeedingPRCPImpaired 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 changesNeurons
2019
Dopamine neuronal protection in the mouse Substantia nigra by GHSR is independent of electric activity
Stutz B, Nasrallah C, Nigro M, Curry D, Liu ZW, Gao XB, Elsworth JD, Mintz L, Horvath TL. Dopamine neuronal protection in the mouse Substantia nigra by GHSR is independent of electric activity. Molecular Metabolism 2019, 24: 120-138. PMID: 30833218, PMCID: PMC6531791, DOI: 10.1016/j.molmet.2019.02.005.Peer-Reviewed Original ResearchConceptsSN DA neuronsDA neuronsSubstantia nigraDA cellsDopamine outputNeuronal protectionNeuronal survivalParkinson's diseaseDA neuron survivalDA neuronal survivalDesigner drugs (DREADD) technologyNeuronal pacemaker activityElectrical activityMouse substantia nigraElectric activityNeuron electrical activityAnimal motor behaviorGhrelin activationGHSR activationTetrahydropyridine (MPTP) treatmentNeuroprotective factorsNeuron survivalDopamine neuronsGhrelin receptorExogenous administration
2018
The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development
Tebbenkamp ATN, Varela L, Choi J, Paredes MI, Giani AM, Song JE, Sestan-Pesa M, Franjic D, Sousa AMM, Liu ZW, Li M, Bichsel C, Koch M, Szigeti-Buck K, Liu F, Li Z, Kawasawa YI, Paspalas CD, Mineur YS, Prontera P, Merla G, Picciotto MR, Arnsten AFT, Horvath TL, Sestan N. The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development. Cell 2018, 175: 1088-1104.e23. PMID: 30318146, PMCID: PMC6459420, DOI: 10.1016/j.cell.2018.09.014.Peer-Reviewed Original ResearchConceptsCopy number variationsATP synthase dimersOxidative phosphorylation supercomplexesHuman neurodevelopmental disordersATP synthaseWS pathogenesisGene contributionMitochondrial featuresBrain developmentWilliams syndromeMitochondrial dysfunctionNeocortical pyramidal neuronsNeural phenotypesMitochondriaPyramidal neuronsMachineryMorphological featuresNeurodevelopmental disordersDysfunctionSupercomplexesPhenotypeA Neural Circuit for Gut-Induced Reward
Han W, Tellez LA, Perkins MH, Perez IO, Qu T, Ferreira J, Ferreira TL, Quinn D, Liu ZW, Gao XB, Kaelberer MM, Bohórquez DV, Shammah-Lagnado SJ, de Lartigue G, de Araujo IE. A Neural Circuit for Gut-Induced Reward. Cell 2018, 175: 665-678.e23. PMID: 30245012, PMCID: PMC6195474, DOI: 10.1016/j.cell.2018.08.049.Peer-Reviewed Original ResearchConceptsSubstantia nigraVagal sensory gangliaVagal sensory neuronsTransneuronal labelingTransneuronal tracingVagal originBrain axisGlutamatergic neuronsSelf-stimulation behaviorParabrachial regionSensory gangliaDopamine cellsObligatory relayDopamine releaseSensory neuronsRewarding effectsNeuronal circuitryPlace preferenceReward pathwayNeural circuitsNeuronsStimulation approachesReward neuronsMajor regulatorNigraEndometriosis alters brain electrophysiology, gene expression and increases pain sensitization, anxiety, and depression in female mice†
Li T, Mamillapalli R, Ding S, Chang H, Liu ZW, Gao XB, Taylor HS. Endometriosis alters brain electrophysiology, gene expression and increases pain sensitization, anxiety, and depression in female mice†. Biology Of Reproduction 2018, 99: 349-359. PMID: 29425272, PMCID: PMC6692844, DOI: 10.1093/biolre/ioy035.Peer-Reviewed Original ResearchConceptsEffect of endometriosisPain sensitizationPain perceptionBrain electrophysiologyEstrogen-dependent inflammatory disorderReproductive-aged womenDetection of endometriosisRegions of brainPatch-clamp recordingsCentral sensitizationPelvic painGene expressionInflammatory disordersEndometriosis miceFemale miceSham controlsMood disordersEndometriosisPainClamp recordingsBehavioral testsMiceBrain gene expressionSensitizationElectrophysiology
2017
Plasticity of calcium-permeable AMPA glutamate receptors in Pro-opiomelanocortin neurons
Suyama S, Ralevski A, Liu ZW, Dietrich MO, Yada T, Simonds SE, Cowley MA, Gao XB, Diano S, Horvath TL. Plasticity of calcium-permeable AMPA glutamate receptors in Pro-opiomelanocortin neurons. ELife 2017, 6: e25755. PMID: 28762946, PMCID: PMC5538821, DOI: 10.7554/elife.25755.Peer-Reviewed Original ResearchConceptsExcitatory postsynaptic currentsPOMC neuronsCP-AMPARsFasted stateAMPAR-mediated excitatory postsynaptic currentsCalcium-permeable AMPA glutamate receptorsInhibition of EPSCsHigh-fat diet exposurePOMC neuronal activityPro-opiomelanocortin (POMC) neuronsCalcium-permeable AMPARsElevated leptin levelsAMPA glutamate receptorsAmplitude of mEPSCsFood deprivationEntry of calciumAMPA receptor complexesDiet exposureLeptin levelsPostsynaptic currentsEPSC amplitudeGlutamate receptorsNeuronal activityExtracellular calciumLinear current-voltage relationshipDRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons
Santoro A, Campolo M, Liu C, Sesaki H, Meli R, Liu ZW, Kim JD, Diano S. DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons. Cell Metabolism 2017, 25: 647-660. PMID: 28190775, PMCID: PMC5366041, DOI: 10.1016/j.cmet.2017.01.003.Peer-Reviewed Original ResearchConceptsPeroxisome proliferator-activated receptorPOMC neuronsLeptin sensitivityHypothalamic pro-opiomelanocortin (POMC) neuronsPro-opiomelanocortin (POMC) neuronsCounter-regulatory responseProliferator-activated receptorMitochondrial sizeFed miceGlucoprivic stimuliNeuronal activationFl/Glucose metabolismMetabolic environmentNeuronsFasted animalsIntracellular mechanismsReduced expressionGlucose responsivenessGreater activationInducible deletionROS productionMiceStrong inhibitionMitochondrial fission regulator
2016
UCP2 Regulates Mitochondrial Fission and Ventromedial Nucleus Control of Glucose Responsiveness
Toda C, Kim JD, Impellizzeri D, Cuzzocrea S, Liu ZW, Diano S. UCP2 Regulates Mitochondrial Fission and Ventromedial Nucleus Control of Glucose Responsiveness. Cell 2016, 164: 872-883. PMID: 26919426, PMCID: PMC4770556, DOI: 10.1016/j.cell.2016.02.010.Peer-Reviewed Original ResearchConceptsSystemic glucose homeostasisMitochondrial fissionCellular biological processesMitochondrial dynamicsGenetic manipulationGlucose homeostasisReactive oxygen speciesBiological processesMitochondrial adaptationsProtein 2Reduced reactive oxygen speciesOxygen speciesHomeostasisCritical roleMetabolic environmentGlucose-excited neuronsGlucose responsivenessFissionNeuronal circuitrySpeciesNeuronsRegulationVMH neuronsGlucose loadPool
2014
O-GlcNAc Transferase Enables AgRP Neurons to Suppress Browning of White Fat
Ruan HB, Dietrich MO, Liu ZW, Zimmer MR, Li MD, Singh JP, Zhang K, Yin R, Wu J, Horvath TL, Yang X. O-GlcNAc Transferase Enables AgRP Neurons to Suppress Browning of White Fat. Cell 2014, 159: 306-317. PMID: 25303527, PMCID: PMC4509746, DOI: 10.1016/j.cell.2014.09.010.Peer-Reviewed Original ResearchConceptsAgRP neuronsFundamental cellular processesWhite fatN-acetylglucosamine (O-GlcNAc) modificationOrexigenic AgRP neuronsVoltage-dependent potassium channelsCellular processesGlcNAc transferaseDynamic physiological processesNuclear proteinsWhite adipose tissue browningPhysiological processesAdipose tissue browningDiet-induced obesityPhysiological relevanceTissue browningGenetic ablationBeige cellsEnergy metabolismInsulin resistanceNeuronal excitabilityPotassium channelsAdipose tissueCentral mechanismsNeuronsLeptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding
Kim JG, Suyama S, Koch M, Jin S, Argente-Arizon P, Argente J, Liu ZW, Zimmer MR, Jeong JK, Szigeti-Buck K, Gao Y, Garcia-Caceres C, Yi CX, Salmaso N, Vaccarino FM, Chowen J, Diano S, Dietrich MO, Tschöp MH, Horvath TL. Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nature Neuroscience 2014, 17: 908-910. PMID: 24880214, PMCID: PMC4113214, DOI: 10.1038/nn.3725.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAstrocytesCell CountEatingExcitatory Postsynaptic PotentialsGlial Fibrillary Acidic ProteinHypothalamusImmunohistochemistryIn Situ HybridizationLeptinMaleMelanocortinsMiceMice, KnockoutMicroscopy, ElectronNerve NetNeuronsPrimary Cell CulturePro-OpiomelanocortinPulmonary Gas ExchangeReal-Time Polymerase Chain ReactionRNA, MessengerSignal Transduction
2013
Mitochondrial Dynamics Controlled by Mitofusins Regulate Agrp Neuronal Activity and Diet-Induced Obesity
Dietrich MO, Liu ZW, Horvath TL. Mitochondrial Dynamics Controlled by Mitofusins Regulate Agrp Neuronal Activity and Diet-Induced Obesity. Cell 2013, 155: 188-199. PMID: 24074868, PMCID: PMC4142434, DOI: 10.1016/j.cell.2013.09.004.Peer-Reviewed Original ResearchConceptsMitochondrial dynamicsEnergy metabolismCell-type specificCellular energy metabolismWhole-body energy metabolismKey organellesMitofusin 1Mitofusin 2High-fat dietMitochondria sizeAgRP neuronsMfn1Anorexigenic pro-opiomelanocortin (POMC) neuronsAgRP neuronal activityKnockout miceMetabolismPro-opiomelanocortin (POMC) neuronsFusion mechanismDiet-Induced ObesityMitofusinsOverfed stateImportant roleCellsDynamic changesOrganellesHypothalamic melanin concentrating hormone neurons communicate the nutrient value of sugar
Domingos AI, Sordillo A, Dietrich MO, Liu ZW, Tellez LA, Vaynshteyn J, Ferreira JG, Ekstrand MI, Horvath TL, de Araujo IE, Friedman JM. Hypothalamic melanin concentrating hormone neurons communicate the nutrient value of sugar. ELife 2013, 2: e01462. PMID: 24381247, PMCID: PMC3875383, DOI: 10.7554/elife.01462.Peer-Reviewed Original ResearchConceptsRewarding effectsHormone neuronsMelanin-concentrating hormone (MCH) neuronsMCH neurons projectStriatal dopamine levelsStriatal DA releaseStriatal dopamine releaseMCH neuronsSucrose ingestionNeurons projectDA releaseDopamine levelsDopamine releaseOptogenetic activationNeural pathwaysArtificial sweetenersNeural circuitryNeuronsNormal preferenceFood preferencesFood rewardGlucoseNutrient sensingMiceSweetener sucralose
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