2023
Impaired Ghrelin Signaling Does Not Lead to Alterations of Anxiety-like Behaviors in Adult Mice Chronically Exposed to THC during Adolescence
Sestan-Pesa M, Shanabrough M, Horvath T, Miletta M. Impaired Ghrelin Signaling Does Not Lead to Alterations of Anxiety-like Behaviors in Adult Mice Chronically Exposed to THC during Adolescence. Biomedicines 2023, 11: 144. PMID: 36672651, PMCID: PMC9855766, DOI: 10.3390/biomedicines11010144.Peer-Reviewed Original ResearchAnxiety-like behaviorGrowth hormone secretagogue receptorTHC exposureAdult miceGHSR knockout miceDepression-like behaviorLate adolescenceWild-type littermatesLong-term useGHSR signalingGhrelin signalingSecretagogue receptorKnockout miceAnimal modelsTetrahydrocannabinol (THC) administrationMental illnessMiceSignificant alterationsGhrelinMarijuana useAdolescenceReceptorsProlonged periodExposureLong-term impact
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 targetsMicePeVNInnervationA hypothalamic pathway for Augmentor α–controlled body weight regulation
Ahmed M, Kaur N, Cheng Q, Shanabrough M, Tretiakov EO, Harkany T, Horvath TL, Schlessinger J. A hypothalamic pathway for Augmentor α–controlled body weight regulation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2200476119. PMID: 35412887, PMCID: PMC9169862, DOI: 10.1073/pnas.2200476119.Peer-Reviewed Original ResearchConceptsParaventricular nucleusBody weightDiet-induced obesityBody weight regulationDiscrete neuronal populationsMelanocortin receptor 4Whole-body energy homeostasisPhysiological rolePeptide neuronsHypothalamic pathwaysReceptor 4Neuronal pathwaysPhysical activityLittermate controlsWeight regulationNeuronal populationsMetabolic diseasesTherapeutic opportunitiesMutant miceEnergy homeostasisMiceALKCancerHuman cancersALK mutants
2021
Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice
Ryu S, Shchukina I, Youm YH, Qing H, Hilliard B, Dlugos T, Zhang X, Yasumoto Y, Booth CJ, Fernández-Hernando C, Suárez Y, Khanna K, Horvath TL, Dietrich MO, Artyomov M, Wang A, Dixit VD. Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice. ELife 2021, 10: e66522. PMID: 34151773, PMCID: PMC8245129, DOI: 10.7554/elife.66522.Peer-Reviewed Original ResearchConceptsΓδ T cellsKetogenic dietCoronavirus infectionAged miceT cellsHigher systemic inflammationInfected aged miceCOVID-19 severityCOVID-19 infectionActivation of ketogenesisMouse hepatitis virus strain A59Systemic inflammationInflammatory damageInfluenza infectionClinical hallmarkNLRP3 inflammasomeImmune surveillanceAdipose tissuePotential treatmentInfectionMiceStrongest predictorLungMortalityAgeAdiponectin 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
Impaired 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
Mitofusin 2 in Mature Adipocytes Controls Adiposity and Body Weight
Mancini G, Pirruccio K, Yang X, Blücher M, Rodeheffer M, Horvath TL. Mitofusin 2 in Mature Adipocytes Controls Adiposity and Body Weight. Cell Reports 2019, 26: 2849-2858.e4. PMID: 30865877, PMCID: PMC6876693, DOI: 10.1016/j.celrep.2019.02.039.Peer-Reviewed Original ResearchConceptsKnockout miceBody weightMitochondria-endoplasmic reticulum interactionSystemic metabolic dysregulationImpaired glucose metabolismHigh-fat dietObese human subjectsCalorie-dense foodsMitofusin 2Control miceStandard chowLean controlsMetabolic dysregulationFood intakeAdult miceGlucose metabolismStandard dietAdipose tissueBrown fatGlucose utilizationAdiposityTissue levelsSystemic levelsMiceAdult animals
2018
Effects of myeloid sirtuin 1 deficiency on hypothalamic neurogranin in mice fed a high-fat diet
Kim KE, Jeong EA, Shin HJ, Lee JY, Choi EB, An HS, Park KA, Jin Z, Lee DK, Horvath TL, Roh GS. Effects of myeloid sirtuin 1 deficiency on hypothalamic neurogranin in mice fed a high-fat diet. Biochemical And Biophysical Research Communications 2018, 508: 123-129. PMID: 30471862, DOI: 10.1016/j.bbrc.2018.11.126.Peer-Reviewed Original ResearchConceptsHigh-fat dietHypothalamic inflammationSIRT1 deletionWT miceInsulin resistanceKO miceFood intakeNeurogranin expressionParvalbumin protein levelsSIRT1 knockout miceAnorexigenic proopiomelanocortinArcuate nucleusVentromedial hypothalamusHigher food intakeHFDKnockout miceLow expressionMiceWeight gainInflammationProtein levelsNeurograninHypothalamusIntakeDietMild 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 impairmentMetabolic regulation and glucose sensitivity of cortical radial glial cells
Rash BG, Micali N, Huttner AJ, Morozov YM, Horvath TL, Rakic P. Metabolic regulation and glucose sensitivity of cortical radial glial cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: 10142-10147. PMID: 30224493, PMCID: PMC6176632, DOI: 10.1073/pnas.1808066115.Peer-Reviewed Original ResearchConceptsRadial glial cellsGlial cellsRGC fibersCortical radial glial cellsEmbryonic cortical slicesGestational obesityCerebral cortexCortical slicesMetabolic disturbancesCortical neurogenesisMetabolic supportBrain disordersAcute lossMitochondrial transportBrain developmentIntracellular CaPotential mechanismsHyperglycemiaMitochondrial functionGlucose sensitivityMiceStem cellsPrimary stem cellsPhysiological mechanismsCellsMyeloid sirtuin1 deficiency aggravates hippocampal inflammation in mice fed high-fat diets
Kim KE, Jeong EA, Lee JY, Yi CO, Park KA, Jin Z, Lee JE, Horvath TL, Roh GS. Myeloid sirtuin1 deficiency aggravates hippocampal inflammation in mice fed high-fat diets. Biochemical And Biophysical Research Communications 2018, 499: 1025-1031. PMID: 29634925, DOI: 10.1016/j.bbrc.2018.04.044.Peer-Reviewed Original ResearchConceptsSirt1 KO miceHigh-fat dietInsulin resistanceKO miceLipocalin-2Inflammation-induced insulin resistanceObesity-associated insulin resistanceAnti-inflammatory effectsPrecursor protein levelsWild-type miceHippocampal inflammationWT miceMacrophage infiltrationObese miceLCN2 expressionSIRT1 knockoutType miceHFDAdipose tissueMiceProtein levelsNeuroinflammationSIRT1DietDeficiency
2017
Cannabis in fat: high hopes to treat obesity
Hawkins MN, Horvath TL. Cannabis in fat: high hopes to treat obesity. Journal Of Clinical Investigation 2017, 127: 3918-3920. PMID: 29035279, PMCID: PMC5663345, DOI: 10.1172/jci97042.Peer-Reviewed Original ResearchConceptsCannabinoid receptor type 1Body weightNovel peripheral targetsReduced body weightSystemic metabolic changesAdipocyte-specific deletionReceptor type 1Sympathetic toneTotal adiposityCNS effectsPeripheral mechanismsSystemic metabolismPeripheral targetsAdipocyte physiologyAdipose tissueType 1Metabolic changesMetabolic profileEnergy metabolismMetabolismAdiposityObesityCausal relationshipMiceMacrophagesFetal Growth Restriction Caused by Sexual Transmission of Zika Virus in Mice
Uraki R, Jurado KA, Hwang J, Szigeti-Buck K, Horvath TL, Iwasaki A, Fikrig E. Fetal Growth Restriction Caused by Sexual Transmission of Zika Virus in Mice. The Journal Of Infectious Diseases 2017, 215: 1720-1724. PMID: 28472297, PMCID: PMC5853330, DOI: 10.1093/infdis/jix204.Peer-Reviewed Original ResearchConceptsZika virusSexual transmissionWeight of fetusesFetal growth restrictionNaive female miceType I interferon receptorEmbryonic day 18.5Female miceGrowth restrictionMale miceOcular deformityMosquito bitesControl groupDay 18.5Fetal abnormalitiesSexual contactInterferon receptorMiceFetusesInfected malesVirusDeformityAbnormalitiesReceptorsEndothelial 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
2015
Synaptic lipids in cortical function and psychiatric disorders
Stutz B, Horvath TL. Synaptic lipids in cortical function and psychiatric disorders. EMBO Molecular Medicine 2015, 8: 3-5. PMID: 26671988, PMCID: PMC4718156, DOI: 10.15252/emmm.201505749.Peer-Reviewed Original ResearchConceptsPsychiatric disordersClinical therapeutic strategiesPathophysiologic mechanismsCortical circuitryCortical functionExcitatory neuronsTherapeutic strategiesAnimal modelsReliable biomarkersPsychiatric diseasesPsychiatric consequencesEMBO Molecular MedicinePsychiatric conditionsMillions of peopleHuman subjectsCircuit functionDisordersLipidsMolecular medicinePatientsPathophysiologyEtiologyDiseaseMiceNeuronsReducing Adiposity in a Critical Developmental Window Has Lasting Benefits in Mice
Lerea JS, Ring LE, Hassouna R, Chong AC, Szigeti-Buck K, Horvath TL, Zeltser LM. Reducing Adiposity in a Critical Developmental Window Has Lasting Benefits in Mice. Endocrinology 2015, 157: 666-678. PMID: 26587784, PMCID: PMC4733128, DOI: 10.1210/en.2015-1753.Peer-Reviewed Original ResearchConceptsDietary interventionBrown adipose tissue thermogenesisWeight lossEarly-onset hyperphagiaRapid weight regainEarly-onset obesityEnergy expenditureAdipose tissue thermogenesisCritical developmental windowWeight regainSympathetic toneMetabolic improvementHypothalamic leptinTissue thermogenesisEarly interventionCompensatory decreaseUnfavorable responseMiceMost adultsObesityAdiposityInterventionDevelopmental windowAdultsBrown adipose tissue mitochondriaAgRP 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 integrity
2014
PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding
Long L, Toda C, Jeong JK, Horvath TL, Diano S. PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding. Journal Of Clinical Investigation 2014, 124: 4017-4027. PMID: 25083994, PMCID: PMC4151211, DOI: 10.1172/jci76220.Peer-Reviewed Original ResearchConceptsHigh-fat dietPOMC neuronsFood intakeImproved glucose metabolismHigh-fat feedingWhole-body energy balanceBody weight gainProopiomelanocortin neuronsPeripheral administrationFat massLeptin sensitivityControl animalsGlucose metabolismBody weightPPARγ activatorsLocomotor activityEnergy homeostasisPPARγWeight gainNeuronsSelective ablationEnergy expenditureIntakeNuclear receptorsMice
2013
The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry
Hess ME, Hess S, Meyer KD, Verhagen LA, Koch L, Brönneke HS, Dietrich MO, Jordan SD, Saletore Y, Elemento O, Belgardt BF, Franz T, Horvath TL, Rüther U, Jaffrey SR, Kloppenburg P, Brüning JC. The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nature Neuroscience 2013, 16: 1042-1048. PMID: 23817550, DOI: 10.1038/nn.3449.Peer-Reviewed Original ResearchMeSH KeywordsAdenineAlpha-Ketoglutarate-Dependent Dioxygenase FTOAnimalsCocaineCorpus StriatumDopamineDopaminergic NeuronsExploratory BehaviorFemaleG Protein-Coupled Inwardly-Rectifying Potassium ChannelsLocomotionMaleMesencephalonMethylationMethyltransferasesMiceMice, Inbred C57BLMice, KnockoutMixed Function OxygenasesOxo-Acid-LyasesPhenotypeQuinpiroleReceptors, Dopamine D2Receptors, Dopamine D3RewardRNA Processing, Post-TranscriptionalRNA, MessengerSignal Transduction