2024
Hypothalamic hormone deficiency enables physiological anorexia in ground squirrels during hibernation
Mohr S, Dai Pra R, Platt M, Feketa V, Shanabrough M, Varela L, Kristant A, Cao H, Merriman D, Horvath T, Bagriantsev S, Gracheva E. Hypothalamic hormone deficiency enables physiological anorexia in ground squirrels during hibernation. Nature Communications 2024, 15: 5803. PMID: 38987241, PMCID: PMC11236985, DOI: 10.1038/s41467-024-49996-2.Peer-Reviewed Original ResearchConceptsHypothalamic feeding centersHormone deficiencyHypothalamic arcuate nucleus neuronsArcuate nucleus neuronsThyroid hormone deficiencyFeeding centerEffects of ghrelinAnorexigenic effectNucleus neuronsPhysiological anorexiaThyroid hormonesNormal physiological functionsGround squirrelsInterbout arousalAnorexiaThirteen-lined ground squirrelsProlonged periodReduced sensitivityPhysiological functionsDeficiency
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 predictorLungMortalityAgeHunger-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 crucialFeedingObesityGABAExcitabilityChemogeneticsObesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension
Gruber T, Pan C, Contreras RE, Wiedemann T, Morgan DA, Skowronski AA, Lefort S, De Bernardis Murat C, Le Thuc O, Legutko B, Ruiz-Ojeda FJ, de la Fuente-Fernández M, García-Villalón AL, González-Hedström D, Huber M, Szigeti-Buck K, Müller TD, Ussar S, Pfluger P, Woods SC, Ertürk A, LeDuc CA, Rahmouni K, Granado M, Horvath TL, Tschöp MH, García-Cáceres C. Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension. Cell Metabolism 2021, 33: 1155-1170.e10. PMID: 33951475, PMCID: PMC8183500, DOI: 10.1016/j.cmet.2021.04.007.Peer-Reviewed Original ResearchConceptsBlood pressureObesity-associated increaseObesity-induced hypertensionElevated blood pressureSystemic blood pressureEndothelial growth factorHIF1α-VEGFArterial hypertensionNovel mechanistic linkSympathetic hyperactivityHemodynamic homeostasisHypothalamic astrocytesMetabolic syndromeRegion-specific lossMacrovascular systemsLeptin signalingBrain centersPathophysiological processesHypertensionGliovascular interfacePathway disruptionGrowth factorAstrocytesMechanistic linkAngiopathyAdiponectin 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 processUcp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior
Yasumoto Y, Stoiljkovic M, Kim JD, Sestan-Pesa M, Gao XB, Diano S, Horvath TL. Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior. Molecular Psychiatry 2021, 26: 2740-2752. PMID: 33879866, PMCID: PMC8056795, DOI: 10.1038/s41380-021-01105-1.Peer-Reviewed Original ResearchConceptsAnxiety-like behaviorReactive oxygen speciesMicroglia-synapse contactsSpine synapse numberHippocampal circuit functionNeuronal circuit dysfunctionMicroglial productionVentral hippocampusCircuit dysfunctionSpine synapsesSynapse numberAdult brainTransient riseMitochondrial ROS generationMicrogliaBrain functionConditional ablationPhagocytic inclusionsSynaptic elementsProtein 2ROS generationSignificant reductionCircuit functionConsequent accumulationOxygen speciesAge‐related calcium dysregulation linked with tau pathology and impaired cognition in non‐human primates
Datta D, Leslie SN, Wang M, Morozov YM, Yang S, Mentone S, Zeiss C, Duque A, Rakic P, Horvath TL, van Dyck C, Nairn AC, Arnsten AFT. Age‐related calcium dysregulation linked with tau pathology and impaired cognition in non‐human primates. Alzheimer's & Dementia 2021, 17: 920-932. PMID: 33829643, PMCID: PMC8195842, DOI: 10.1002/alz.12325.Peer-Reviewed Original ResearchConceptsTau pathologyCalcium leakTau phosphorylationNeuronal firingAlzheimer's diseaseEarly tau phosphorylationPyramidal cell dendritesSporadic Alzheimer's diseasePrimary cortical neuronsPotential therapeutic targetCognitive performanceAge-related reductionMacaque dorsolateral prefrontal cortexDorsolateral prefrontal cortexNon-human primatesCalcium dysregulationCell dendritesCortical neuronsCalcium-binding proteinsAD biomarkersPathology markersTherapeutic targetAnimal modelsAged monkeysPrefrontal cortexCerebellar Kv3.3 potassium channels activate TANK-binding kinase 1 to regulate trafficking of the cell survival protein Hax-1
Zhang Y, Varela L, Szigeti-Buck K, Williams A, Stoiljkovic M, Šestan-Peša M, Henao-Mejia J, D’Acunzo P, Levy E, Flavell RA, Horvath TL, Kaczmarek LK. Cerebellar Kv3.3 potassium channels activate TANK-binding kinase 1 to regulate trafficking of the cell survival protein Hax-1. Nature Communications 2021, 12: 1731. PMID: 33741962, PMCID: PMC7979925, DOI: 10.1038/s41467-021-22003-8.Peer-Reviewed Original ResearchConceptsTank Binding Kinase 1HAX-1Kv3.3 potassium channelMultivesicular bodiesKinase 1TANK-binding kinase 1Activation of caspasesAnti-apoptotic proteinsPotassium channelsMembrane proteinsBiochemical pathwaysCerebellar neuronsChannels bindCell deathTBK1 activityIon channelsMutant channelsCellular constituentsTraffickingKv3.3 channelsProteinNeuronal survivalMutationsChannel inactivationCaspasesDiscovery and functional interrogation of SARS-CoV-2 RNA-host protein interactions
Flynn RA, Belk JA, Qi Y, Yasumoto Y, Wei J, Alfajaro MM, Shi Q, Mumbach MR, Limaye A, DeWeirdt PC, Schmitz CO, Parker KR, Woo E, Chang HY, Horvath TL, Carette JE, Bertozzi CR, Wilen CB, Satpathy AT. Discovery and functional interrogation of SARS-CoV-2 RNA-host protein interactions. Cell 2021, 184: 2394-2411.e16. PMID: 33743211, PMCID: PMC7951565, DOI: 10.1016/j.cell.2021.03.012.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 RNASARS-CoV-2Virus-induced cell deathHost protein interactionsRNA-binding proteinActive infectionRNA virusesHost-virus interfaceGlobal mortalityTherapeutic benefitCRISPR screensAntiviral factorsProtein interactionsAntiviral activityViral specificityHost pathwaysFunctional RNA-binding proteinsFunctional connectionsRNA-centric approachesCell deathHost proteinsVirusFunctional interrogationRNAComprehensive catalogDrp1 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 utilizationDefective autophagy in Sf1 neurons perturbs the metabolic response to fasting and causes mitochondrial dysfunction
Coupé B, Leloup C, Asiedu K, Maillard J, Pénicaud L, Horvath TL, Bouret SG. Defective autophagy in Sf1 neurons perturbs the metabolic response to fasting and causes mitochondrial dysfunction. Molecular Metabolism 2021, 47: 101186. PMID: 33571700, PMCID: PMC7907893, DOI: 10.1016/j.molmet.2021.101186.Peer-Reviewed Original ResearchConceptsLoss of Atg7Energy homeostasisCellular homeostasisGene Atg7Defective autophagyMitochondria morphologyPhysiological processesCellular responsesCellular componentsMetabolic responseMitochondrial dysfunctionAutophagyAtg7SF1 neuronsHomeostasisMutant miceNeurons displayLoxP/Energy expenditure regulationImportant roleVMH neuronsVentromedial nucleusLeptin sensitivityStarvationCentral responseNeuroinvasion of SARS-CoV-2 in human and mouse brain
Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, Lu P, Weizman OE, Liu F, Dai Y, Szigeti-Buck K, Yasumoto Y, Wang G, Castaldi C, Heltke J, Ng E, Wheeler J, Alfajaro MM, Levavasseur E, Fontes B, Ravindra NG, Van Dijk D, Mane S, Gunel M, Ring A, Kazmi SAJ, Zhang K, Wilen CB, Horvath TL, Plu I, Haik S, Thomas JL, Louvi A, Farhadian SF, Huttner A, Seilhean D, Renier N, Bilguvar K, Iwasaki A. Neuroinvasion of SARS-CoV-2 in human and mouse brain. Journal Of Experimental Medicine 2021, 218: e20202135. PMID: 33433624, PMCID: PMC7808299, DOI: 10.1084/jem.20202135.Peer-Reviewed Original ResearchConceptsSARS-CoV-2Central nervous systemSARS-CoV-2 neuroinvasionImmune cell infiltratesCOVID-19 patientsType I interferon responseMultiple organ systemsCOVID-19I interferon responseHuman brain organoidsNeuroinvasive capacityCNS infectionsCell infiltrateNeuronal infectionPathological featuresCortical neuronsRespiratory diseaseDirect infectionCerebrospinal fluidNervous systemMouse brainInterferon responseOrgan systemsHuman ACE2Infection
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 changesNeuronsGLP-1 Receptor Signaling in Astrocytes Regulates Fatty Acid Oxidation, Mitochondrial Integrity, and Function
Timper K, del Río-Martín A, Cremer AL, Bremser S, Alber J, Giavalisco P, Varela L, Heilinger C, Nolte H, Trifunovic A, Horvath TL, Kloppenburg P, Backes H, Brüning JC. GLP-1 Receptor Signaling in Astrocytes Regulates Fatty Acid Oxidation, Mitochondrial Integrity, and Function. Cell Metabolism 2020, 31: 1189-1205.e13. PMID: 32433922, PMCID: PMC7272126, DOI: 10.1016/j.cmet.2020.05.001.Peer-Reviewed Original ResearchMetabolic Lateralization in the Hypothalamus of Male Rats Related to Reproductive and Satiety States
Kiss DS, Toth I, Jocsak G, Bartha T, Frenyo LV, Barany Z, Horvath TL, Zsarnovszky A. Metabolic Lateralization in the Hypothalamus of Male Rats Related to Reproductive and Satiety States. Reproductive Sciences 2020, 27: 1197-1205. PMID: 32046448, PMCID: PMC7181557, DOI: 10.1007/s43032-019-00131-3.Peer-Reviewed Original ResearchConceptsSatiety stateMale ratsFood intakeImpact of gonadectomyRight hemisphereSleep-wake behaviorHypothalamic functionMale rodentsMetabolic asymmetryScheduled feedingFunctional lateralizationHypothalamusEx vivoRegulatory centersRatsMetabolic differencesHomeostatic processesFunctional asymmetryIntakeLateralizationRecent findingsPresent studyReproductive controlGonadectomySatiety
2019
Mediation of the Acute Stress Response by the Skeleton
Berger JM, Singh P, Khrimian L, Morgan DA, Chowdhury S, Arteaga-Solis E, Horvath TL, Domingos AI, Marsland AL, Yadav V, Rahmouni K, Gao XB, Karsenty G. Mediation of the Acute Stress Response by the Skeleton. Cell Metabolism 2019, 30: 890-902.e8. PMID: 31523009, PMCID: PMC6834912, DOI: 10.1016/j.cmet.2019.08.012.Peer-Reviewed Original ResearchConceptsStress responseBony vertebratesAcute stress responseBone-derived signalsWild-type animalsGenetic studiesEndocrine mediationAdrenal insufficient patientsVertebratesOsteocalcinSympathetic toneParasympathetic neuronsWildOsteocalcin levelsStressorsTypes of stressorsSelective surgeOsteoblastsInactivationRodentsResponseGlutamateUptakePrefrontal Cortical and Behavioral Adaptations to Surgical Delivery Mediated by Metabolic Principles
Taylor-Giorlando M, Scheinost D, Ment L, Rothman D, Horvath TL. Prefrontal Cortical and Behavioral Adaptations to Surgical Delivery Mediated by Metabolic Principles. Cerebral Cortex 2019, 29: 5061-5071. PMID: 30877804, PMCID: PMC6918927, DOI: 10.1093/cercor/bhz046.Peer-Reviewed Original ResearchConceptsMode of deliverySurgical deliveryLayer 3 pyramidal neuronsAlters mitochondrial dynamicsValues of miceMurine findingsCerebral cortexPyramidal neuronsAdult behaviorHuman neonatesMaze testPrepulse inhibitionSpine synapsesPsychiatric illnessAdult miceNeuronal circuitryAnimal modelsClinical relevanceHuman clinical relevanceUCP-2Prefrontal cortexMitochondrial adaptationsImpaired performanceMitochondrial mechanismsBehavioral phenotypesMitofusin 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 animalsMitochondrial unfolded protein response: a stress response with implications for fertility and reproductive aging
Seli E, Wang T, Horvath TL. Mitochondrial unfolded protein response: a stress response with implications for fertility and reproductive aging. Fertility And Sterility 2019, 111: 197-204. PMID: 30691623, DOI: 10.1016/j.fertnstert.2018.11.048.Peer-Reviewed Original ResearchConceptsMitochondrial unfolded protein responseTwo-cell embryo developmentUnfolded protein responseImpaired oocyte maturationMorphology of mitochondriaMitochondrial dysfunction resultsPremature reproductive agingNovel mechanistic insightsMitochondrial DNA contentReactive oxygen species productionPrevention of agingCLPP resultsProtein responseOxygen species productionReproductive agingPreimplantation embryosAge-related accumulationOxidative phosphorylationStress responseEmbryo developmentForm blastocystsMitochondrial functionMitochondriaMitochondrial dysfunctionEnergy metabolism