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 levelsNeurograninHypothalamusIntakeDietLoss of Nucleobindin-2 Causes Insulin Resistance in Obesity without Impacting Satiety or Adiposity
Ravussin A, Youm YH, Sander J, Ryu S, Nguyen K, Varela L, Shulman GI, Sidorov S, Horvath TL, Schultze JL, Dixit VD. Loss of Nucleobindin-2 Causes Insulin Resistance in Obesity without Impacting Satiety or Adiposity. Cell Reports 2018, 24: 1085-1092.e6. PMID: 30067966, PMCID: PMC6223120, DOI: 10.1016/j.celrep.2018.06.112.Peer-Reviewed Original ResearchConceptsHigh-fat dietInsulin resistanceFood intakeMetabolic inflammationNucleobindin-2M2-like macrophage polarizationHigh-fat diet feedingWeight lossAdipose tissue macrophagesObesity-associated diseasesNesfatin-1Insulin sensitivityDiet feedingMacrophage polarizationNUCB2 proteinMyeloid cellsTissue macrophagesGlobal deletionClassical M1NUCB2NFκB-dependent mannerWeight gainSatietyIntakeAdiposity
2016
Feeding Behavior: Hypocretin/Orexin Neurons Act between Food Seeking and Eating
Gao XB, Horvath TL. Feeding Behavior: Hypocretin/Orexin Neurons Act between Food Seeking and Eating. Current Biology 2016, 26: r845-r847. PMID: 27676302, DOI: 10.1016/j.cub.2016.07.069.Peer-Reviewed Original Research
2015
Hypothalamic POMC neurons promote cannabinoid-induced feeding
Koch M, Varela L, Kim JG, Kim JD, Hernández-Nuño F, Simonds SE, Castorena CM, Vianna CR, Elmquist JK, Morozov YM, Rakic P, Bechmann I, Cowley MA, Szigeti-Buck K, Dietrich MO, Gao XB, Diano S, Horvath TL. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 2015, 519: 45-50. PMID: 25707796, PMCID: PMC4496586, DOI: 10.1038/nature14260.Peer-Reviewed Original ResearchConceptsPOMC neuronsΒ-endorphinHypothalamic pro-opiomelanocortin (POMC) neuronsOpioid peptide β-endorphinHypothalamic POMC neuronsPromotion of feedingPro-opiomelanocortin (POMC) neuronsCannabinoid receptor 1CB1R activityPOMC activitySated miceHormone releaseHypothalamic administrationFood intakeCentral regulationNeuronal activityParadoxical increaseCB1RReceptor 1POMC cellsNeuronsMitochondrial adaptationsDecreased activityPOMC geneUnsuspected role
2014
Leptin 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 TransductionMolecular 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
2012
Limitations in anti-obesity drug development: the critical role of hunger-promoting neurons
Dietrich MO, Horvath TL. Limitations in anti-obesity drug development: the critical role of hunger-promoting neurons. Nature Reviews Drug Discovery 2012, 11: 675-691. PMID: 22858652, DOI: 10.1038/nrd3739.Peer-Reviewed Original ResearchConceptsNPY/AgRP neuronsNegative energy balanceSevere side effectsAgRP neuronsPOMC neuronsPositive energy balanceChronic disordersPeripheral tissuesReactive oxygen speciesSide effectsLong-term positive energy balanceCalorie restrictionAnti-obesity drug developmentBehavioral interventionsIntense behavioral interventionsPro-opiomelanocortin (POMC) neuronsChronic metabolic disorderLong-term treatmentWhite adipose tissueAlternative therapeutic approachAnti-obesity therapiesPromotion of satietyNew drug therapiesPopulations of neuronsHigher brain functionsFoxO1 Target Gpr17 Activates AgRP Neurons to Regulate Food Intake
Ren H, Orozco IJ, Su Y, Suyama S, Gutiérrez-Juárez R, Horvath TL, Wardlaw SL, Plum L, Arancio O, Accili D. FoxO1 Target Gpr17 Activates AgRP Neurons to Regulate Food Intake. Cell 2012, 149: 1314-1326. PMID: 22682251, PMCID: PMC3613436, DOI: 10.1016/j.cell.2012.04.032.Peer-Reviewed Original ResearchConceptsFood intakeAgRP neuronsG-protein-coupled receptor GPR17Intracerebroventricular injectionHypothalamic neuronsReceptor GPR17Pharmacological modulationGlucose homeostasisNutritional statusTherapeutic potentialMice resultsGenetic ablationNeuronsFoxO1 ablationIntakeSatietyGPR17InsulinExpression profilingAblationPathwayCangrelorObesityLeptinAgonists
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 ResearchNicotine Decreases Food Intake Through Activation of POMC Neurons
Mineur YS, Abizaid A, Rao Y, Salas R, DiLeone RJ, Gündisch D, Diano S, De Biasi M, Horvath TL, Gao XB, Picciotto MR. Nicotine Decreases Food Intake Through Activation of POMC Neurons. Science 2011, 332: 1330-1332. PMID: 21659607, PMCID: PMC3113664, DOI: 10.1126/science.1201889.Peer-Reviewed Original ResearchConceptsFood intakePOMC neuronsNicotine decreases food intakeDecrease food intakePro-opiomelanocortin (POMC) neuronsΑ3β4 nicotinic acetylcholine receptorsHypothalamic melanocortin systemNicotine-induced decreasesMelanocortin-4 receptorNicotinic acetylcholine receptorsAnorexic effectDecrease appetiteSmoking cessationSynaptic mechanismsMelanocortin systemNovel treatmentsBody weightAcetylcholine receptorsNeurobiological mechanismsNeuronsIntakeSubsequent activationAppetiteActivationReceptorsHigh-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons
Klöckener T, Hess S, Belgardt BF, Paeger L, Verhagen LA, Husch A, Sohn JW, Hampel B, Dhillon H, Zigman JM, Lowell BB, Williams KW, Elmquist JK, Horvath TL, Kloppenburg P, Brüning JC. High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nature Neuroscience 2011, 14: 911-918. PMID: 21642975, PMCID: PMC3371271, DOI: 10.1038/nn.2847.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAge FactorsAnimalsAnimals, NewbornBlood GlucoseBody WeightCalorimetryDietary FatsDose-Response Relationship, DrugEatingEnzyme InhibitorsEnzyme-Linked Immunosorbent AssayFemaleGene Expression RegulationGlucose Tolerance TestGreen Fluorescent ProteinsHypoglycemic AgentsIn Vitro TechniquesInjections, IntraventricularInsulinLeptinMaleMiceMice, Inbred C57BLMice, TransgenicNeuronsObesityPatch-Clamp TechniquesPhosphatidylinositol 3-KinasesReceptor, InsulinRNA, MessengerSignal TransductionSteroidogenic Factor 1Time FactorsTolbutamideVentromedial Hypothalamic NucleusGhrelin-induced hypothermia: A physiological basis but no clinical risk
Wiedmer P, Strasser F, Horvath TL, Blum D, DiMarchi R, Lutz T, Schürmann A, Joost HG, Tschöp MH, Tong J. Ghrelin-induced hypothermia: A physiological basis but no clinical risk. Physiology & Behavior 2011, 105: 43-51. PMID: 21513721, PMCID: PMC3146973, DOI: 10.1016/j.physbeh.2011.03.027.Peer-Reviewed Original ResearchConceptsGhrelin treatmentBody temperatureApplication of ghrelinMedial preoptic areaPotential anatomical basisCold-sensitive neuronsGhrelin infusionBody core temperatureChronic i.Positive energy balanceGhrelin receptorPreoptic areaAxon terminalsClinical riskFood intakeGhrelinHealthy humansSerious hypothermiaMale subjectsPhysiologic circumstancesAnatomical basisHypothermiaCold exposureRelevant decreaseEnergy expenditure
2010
Enhanced 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 miceAgrp Neurons Mediate Sirt1's Action on the Melanocortin System and Energy Balance: Roles for Sirt1 in Neuronal Firing and Synaptic Plasticity
Dietrich MO, Antunes C, Geliang G, Liu ZW, Borok E, Nie Y, Xu AW, Souza DO, Gao Q, Diano S, Gao XB, Horvath TL. Agrp Neurons Mediate Sirt1's Action on the Melanocortin System and Energy Balance: Roles for Sirt1 in Neuronal Firing and Synaptic Plasticity. Journal Of Neuroscience 2010, 30: 11815-11825. PMID: 20810901, PMCID: PMC2965459, DOI: 10.1523/jneurosci.2234-10.2010.Peer-Reviewed Original ResearchConceptsFood intakeMelanocortin systemAgRP neuronal activityAnorexigenic POMC neuronsHypothalamic melanocortin systemAction of SIRT1Negative energy balanceAgRP neuronsPOMC neuronsCre-lox technologyInhibitory toneMC4R antagonistFat massLean massSynaptic inputsNeuronal activityNeuronal firingAdult miceBody weightSIRT1 inhibitorSynaptic plasticityCalorie restrictionMelanocortin receptorsSIRT1 activityBody metabolism
2009
Feeding signals and brain circuitry
Dietrich MO, Horvath TL. Feeding signals and brain circuitry. European Journal Of Neuroscience 2009, 30: 1688-1696. PMID: 19878280, DOI: 10.1111/j.1460-9568.2009.06963.x.Peer-Reviewed Original ResearchReduced anticipatory locomotor responses to scheduled meals in ghrelin receptor deficient mice
Blum ID, Patterson Z, Khazall R, Lamont EW, Sleeman MW, Horvath TL, Abizaid A. Reduced anticipatory locomotor responses to scheduled meals in ghrelin receptor deficient mice. Neuroscience 2009, 164: 351-359. PMID: 19666088, PMCID: PMC2996828, DOI: 10.1016/j.neuroscience.2009.08.009.Peer-Reviewed Original ResearchConceptsAnticipatory locomotor activityGHSR KO miceLocomotor activityKO miceGhrelin receptor deficient miceReceptor-deficient miceFeeding scheduleFos expression patternsWild-type littermatesRestricted feeding scheduleGhrelin receptor geneGhrelin injectionOrexigenic hormoneFos immunoreactivityHypothalamic nucleiDeficient miceLocomotor responseGhrelinH dailyMiceReceptor geneMealH patternTargeted mutationsBehavioral measuresLeptin Acts via Leptin Receptor-Expressing Lateral Hypothalamic Neurons to Modulate the Mesolimbic Dopamine System and Suppress Feeding
Leinninger GM, Jo YH, Leshan RL, Louis GW, Yang H, Barrera JG, Wilson H, Opland DM, Faouzi MA, Gong Y, Jones JC, Rhodes CJ, Chua S, Diano S, Horvath TL, Seeley RJ, Becker JB, Münzberg H, Myers MG. Leptin Acts via Leptin Receptor-Expressing Lateral Hypothalamic Neurons to Modulate the Mesolimbic Dopamine System and Suppress Feeding. Cell Metabolism 2009, 10: 89-98. PMID: 19656487, PMCID: PMC2723060, DOI: 10.1016/j.cmet.2009.06.011.Peer-Reviewed Original ResearchConceptsLateral hypothalamic areaVentral tegmental areaMesolimbic DA systemLepRb neuronsMesolimbic dopamine systemLeptin actionLeptin receptorDopamine systemDA systemLeptin-deficient animalsLateral hypothalamic neuronsAnorexigenic hormone leptinLeptin actsHypothalamic areaHypothalamic neuronsSuppress feedingHormone leptinTegmental areaDA contentInhibitory neuronsRate-limiting enzymeBody weightNeuronsLeptinReceptors
2008
Fuel utilization by hypothalamic neurons: roles for ROS
Horvath TL, Andrews ZB, Diano S. Fuel utilization by hypothalamic neurons: roles for ROS. Trends In Endocrinology And Metabolism 2008, 20: 78-87. PMID: 19084428, DOI: 10.1016/j.tem.2008.10.003.Peer-Reviewed Original ResearchConceptsEnergy homeostasisFree radical productionAnorexigenic neuronsNeuronal doctrineArcuate nucleusHypothalamic neuronsHypothalamic outputMelanocortin systemEffect of glucoseNeuronal functionFree radical formationSpecific neuronsAcid levelsNeuronsAmino acid levelsNeurobiological aspectsRadical productionEvidence pointsFatty acidsFuel sensingIntracellular substratesHomeostasisNutritional signalsGlucoseHypothalamusBsx, a Novel Hypothalamic Factor Linking Feeding with Locomotor Activity, Is Regulated by Energy Availability
Nogueiras R, López M, Lage R, Perez-Tilve D, Pfluger P, Mendieta-Zerón H, Sakkou M, Wiedmer P, Benoit SC, Datta R, Dong JZ, Culler M, Sleeman M, Vidal-Puig A, Horvath T, Treier M, Diéguez C, Tschöp M. Bsx, a Novel Hypothalamic Factor Linking Feeding with Locomotor Activity, Is Regulated by Energy Availability. Endocrinology 2008, 149: 3009-3015. PMID: 18308842, PMCID: PMC2408820, DOI: 10.1210/en.2007-1684.Peer-Reviewed Original ResearchConceptsHigh-fat dietArcuate nucleusLeptin resistanceMelanocortin-4 receptor knockout miceObese leptin-deficient miceAgouti gene-related proteinCentral nervous system controlNovel hypothalamic factorPeripheral energy balanceOrexigenic neuropeptide YReceptor knockout miceSpontaneous physical activityGhrelin receptor antagonistLeptin-deficient miceNervous system controlEnergy balance signalsFasting-induced increaseGene-related proteinGhrelin administrationLeptin injectionPharmacological modificationNeuropeptide YGhrelin signalingHypothalamic factorsReceptor antagonist