2021
Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis
Gómez-Valadés AG, Pozo M, Varela L, Boudjadja MB, Ramírez S, Chivite I, Eyre E, Haddad-Tóvolli R, Obri A, Milà-Guasch M, Altirriba J, Schneeberger M, Imbernón M, Garcia-Rendueles AR, Gama-Perez P, Rojo-Ruiz J, Rácz B, Alonso MT, Gomis R, Zorzano A, D’Agostino G, Alvarez CV, Nogueiras R, Garcia-Roves PM, Horvath TL, Claret M. Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis. Cell Metabolism 2021, 33: 1820-1835.e9. PMID: 34343501, PMCID: PMC8432968, DOI: 10.1016/j.cmet.2021.07.008.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAnimalsGTP PhosphohydrolasesHomeostasisLipolysisMiceNeuronsPro-OpiomelanocortinConceptsProtein OPA1Mitochondrial CaMitochondrial cristae architectureAdipose tissue lipolysisKey metabolic sensorPOMC neuronsCellular metabolic adaptationTissue lipolysisCristae architectureMetabolic sensorNutrient availabilityWhite adipose tissue lipolysisAlpha-melanocyte stimulating hormoneGenetic inactivationNovel axisMitochondrial functionOPA1Metabolic adaptationMitochondrial cristaeDramatic alterationsMutant miceProopiomelanocortin neuronsLipolysis controlWAT lipolysisPharmacological blockade
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 impairmentInsulin regulates POMC neuronal plasticity to control glucose metabolism
Dodd GT, Michael NJ, Lee-Young RS, Mangiafico SP, Pryor JT, Munder AC, Simonds SE, Brüning JC, Zhang ZY, Cowley MA, Andrikopoulos S, Horvath TL, Spanswick D, Tiganis T. Insulin regulates POMC neuronal plasticity to control glucose metabolism. ELife 2018, 7: e38704. PMID: 30230471, PMCID: PMC6170188, DOI: 10.7554/elife.38704.Peer-Reviewed Original ResearchConceptsHepatic glucose productionPOMC neuronsSuch adaptive processesNutritional cuesGene expressionMolecular mechanismsGlucose metabolismInsulin receptorDiet-induced obesityTCPTPNeuronal plasticityAdaptive processHypothalamic neuronsNeuronal excitabilityGlucose productionMetabolismInsulinNeuronsRepressionNeural responsesObesityRegulationMechanismPlasticityExpression
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 relationshipRegulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1
Rathjen T, Yan X, Kononenko NL, Ku MC, Song K, Ferrarese L, Tarallo V, Puchkov D, Kochlamazashvili G, Brachs S, Varela L, Szigeti-Buck K, Yi CX, Schriever SC, Tattikota SG, Carlo AS, Moroni M, Siemens J, Heuser A, van der Weyden L, Birkenfeld AL, Niendorf T, Poulet JFA, Horvath TL, Tschöp MH, Heinig M, Trajkovski M, Haucke V, Poy MN. Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1. Nature Neuroscience 2017, 20: 1096-1103. PMID: 28628102, PMCID: PMC5533218, DOI: 10.1038/nn.4590.Peer-Reviewed Original ResearchMitochondrial Dynamics Mediated by Mitofusin 1 Is Required for POMC Neuron Glucose-Sensing and Insulin Release Control
Ramírez S, Gómez-Valadés AG, Schneeberger M, Varela L, Haddad-Tóvolli R, Altirriba J, Noguera E, Drougard A, Flores-Martínez Á, Imbernón M, Chivite I, Pozo M, Vidal-Itriago A, Garcia A, Cervantes S, Gasa R, Nogueiras R, Gama-Pérez P, Garcia-Roves PM, Cano DA, Knauf C, Servitja JM, Horvath TL, Gomis R, Zorzano A, Claret M. Mitochondrial Dynamics Mediated by Mitofusin 1 Is Required for POMC Neuron Glucose-Sensing and Insulin Release Control. Cell Metabolism 2017, 25: 1390-1399.e6. PMID: 28591639, DOI: 10.1016/j.cmet.2017.05.010.Peer-Reviewed Original ResearchConceptsMitofusin 1Mitochondrial dynamicsGene expression programsNutrient sensing mechanismsExpression programsMitochondrial architectureMitochondrial oxygen fluxNutrient sensingMitochondrial flexibilityNutrient availabilityPancreatic β-cellsUnrecognized linkDefective insulin secretionOxygen species generationMetabolism controlΒ-cellsSubset of neuronsSystemic glucose metabolismPOMC neuronsCritical sensorsSpecies generationPrecise mechanismGlucose homeostasisEndothelial 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
2016
Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability
García-Cáceres C, Quarta C, Varela L, Gao Y, Gruber T, Legutko B, Jastroch M, Johansson P, Ninkovic J, Yi CX, Le Thuc O, Szigeti-Buck K, Cai W, Meyer CW, Pfluger PT, Fernandez AM, Luquet S, Woods SC, Torres-Alemán I, Kahn CR, Götz M, Horvath TL, Tschöp MH. Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability. Cell 2016, 166: 867-880. PMID: 27518562, PMCID: PMC8961449, DOI: 10.1016/j.cell.2016.07.028.Peer-Reviewed Original ResearchConceptsBlood-brain barrierSystemic glucose metabolismInsulin receptorGlucose metabolismGlucose uptakeGlial fibrillary acidic proteinBrain glucose uptakePostnatal ablationHypothalamic glucose sensingGlutamate-aspartate transporterFibrillary acidic proteinPositron emission tomographyMelanocortin neuronsKO miceGlucose levelsAstrocyte morphologyNormal responseEmission tomographyGlucose-induced activationAcidic proteinAspartate transporterCircuit connectivityInsulinGlucose availabilityMitochondrial functionHypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis
Jin S, Kim JG, Park JW, Koch M, Horvath TL, Lee BJ. Hypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis. Scientific Reports 2016, 6: 29424. PMID: 27405276, PMCID: PMC4942617, DOI: 10.1038/srep29424.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnorexiaArcuate Nucleus of HypothalamusCyclooxygenase InhibitorsEnergy MetabolismFeverInflammationLipopeptidesMaleMiceMice, KnockoutMicrogliaMyeloid Differentiation Factor 88NF-kappa BPro-OpiomelanocortinRatsReceptor, Melanocortin, Type 3Receptor, Melanocortin, Type 4Toll-Like Receptor 2Weight LossConceptsSickness behaviorHypothalamic inflammationToll-like receptor 2 (TLR2) activationSickness behavior symptomsNuclear factor kappa BBody weight lossReceptor 2 activationFactor kappa BNeuronal circuit functionHypothalamic microgliaProopiomelanocortin neuronsInflammatory mechanismsIntracerebroventricular injectionPathophysiologic mechanismsTLR2 activationInflammatory processCyclooxygenase pathwayNeuronal activationKappa BBehavior symptomsWeight lossInput organizationMicrogliaTLR2Inflammation
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
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 receptorsMiceLeptin 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 diseasesNeonatal Insulin Action Impairs Hypothalamic Neurocircuit Formation in Response to Maternal High-Fat Feeding
Vogt MC, Paeger L, Hess S, Steculorum SM, Awazawa M, Hampel B, Neupert S, Nicholls HT, Mauer J, Hausen AC, Predel R, Kloppenburg P, Horvath TL, Brüning JC. Neonatal Insulin Action Impairs Hypothalamic Neurocircuit Formation in Response to Maternal High-Fat Feeding. Cell 2014, 156: 495-509. PMID: 24462248, PMCID: PMC4101521, DOI: 10.1016/j.cell.2014.01.008.Peer-Reviewed Original ResearchConceptsPOMC neuronsMaternal high-fat diet (HFD) feedingOrexigenic agouti-related peptide (AgRP) neuronsHealth outcomesMaternal high-fat feedingHigh-fat diet feedingImpaired glucose-stimulated insulin secretionMaternal HFD feedingGlucose-stimulated insulin secretionImpaired glucose homeostasisOffspring health outcomesHigh-fat feedingPOMC projectionsParasympathetic innervationHFD feedingMaternal overnutritionPeptide neuronsAbnormal insulinAnorexigenic proopiomelanocortinParaventricular nucleusDiet feedingInsulin secretionMelanocortin circuitryNeuropeptide expressionLong-term effects
2013
Mitofusin 2 in POMC Neurons Connects ER Stress with Leptin Resistance and Energy Imbalance
Schneeberger M, Dietrich MO, Sebastián D, Imbernón M, Castaño C, Garcia A, Esteban Y, Gonzalez-Franquesa A, Rodríguez IC, Bortolozzi A, Garcia-Roves PM, Gomis R, Nogueiras R, Horvath TL, Zorzano A, Claret M. Mitofusin 2 in POMC Neurons Connects ER Stress with Leptin Resistance and Energy Imbalance. Cell 2013, 155: 172-187. PMID: 24074867, PMCID: PMC3839088, DOI: 10.1016/j.cell.2013.09.003.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEndoplasmic Reticulum StressGTP PhosphohydrolasesHypothalamusLeptinMiceMice, Inbred C57BLNeuronsObesityPro-OpiomelanocortinConceptsHypothalamic ER stressER stress-induced leptin resistanceLeptin resistanceMitofusin 2ER stressMitochondria-endoplasmic reticulum interactionAnorexigenic pro-opiomelanocortin (POMC) neuronsPro-opiomelanocortin (POMC) neuronsDiet-induced obesityMitochondria-ER contactsSystemic energy balancePOMC neuronsMetabolic alterationsCausative factorsEnergy expenditurePOMC processingObesityUnderlying mechanismCrucial involvementNeuronsEnergy imbalanceEssential regulatorCritical roleHyperphagiaHypothalamus
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 regulatorLoss of Autophagy in Pro-opiomelanocortin Neurons Perturbs Axon Growth and Causes Metabolic Dysregulation
Coupé B, Ishii Y, Dietrich MO, Komatsu M, Horvath TL, Bouret SG. Loss of Autophagy in Pro-opiomelanocortin Neurons Perturbs Axon Growth and Causes Metabolic Dysregulation. Cell Metabolism 2012, 15: 247-255. PMID: 22285542, PMCID: PMC3278575, DOI: 10.1016/j.cmet.2011.12.016.Peer-Reviewed Original ResearchMeSH KeywordsAdiposityAnimalsArcuate Nucleus of HypothalamusAutophagyAutophagy-Related Protein 7AxonsBody WeightGlucose IntoleranceImmunoblottingMetabolic Networks and PathwaysMiceMicroscopy, ElectronMicrotubule-Associated ProteinsNeuronsPro-OpiomelanocortinTranscription Factor TFIIHTranscription FactorsUbiquitinConceptsPOMC neuronsHypothalamic melanocortin systemPathogenesis of obesityImportant intracellular mechanismNormal metabolic regulationP62-positive aggregatesFunctional neural systemsGlucose intoleranceAge-dependent accumulationNeonatal lifeAxonal projectionsMetabolic dysregulationMetabolic impairmentMelanocortin systemEssential autophagy geneBody weightLoss of autophagyMajor negative regulatorAxon growthIntracellular mechanismsNeuronsAutophagy deficiencyNeural developmentDirect genetic evidenceAtg7
2011
Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism
Diano S, Horvath TL. Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism. Trends In Molecular Medicine 2011, 18: 52-58. PMID: 21917523, DOI: 10.1016/j.molmed.2011.08.003.Peer-Reviewed Original ResearchConceptsProtein 2Lipid metabolismExcess of nutrientsHypothalamic neuronal circuitsNutrient availabilityPeripheral tissue functionsPhysiological functionsMetabolism regulationChronic diseasesMetabolism-related chronic diseasesTissue functionFuture therapeutic strategiesPathological processesPeripheral mechanismsLipid levelsNeuronal circuitsTherapeutic strategiesMetabolismImpairs healthMitochondriaDiseaseUCP2GlucoseRegulationNutrientsPeroxisome 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