2018
Insulin 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 responsesObesityRegulationMechanismPlasticityExpressionAbsence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis
Aryal B, Singh AK, Zhang X, Varela L, Rotllan N, Goedeke L, Chaube B, Camporez JP, Vatner DF, Horvath TL, Shulman GI, Suárez Y, Fernández-Hernando C. Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis. JCI Insight 2018, 3: e97918. PMID: 29563332, PMCID: PMC5926923, DOI: 10.1172/jci.insight.97918.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesAdipose TissueAllelesAngiopoietin-Like Protein 4AnimalsAtherosclerosisBody WeightChemokinesCytokinesDiet, High-FatDiet, WesternFatty AcidsGene Expression ProfilingGene Expression RegulationGene Knockout TechniquesGlucoseInsulinIntegrasesIntercellular Signaling Peptides and ProteinsLipid MetabolismLipoprotein LipaseLipoproteinsLiverMaleMiceMice, Inbred C57BLMice, KnockoutMusclesObesityProprotein Convertase 9TriglyceridesConceptsAngiopoietin-like protein 4High-fat dietEctopic lipid depositionLipid depositionGlucose toleranceLipoprotein lipaseShort-term high-fat dietSevere metabolic abnormalitiesProgression of atherosclerosisMajor risk factorTriacylglycerol-rich lipoproteinsFatty acid uptakeAdipose tissue resultsProatherogenic lipoproteinsCardiometabolic diseasesMetabolic abnormalitiesKO miceRisk factorsWhole body lipidMetabolic disordersGlucose metabolismLPL activityAdipose tissueGenetic ablationRapid clearance
2017
Mitochondrial 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 homeostasis
2016
CD301b+ Mononuclear Phagocytes Maintain Positive Energy Balance through Secretion of Resistin-like Molecule Alpha
Kumamoto Y, Camporez JP, Jurczak MJ, Shanabrough M, Horvath T, Shulman GI, Iwasaki A. CD301b+ Mononuclear Phagocytes Maintain Positive Energy Balance through Secretion of Resistin-like Molecule Alpha. Immunity 2016, 45: 583-596. PMID: 27566941, PMCID: PMC5033704, DOI: 10.1016/j.immuni.2016.08.002.Peer-Reviewed Original ResearchConceptsMononuclear phagocytesResistin-like molecule αResistin-like molecule alphaSignificant weight lossPositive energy balanceInsulin sensitivityGlucose metabolismAdipose tissueBody weightMultiple organsMultifunctional cytokineBody homeostasisMarked reductionHeterogeneous groupWeight lossPhagocytesMolecule αHomeostasisEnergy balanceRELMαCD301bNormoglycemiaCytokinesMacrophagesAstrocytic 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 functionMetabolism and Mental Illness
Sestan-Pesa M, Horvath TL. Metabolism and Mental Illness. Trends In Molecular Medicine 2016, 22: 174-183. PMID: 26776095, DOI: 10.1016/j.molmed.2015.12.003.Peer-Reviewed Original ResearchConceptsCentral nervous systemMental illnessBasic metabolic principlesHigher brain functionsCerebral cortexNovel therapiesNervous systemBrain functionSystemic controlPathological conditionsIllnessAppetiteCrucial regulatorFuture research strategiesOverwhelming evidenceMetabolic principlesFeeding behaviorMetabolismHypothalamusTherapyCortexBrain
2014
Neonatal 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
2012
Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis
Varela L, Horvath TL. Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO Reports 2012, 13: 1079-1086. PMID: 23146889, PMCID: PMC3512417, DOI: 10.1038/embor.2012.174.Peer-Reviewed Original ResearchConceptsGlucose homeostasisEnergy homeostasisPrevalence of obesityWhole-body energy homeostasisBody energy homeostasisAnorectic hormonesAgRP neuronsObese patientsProtein (AgRP) neuronsCentral effectsHypothalamic proopiomelanocortinBody weightInsulin actionLeptinHormonal actionMajor targetInsulin pathwayHomeostasisInsulinNeuronsHormoneBrainLatest findingsEnergy balanceSteady rise
2011
High-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 Nucleus
2009
Divergent Regulation of Energy Expenditure and Hepatic Glucose Production by Insulin Receptor in Agouti-Related Protein and POMC Neurons
Lin HV, Plum L, Ono H, Gutiérrez-Juárez R, Shanabrough M, Borok E, Horvath TL, Rossetti L, Accili D. Divergent Regulation of Energy Expenditure and Hepatic Glucose Production by Insulin Receptor in Agouti-Related Protein and POMC Neurons. Diabetes 2009, 59: 337-346. PMID: 19933998, PMCID: PMC2809966, DOI: 10.2337/db09-1303.Peer-Reviewed Original ResearchConceptsHepatic glucose productionAgRP neuronsPOMC neuronsInsulin receptorEnergy expenditureInsulin actionGlucose productionInhibitory synaptic contactsSulfonylurea receptor 1 (SUR1) subunitsCentral nervous systemL1 miceProopiomelanocortin neuronsHypothalamic insulinDivergent regulationInsulin resistanceSynaptic contactsInsulin suppressionGlucose metabolismHypothalamic deficiencyNervous systemLocomotor activityDecreased expressionEnergy homeostasisINSRNeuronsSirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats
Erion DM, Yonemitsu S, Nie Y, Nagai Y, Gillum MP, Hsiao JJ, Iwasaki T, Stark R, Weismann D, Yu XX, Murray SF, Bhanot S, Monia BP, Horvath TL, Gao Q, Samuel VT, Shulman GI. SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats. Proceedings Of The National Academy Of Sciences Of The United States Of America 2009, 106: 11288-11293. PMID: 19549853, PMCID: PMC2700142, DOI: 10.1073/pnas.0812931106.Peer-Reviewed Original Research
2008
Bsx, 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 antagonistBrain circuits regulating energy homeostasis
Abizaid A, Horvath TL. Brain circuits regulating energy homeostasis. Peptides 2008, 149: 3-10. PMID: 18514925, PMCID: PMC2605273, DOI: 10.1016/j.regpep.2007.10.006.Peer-Reviewed Original Research
2006
Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity
Plum L, Ma X, Hampel B, Balthasar N, Coppari R, Münzberg H, Shanabrough M, Burdakov D, Rother E, Janoschek R, Alber J, Belgardt BF, Koch L, Seibler J, Schwenk F, Fekete C, Suzuki A, Mak TW, Krone W, Horvath TL, Ashcroft FM, Brüning JC. Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. Journal Of Clinical Investigation 2006, 116: 1886-1901. PMID: 16794735, PMCID: PMC1481658, DOI: 10.1172/jci27123.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsChromonesDietEatingFemaleHypoglycemic AgentsHypothalamusInsulinLeptinMaleMembrane PotentialsMiceMice, KnockoutMorpholinesNeuronsObesityPhosphatidylinositol 3-KinasesPhosphatidylinositol PhosphatesPhosphoinositide-3 Kinase InhibitorsPotassium ChannelsPro-OpiomelanocortinPTEN PhosphohydrolaseSecond Messenger SystemsTolbutamideConceptsPOMC neuronsATP-sensitive potassium channel activityBasal firing rateHypothalamic proopiomelanocortin (POMC) neuronsElectrical activityKATP channel activationPI3K inhibitor LY294002PTEN knockout micePotassium channel activityK inhibitor LY294002PI3K pathwayProopiomelanocortin neuronsHypothalamic receptorsICV administrationFood intakeKATP channelsKnockout miceMelanocortin systemLeptinFiring rateNeuronsMiceSTAT3 phosphorylationK pathwayInhibitor LY294002