2022
Ventromedial hypothalamic OGT drives adipose tissue lipolysis and curbs obesity
Wang Q, Zhang B, Stutz B, Liu ZW, Horvath TL, Yang X. Ventromedial hypothalamic OGT drives adipose tissue lipolysis and curbs obesity. Science Advances 2022, 8: eabn8092. PMID: 36044565, PMCID: PMC9432828, DOI: 10.1126/sciadv.abn8092.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAnimalsBody WeightHypothalamusLipolysisMiceN-AcetylglucosaminyltransferasesObesityConceptsVentromedial hypothalamusWhite adipose tissueVMH neuronsAdipose tissueBody weightLipid metabolismRapid weight gainCounterregulatory responsesSympathetic activitySympathetic innervationAdipocyte hypertrophyTissue lipolysisNeuronal excitabilityFood intakePhysical activityObesity phenotypesGenetic ablationWeight gainHomeostatic set pointEnergy expenditureNeuronsInnervationLipolysisSignificant changesCellular sensorsA 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
Drp1 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 utilization
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 content
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
Myeloid 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 levelsNeuroinflammationSIRT1DietDeficiencyAbsence 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
Regulation 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 Research
2016
Caloric restriction of db/db mice reverts hepatic steatosis and body weight with divergent hepatic metabolism
Kim KE, Jung Y, Min S, Nam M, Heo RW, Jeon BT, Song DH, Yi CO, Jeong EA, Kim H, Kim J, Jeong SY, Kwak W, Ryu do H, Horvath TL, Roh GS, Hwang GS. Caloric restriction of db/db mice reverts hepatic steatosis and body weight with divergent hepatic metabolism. Scientific Reports 2016, 6: 30111. PMID: 27439777, PMCID: PMC4954985, DOI: 10.1038/srep30111.Peer-Reviewed Original ResearchConceptsNon-alcoholic fatty liver diseaseDb/db miceDb miceEffects of CRCaloric restrictionLiver diseaseHepatic steatosisHepatic metabolismObese diabetic db/db miceBody weightDiabetic db/db miceFatty liver diseaseObesity-related diseasesInflammation-related proteinsSignificant metabolic alterationsMultiple pathological mechanismsEndoplasmic reticulum stressWestern blot analysisMultiple complicationsInsulin resistanceLipocalin-2Metabolic dysfunctionTherapeutic effectFrequent causeClinical problem
2012
Loss 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
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 NucleusEffects of chronic weight perturbation on energy homeostasis and brain structure in mice
Ravussin Y, Gutman R, Diano S, Shanabrough M, Borok E, Sarman B, Lehmann A, LeDuc CA, Rosenbaum M, Horvath TL, Leibel RL. Effects of chronic weight perturbation on energy homeostasis and brain structure in mice. AJP Regulatory Integrative And Comparative Physiology 2011, 300: r1352-r1362. PMID: 21411766, PMCID: PMC3119157, DOI: 10.1152/ajpregu.00429.2010.Peer-Reviewed Original ResearchConceptsDiet-induced obeseEnergy expenditureArcuate nucleus proopiomelanocortin neuronsWeight lossWeight-reduced individualsSustained weight lossReduced body weightObese human subjectsCentral nervous systemHuman subjectsSustained weight gainProopiomelanocortin neuronsBody massUpward resettingMale miceExcitatory synapsesBody fatMouse modelBody weightNervous systemSynaptic changesPersistent decreaseEnergy homeostasisWeight gainBrain structures
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 mice
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 homeostasisINSRNeuronsReduced 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 weightNeuronsLeptinReceptorsCorrelation between body weight changes and postoperative pain in rats treated with meloxicam or buprenorphine
Brennan MP, Sinusas AJ, Horvath TL, Collins JG, Harding MJ. Correlation between body weight changes and postoperative pain in rats treated with meloxicam or buprenorphine. Lab Animal 2009, 38: 87-93. PMID: 19229225, PMCID: PMC2805902, DOI: 10.1038/laban0309-87.Peer-Reviewed Original ResearchConceptsPostoperative painBody weightAdult male Lewis ratsWeight changeMajor surgical proceduresGeneral endotracheal anesthesiaMale Lewis ratsEfficacy of meloxicamRat body weightYoung adult ratsBody weight changesBody weight gainBuprenorphine analgesiaPostoperative changesLewis ratsEndotracheal anesthesiaSurgical proceduresPhysiologic effectsAdult ratsControl groupPainBuprenorphineRatsNormal levelsWeight gain
2008
N-acylphosphatidylethanolamine, a Gut- Derived Circulating Factor Induced by Fat Ingestion, Inhibits Food Intake
Gillum MP, Zhang D, Zhang XM, Erion DM, Jamison RA, Choi C, Dong J, Shanabrough M, Duenas HR, Frederick DW, Hsiao JJ, Horvath TL, Lo CM, Tso P, Cline GW, Shulman GI. N-acylphosphatidylethanolamine, a Gut- Derived Circulating Factor Induced by Fat Ingestion, Inhibits Food Intake. Cell 2008, 135: 813-824. PMID: 19041747, PMCID: PMC2643061, DOI: 10.1016/j.cell.2008.10.043.Peer-Reviewed Original ResearchConceptsFood intakeInhibits food intakeTreatment of obesityNovel therapeutic targetCentral nervous systemUnknown physiological significanceFat ingestionCirculating factorsN-acylphosphatidylethanolaminePlasma lipidsIntracerebroventricular infusionPhysiologic dosesSystemic administrationTherapeutic targetBody weightNervous systemIngested fatSmall intestineIntakeTaste aversionInfusionPhysiological significanceNanomolar amountsObesityHypothalamus
2007
Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure
Pfluger PT, Kirchner H, Günnel S, Schrott B, Perez-Tilve D, Fu S, Benoit SC, Horvath T, Joost HG, Wortley KE, Sleeman MW, Tschöp M. Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure. AJP Gastrointestinal And Liver Physiology 2007, 294: g610-g618. PMID: 18048479, DOI: 10.1152/ajpgi.00321.2007.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAnimalsAnthropometryBlood GlucoseBody CompositionBody TemperatureBody WeightEatingEnergy MetabolismGene DeletionGenotypeGhrelinGlucose Tolerance TestInsulin ResistanceLigandsLipidsMiceMice, KnockoutMotor ActivityReceptors, GhrelinReverse Transcriptase Polymerase Chain ReactionRNA, MessengerConceptsFood intakeSimultaneous deletionStandard dietHigh-fat diet-induced obesityMotor activityWild-type control miceFirst mouse mutantsMetabolic phenotypeDiet-induced obesityEnergy metabolism phenotypesEnergy expenditureGene-deficient miceKnockout mice exhibitSingle gene-deficient miceSame genetic backgroundMost speciesWT miceControl miceStandard chowMolecular controlBody adiposityBiological roleLean massMouse mutantsMeal patterns
2006
Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals
Gao Q, Mezei G, Nie Y, Rao Y, Choi CS, Bechmann I, Leranth C, Toran-Allerand D, Priest CA, Roberts JL, Gao XB, Mobbs C, Shulman GI, Diano S, Horvath TL. Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nature Medicine 2006, 13: 89-94. PMID: 17195839, DOI: 10.1038/nm1525.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnorexiaArcuate Nucleus of HypothalamusBody WeightEstradiolEstrogen Receptor alphaExcitatory Postsynaptic PotentialsFemaleInjections, IntraventricularLeptinMaleMelanocortinsMiceMice, Inbred C57BLMice, KnockoutMice, ObeseMicroscopy, ElectronNeuronsObesityOvariectomyPro-OpiomelanocortinRatsRats, Sprague-DawleySignal TransductionSTAT3 Transcription FactorConceptsArcuate nucleusFood intakeLeptin receptor-deficient miceGonadal steroid estradiolRearrangement of synapsesReceptor-deficient miceBody weight regulationBody weight gainWild-type ratsPOMC neuronsLeptin effectsExcitatory inputsMetabolic hormonesLeptin receptorObese animalsSteroids estradiolWeight regulationBody weightSynaptic plasticityWeight gainRobust increaseInput organizationSTAT3 activationEnergy expenditureAdiposity