2022
A 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
Astrocytic lipid metabolism determines susceptibility to diet-induced obesity
Varela L, Kim JG, Fernández-Tussy P, Aryal B, Liu ZW, Fernández-Hernando C, Horvath TL. Astrocytic lipid metabolism determines susceptibility to diet-induced obesity. Science Advances 2021, 7: eabj2814. PMID: 34890239, PMCID: PMC11323787, DOI: 10.1126/sciadv.abj2814.Peer-Reviewed Original ResearchDiet-induced obesityHypothalamic astrocytesPeroxisome proliferator-activated receptor gammaHypothalamic neuronal circuitsProliferator-activated receptor gammaControl of feedingFatty acid homeostasisSystemic glucoseMetabolic milieuGlucose homeostasisBody weightReceptor gammaSynaptic plasticityNeuronal circuitsNutrient sensingLipid metabolismCellular adaptationObesityAstrocytesAcid homeostasisUnidentified roleFA metabolismEnergy metabolismElevated susceptibilityAvailability of FAHepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice
Singh AK, Chaube B, Zhang X, Sun J, Citrin KM, Canfrán-Duque A, Aryal B, Rotllan N, Varela L, Lee RG, Horvath TL, Price N, Suárez Y, Fernandez-Hernando C. Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice. Journal Of Clinical Investigation 2021, 131 PMID: 34255741, PMCID: PMC8409581, DOI: 10.1172/jci140989.Peer-Reviewed Original ResearchDiet-induced obesityGlucose intoleranceHigh-fat fed conditionsLipoprotein lipaseExcess hepatic lipid accumulationSystemic metabolic dysfunctionRole of ANGPTL4Liver lipid metabolismHepatic lipid accumulationTargeted pharmacologic therapyANGPTL4 gene expressionMetabolic turnover studiesHepatic lipase activityObesity-associated diabetesFatty acidsNovel inhibition strategiesPharmacologic therapyLiver steatosisLiver damageLipoprotein remnantsCholesterol levelsMetabolic dysfunctionHepatic uptakeANGPTL4 deficiencyHL activity
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 responsesObesityRegulationMechanismPlasticityExpression
2014
O-GlcNAc Transferase Enables AgRP Neurons to Suppress Browning of White Fat
Ruan HB, Dietrich MO, Liu ZW, Zimmer MR, Li MD, Singh JP, Zhang K, Yin R, Wu J, Horvath TL, Yang X. O-GlcNAc Transferase Enables AgRP Neurons to Suppress Browning of White Fat. Cell 2014, 159: 306-317. PMID: 25303527, PMCID: PMC4509746, DOI: 10.1016/j.cell.2014.09.010.Peer-Reviewed Original ResearchConceptsAgRP neuronsFundamental cellular processesWhite fatN-acetylglucosamine (O-GlcNAc) modificationOrexigenic AgRP neuronsVoltage-dependent potassium channelsCellular processesGlcNAc transferaseDynamic physiological processesNuclear proteinsWhite adipose tissue browningPhysiological processesAdipose tissue browningDiet-induced obesityPhysiological relevanceTissue browningGenetic ablationBeige cellsEnergy metabolismInsulin resistanceNeuronal excitabilityPotassium channelsAdipose tissueCentral mechanismsNeurons
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 ResearchConceptsHypothalamic 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
Sirtuin 1 and Sirtuin 3: Physiological Modulators of Metabolism
Nogueiras R, Habegger KM, Chaudhary N, Finan B, Banks AS, Dietrich MO, Horvath TL, Sinclair DA, Pfluger PT, Tschöp MH. Sirtuin 1 and Sirtuin 3: Physiological Modulators of Metabolism. Physiological Reviews 2012, 92: 1479-1514. PMID: 22811431, PMCID: PMC3746174, DOI: 10.1152/physrev.00022.2011.Peer-Reviewed Original ResearchConceptsSirtuin 1Sirtuin 3Nonalcoholic fatty liver diseaseMammalian sirtuin 1Multiple metabolic benefitsFatty liver diseaseDiet-induced obesityType 2 diabetesActivation of sirtuinsLiver diseaseCellular energy storesMetabolic benefitsMetabolic disordersPharmacological meansEnergy homeostasisPhysiological modulatorDependent deacetylasesMetabolic processesSirtuinsCellular energy homeostasisEnergy storesCellular sensorsEnergy statusAnabolic processesCatabolic process
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 Research
2010
Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity
Horvath TL, Sarman B, García-Cáceres C, Enriori PJ, Sotonyi P, Shanabrough M, Borok E, Argente J, Chowen JA, Perez-Tilve D, Pfluger PT, Brönneke HS, Levin BE, Diano S, Cowley MA, Tschöp MH. Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 14875-14880. PMID: 20679202, PMCID: PMC2930476, DOI: 10.1073/pnas.1004282107.Peer-Reviewed Original ResearchConceptsHigh-fat dietSynaptic input organizationReactive gliosisPOMC neuronsDIO ratsDR ratsArcuate nucleusMelanocortin systemPOMC cellsNeuropeptide Y cellsInput organizationLoss of synapsesDiet-induced obesityBlood-brain barrierHFD-fed animalsDIO animalsAnorexigenic proopiomelanocortinGlial ensheathmentSynaptic organizationInhibitory inputsLean ratsDR animalsNeuronal circuitsCell bodiesGliosis
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