Featured Publications
BRD7 improves glucose homeostasis independent of IRS proteins.
Kim Y, Lee J, Han Y, Tao R, White M, Liu R, Park S. BRD7 improves glucose homeostasis independent of IRS proteins. Journal Of Endocrinology 2023, 258 PMID: 37578842, PMCID: PMC10430774, DOI: 10.1530/joe-23-0119.Peer-Reviewed Original ResearchConceptsGlucose homeostasisKnockout miceAlternative insulinObese miceGlucose homeostasis independentGlucose metabolism parametersContext of obesityBlood glucose levelsMetabolism parametersGlucose levelsGlucose metabolismInsulinMiceIRS proteinsInsulin receptorProtein 7ObesityHomeostasisUpregulationBRD7InvolvementPathwayNovel insightsEuglycemiaFindingsHepatic follistatin increases basal metabolic rate and attenuates diet-induced obesity during hepatic insulin resistance
Tao R, Stöhr O, Wang C, Qiu W, Copps K, White M. Hepatic follistatin increases basal metabolic rate and attenuates diet-induced obesity during hepatic insulin resistance. Molecular Metabolism 2023, 71: 101703. PMID: 36906067, PMCID: PMC10033741, DOI: 10.1016/j.molmet.2023.101703.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceInsulin resistanceAdipose massBasal metabolic rateHepatic disruptionDiet-induced obesityFat mass accumulationTotal lean massHigh-fat dietBody weight changesHFD consumptionFat massLean massFOXO1-dependent mannerHepatic overexpressionHepatic insulinObesityMetabolic rateLower Hepatic Fat Is Associated With Improved Insulin Secretion in a High-Risk Prediabetes Subphenotype During Lifestyle Intervention
Wagner R, Heni M, Kantartzis K, Sandforth A, Machann J, Schick F, Peter A, Fritsche L, Szendrödi J, Pfeiffer A, Schürmann A, Blüher M, Hauner H, Seissler J, Bornstein S, Roden M, Stefan N, Birkenfeld A, White M, Häring H, Fritsche A. Lower Hepatic Fat Is Associated With Improved Insulin Secretion in a High-Risk Prediabetes Subphenotype During Lifestyle Intervention. Diabetes 2022, 72: 362-366. PMID: 36525512, PMCID: PMC9935494, DOI: 10.2337/db22-0441.Peer-Reviewed Original ResearchConceptsInsulin secretionLifestyle interventionLiver fatOral glucose tolerance testHigh liver fatLifestyle intervention studyGlucose tolerance testHigh-risk clustersHepatic fatTolerance testInsulin sensitivitySpecific subphenotypesIntervention studiesSecretionTime pointsInterventionPrediabetesGlycemic traitsFatSubphenotypesGlycemiaCluster 3The P300 acetyltransferase inhibitor C646 promotes membrane translocation of insulin receptor protein substrate and interaction with the insulin receptor
Peng J, Ramatchandirin B, Wang Y, Pearah A, Namachivayam K, Wolf R, Steele K, MohanKumar K, Yu L, Guo S, White M, Maheshwari A, He L. The P300 acetyltransferase inhibitor C646 promotes membrane translocation of insulin receptor protein substrate and interaction with the insulin receptor. Journal Of Biological Chemistry 2022, 298: 101621. PMID: 35074429, PMCID: PMC8850660, DOI: 10.1016/j.jbc.2022.101621.Peer-Reviewed Original ResearchConceptsAbsence of insulinP300 acetyltransferase activityTyrosine kinase activityAcetyltransferase activityInsulin receptorObese patientsTyrosine phosphorylationRole of acetylationInsulinNormal functionMembrane translocationSubsequent activationC646PatientsLiver hepatocytesProtein substratesInhibitionReceptorsMolecular mechanismsHepatocytesPhosphorylationBeta subunitKinase activityObesityUnique effects
2021
Insulin action at a molecular level – 100 years of progress
White M, Kahn C. Insulin action at a molecular level – 100 years of progress. Molecular Metabolism 2021, 52: 101304. PMID: 34274528, PMCID: PMC8551477, DOI: 10.1016/j.molmet.2021.101304.Peer-Reviewed Original ResearchConceptsAmino acid sequenceType 2 diabetesFunction of insulinAcid sequenceMolecular knowledgeHuman diseasesInsulin-sensitive tissuesPhysiological functionsPhysiological roleInsulin receptorInsulin-resistant statesInsulin 100 yearsInsulin actionBlood glucoseCascadeInsulinDiabetesTissueDiscoveryRegulationTreatmentRemarkable advancesRoleSequenceYearsFoxO1 suppresses Fgf21 during hepatic insulin resistance to impair peripheral glucose utilization and acute cold tolerance
Stöhr O, Tao R, Miao J, Copps K, White M. FoxO1 suppresses Fgf21 during hepatic insulin resistance to impair peripheral glucose utilization and acute cold tolerance. Cell Reports 2021, 34: 108893. PMID: 33761350, PMCID: PMC8529953, DOI: 10.1016/j.celrep.2021.108893.Peer-Reviewed Original ResearchMeSH KeywordsAdaptation, PhysiologicalAdipocytes, BrownAdipose Tissue, BrownAnimalsBlood GlucoseBody WeightCold TemperatureDiet, High-FatFibroblast Growth FactorsForkhead Box Protein O1Gene Expression RegulationGlucoseHomeostasisInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLipid MetabolismLiverMice, KnockoutOrgan SpecificityOxidation-ReductionThermogenesisConceptsHepatic insulin resistanceInsulin resistanceGlucose utilizationHigher plasma Fgf21 levelsSevere hepatic insulin resistanceFGF21 knockout micePlasma FGF21 levelsPeripheral glucose utilizationInsulin-resistant miceThermogenic gene expressionFGF21 resistancePharmacologic formsFGF21 levelsCold intoleranceFGF21 functionMetabolic healthBAT functionGlucose homeostasisKnockout miceFGF21Adenoviral infectionMiceWeight lossSkeletal muscleAcute cold tolerance
2020
From population to neuron: exploring common mediators for metabolic problems and mental illnesses
Takayanagi Y, Ishizuka K, Laursen T, Yukitake H, Yang K, Cascella N, Ueda S, Sumitomo A, Narita Z, Horiuchi Y, Niwa M, Taguchi A, White M, Eaton W, Mortensen P, Sakurai T, Sawa A. From population to neuron: exploring common mediators for metabolic problems and mental illnesses. Molecular Psychiatry 2020, 26: 3931-3942. PMID: 33173197, PMCID: PMC8514126, DOI: 10.1038/s41380-020-00939-5.Peer-Reviewed Original ResearchConceptsMajor mental illnessOlfactory neuronal cellsInsulin resistanceMental illnessBipolar disorderNeuronal cellsPathophysiological mediatorsHigh incidenceSZ patientsCommon mediatorIrs2 knockout miceSame large cohortIRS2 tyrosine phosphorylationDanish registriesBP patientsHealthy controlsHealthy subjectsLarge cohortEpidemiological dataEpidemiological studiesKnockout miceAnimal modelsPatientsMetabolic problemsDiabetesInsulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling
Riehle C, Weatherford E, Wende A, Jaishy B, Seei A, McCarty N, Rech M, Shi Q, Reddy G, Kutschke W, Oliveira K, Pires K, Anderson J, Diakos N, Weiss R, White M, Drakos S, Xiang Y, Abel E. Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling. JCI Insight 2020, 5: e134920. PMID: 32213702, PMCID: PMC7213803, DOI: 10.1172/jci.insight.134920.Peer-Reviewed Original ResearchConceptsTransverse aortic constrictionInsulin receptor substrate-1Left ventricular remodelingHeart failureVentricular remodelingCardiac hypertrophyTAC-induced LV hypertrophyPressure-overload cardiac hypertrophySevere LV dysfunctionInsulin receptor tyrosine kinase activityAkt1 activationReceptor tyrosine kinase activityLV dysfunctionLV hypertrophyWT miceInsulin resistanceLV remodelingAortic constrictionProinflammatory responseProtein kinase GInsulin receptor substrateReceptor substrate-1Kinomic profilingWT controlsTyrosine kinase activity
2019
Phosphorylation of Forkhead Protein FoxO1 at S253 Regulates Glucose Homeostasis in Mice
Zhang K, Guo X, Yan H, Wu Y, Pan Q, Shen J, Li X, Chen Y, Li L, Qi Y, Xu Z, Xie W, Zhang W, Threadgill D, He L, Villarreal D, Sun Y, White M, Zheng H, Guo S. Phosphorylation of Forkhead Protein FoxO1 at S253 Regulates Glucose Homeostasis in Mice. Endocrinology 2019, 160: 1333-1347. PMID: 30951171, PMCID: PMC6482038, DOI: 10.1210/en.2018-00853.Peer-Reviewed Original ResearchConceptsKey phosphorylation sitesForkhead protein FoxO1Protein kinase BTranscription factor forkhead box O1Factor forkhead box O1FOXO1 nuclear localizationMultiple physiological functionsMouse Foxo1Forkhead box O1Pancreatic plasticityPhosphorylation sitesHuman FOXO1Nuclear localizationTarget genesMolecular basisS253Kinase BFoxO1 activityPhysiological functionsGlucose homeostasisBox O1Pancreatic β-cell functionFOXO1PhosphorylationHepatic glucose production
2018
Insulin signaling and reduced glucocorticoid receptor activity attenuate postprandial gene expression in liver
Kalvisa A, Siersbæk M, Præstholm S, Christensen L, Nielsen R, Stohr O, Vettorazzi S, Tuckermann J, White M, Mandrup S, Grøntved L. Insulin signaling and reduced glucocorticoid receptor activity attenuate postprandial gene expression in liver. PLOS Biology 2018, 16: e2006249. PMID: 30532187, PMCID: PMC6301715, DOI: 10.1371/journal.pbio.2006249.Peer-Reviewed Original ResearchConceptsCircadian gene transcriptionGene transcriptionGene expressionCircadian-regulated genesInsulin-regulated genesGenomic approachesGlucocorticoid receptorGene programEnhancer activityCistromic analysisGlucocorticoid receptor activityGenesMechanistic insightsTranscriptionFeeding behaviorSelective disruptionDiet-induced obese animalsEnhancerReceptor activityFeeding responseDiet-induced obesityExpressionDysregulationChromatinFOXO1Ablation of insulin receptor substrates 1 and 2 suppresses Kras-driven lung tumorigenesis
Xu H, Lee M, Tsai P, Adler A, Curry N, Challa S, Freinkman E, Hitchcock D, Copps K, White M, Bronson R, Marcotrigiano M, Wu Y, Clish C, Kalaany N. Ablation of insulin receptor substrates 1 and 2 suppresses Kras-driven lung tumorigenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: 4228-4233. PMID: 29610318, PMCID: PMC5910837, DOI: 10.1073/pnas.1718414115.Peer-Reviewed Original ResearchMeSH KeywordsA549 CellsAmino AcidsAnimalsAutophagyCarcinogenesisCarcinoma, Non-Small-Cell LungCodon, TerminatorGenes, rasHumansInsulinInsulin Receptor Substrate ProteinsInsulin-Like Growth Factor ILung NeoplasmsMiceNeoplasm ProteinsProteolysisProto-Oncogene Proteins c-aktProto-Oncogene Proteins p21(ras)Signal TransductionConceptsIR/IGF1RLung cancerLung tumorigenesisInsulin receptorTumor cellsInsulin-like growth factor 1 receptorCell lung cancerGrowth factor 1 receptorHuman NSCLC cellsEffective therapeutic strategyLung cancer initiationIntracellular levelsKirsten rat sarcomaFactor 1 receptorTumor burdenCancer deathLeading causeMutant NSCLCNSCLC cellsIGF1R inhibitionMouse modelTherapeutic strategiesInsulin/IGF1Acute lossRat sarcoma
2017
Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity
Cao J, Peng J, An H, He Q, Boronina T, Guo S, White M, Cole P, He L. Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity. Nature Communications 2017, 8: 131. PMID: 28743992, PMCID: PMC5526866, DOI: 10.1038/s41467-017-00163-w.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorE1A-Associated p300 ProteinEndoplasmic Reticulum StressEndotoxemiaGene Expression ProfilingImmunoblottingInsulinInsulin ResistanceLipopolysaccharidesLiverMaleMembrane ProteinsMice, Inbred C57BLMice, ObeseObesityProtein Serine-Threonine KinasesReceptor, InsulinSignal TransductionX-Box Binding Protein 1ConceptsInsulin resistanceP300 acetyltransferase activityHigh-fat diet-fedChronic low-grade inflammationObese ob/ob miceOb/ob miceLow-grade inflammationDiet-induced obesityAcetyltransferase activityElevated plasma concentrationsPromising therapeutic targetCytoplasm of hepatocytesEndoplasmic reticulum stressObese patientsObese miceInsulin sensitivityIntestinal permeabilityOb micePlasma concentrationsDisrupts insulinTherapeutic targetImpairs insulinPharmacological inhibitionGlucose productionObesity
2016
Serine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation by Hepatic S6 Kinase*
Copps K, Hançer N, Qiu W, White M. Serine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation by Hepatic S6 Kinase*. Journal Of Biological Chemistry 2016, 291: 8602-8617. PMID: 26846849, PMCID: PMC4861431, DOI: 10.1074/jbc.m116.714915.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SubstitutionAnimalsCHO CellsCricetinaeCricetulusGene DeletionGlucose IntoleranceInsulinInsulin Receptor Substrate ProteinsLiverMechanistic Target of Rapamycin Complex 1MiceMice, TransgenicMultiprotein ComplexesMutation, MissensePhosphatidylinositol 3-KinasesPhosphorylationProto-Oncogene Proteins c-aktRibosomal Protein S6 KinasesSerineSignal TransductionTOR Serine-Threonine KinasesTuberous Sclerosis Complex 1 ProteinTumor Suppressor ProteinsConceptsInsulin receptor substrate-1Receptor substrate-1PI3K associationS6 kinaseSubstrate-1Insulin-stimulated Akt activityAkt phosphorylationK associationRapamycin complex 1S6K signalingInsulin-stimulated IRS1 tyrosine phosphorylationSer-302IRS1 tyrosine phosphorylationMTORC1 inhibitor rapamycinRibosomal S6 proteinTsc1 deletionFeedback phosphorylationIntracellular amino acidsInsulin sensitivityTyrosine phosphorylationAlanine mutationsS6 proteinS6KAkt activityInsulin signaling
2014
IRS2 integrates insulin/IGF1 signalling with metabolism, neurodegeneration and longevity
White M. IRS2 integrates insulin/IGF1 signalling with metabolism, neurodegeneration and longevity. Diabetes Obesity And Metabolism 2014, 16: 4-15. PMID: 25200290, DOI: 10.1111/dom.12347.Peer-Reviewed Original ResearchConceptsInsulin/IGF1Central nervous systemInsulin-like signalingLife spanOrganisms showsCellular functionsNutrient homeostasisInsulin resistanceGenetic manipulationSystemic insulin resistanceClinical Alzheimer's diseaseType 2 diabetesEnergy homeostasisNeurodegenerative diseasesMetabolismNeurodegenerationCompensatory hyperinsulinaemiaHomeostasisProgressive neurodegenerationSystemic metabolismIGF1Excess insulinNervous systemAlzheimer's diseaseClinical perspectiveAPPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor
Ryu J, Galan A, Xin X, Dong F, Abdul-Ghani M, Zhou L, Wang C, Li C, Holmes B, Sloane L, Austad S, Guo S, Musi N, DeFronzo R, Deng C, White M, Liu F, Dong L. APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor. Cell Reports 2014, 7: 1227-1238. PMID: 24813896, PMCID: PMC4380268, DOI: 10.1016/j.celrep.2014.04.006.Peer-Reviewed Original ResearchInsulin and Metabolic Stress Stimulate Multisite Serine/Threonine Phosphorylation of Insulin Receptor Substrate 1 and Inhibit Tyrosine Phosphorylation*
Hançer N, Qiu W, Cherella C, Li Y, Copps K, White M. Insulin and Metabolic Stress Stimulate Multisite Serine/Threonine Phosphorylation of Insulin Receptor Substrate 1 and Inhibit Tyrosine Phosphorylation*. Journal Of Biological Chemistry 2014, 289: 12467-12484. PMID: 24652289, PMCID: PMC4007441, DOI: 10.1074/jbc.m114.554162.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnisomycinAntigens, CDBlotting, WesternCHO CellsCricetinaeCricetulusEnzyme InhibitorsHumansHypoglycemic AgentsInsulinInsulin Receptor Substrate ProteinsPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsPhosphorylationProtein Serine-Threonine KinasesProto-Oncogene Proteins c-aktRatsReceptor, InsulinRibosomal Protein S6 Kinases, 70-kDaSerineSignal TransductionThapsigarginThreonineTOR Serine-Threonine KinasesTunicamycinTyrosineConceptsTyrosine phosphorylationPhospho-specific monoclonal antibodiesSerine/threonine phosphorylationInsulin receptor tyrosine kinasePI3KInsulin receptor substrate-1Insulin-stimulated cellsHuman insulin receptorIRS1 tyrosine phosphorylationReceptor substrate-1Metabolic stressReceptor tyrosine kinasesThreonine phosphorylationThreonine residuesS6 kinasePI3K inhibitionSubstrate-1Mechanistic targetTyrosine kinaseInsulin stimulationMEK pathwayKey substrateInsulin receptorPresence of inhibitorsCHO cells
2013
Insulin receptor substrate signaling suppresses neonatal autophagy in the heart
Riehle C, Wende A, Sena S, Pires K, Pereira R, Zhu Y, Bugger H, Frank D, Bevins J, Chen D, Perry C, Dong X, Valdez S, Rech M, Sheng X, Weimer B, Gottlieb R, White M, Abel E. Insulin receptor substrate signaling suppresses neonatal autophagy in the heart. Journal Of Clinical Investigation 2013, 123: 5319-5333. PMID: 24177427, PMCID: PMC3859408, DOI: 10.1172/jci71171.Peer-Reviewed Original ResearchMeSH KeywordsAmino AcidsAnimalsApoptosisApoptosis Regulatory ProteinsAutophagyBeclin-1Cardiomyopathy, DilatedFetal HeartHeartHeart FailureInsulinInsulin Receptor Substrate ProteinsInsulin-Like Growth Factor IMiceMitochondria, HeartMyocytes, CardiacOxidative PhosphorylationPhosphorylationProtein Processing, Post-TranslationalReceptor, IGF Type 1Signal TransductionTOR Serine-Threonine KinasesConceptsInsulin receptor substrateInduction of autophagyActivation of mTORIGF-1R signalingPostnatal cardiac developmentUnrestrained autophagyCardiomyocyte-specific deletionGenetic suppressionCardiac developmentReceptor substrateIGF-1 receptorEssential adaptationProsurvival signalingAutophagic fluxAutophagy suppressionAutophagyMitochondrial dysfunctionMammalian heartPhysiological suppressionNeonatal starvationAutophagic activationSignalingIRS1IRS2Insulin actionMyocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance
Qi Y, Xu Z, Zhu Q, Thomas C, Kumar R, Feng H, Dostal D, White M, Baker K, Guo S. Myocardial Loss of IRS1 and IRS2 Causes Heart Failure and Is Controlled by p38α MAPK During Insulin Resistance. Diabetes 2013, 62: 3887-3900. PMID: 24159000, PMCID: PMC3806607, DOI: 10.2337/db13-0095.Peer-Reviewed Original ResearchConceptsIRS2 proteinGene expressionType 2 diabetesEnergy metabolism gene expressionInsulin resistanceMetabolic gene expressionBox class ODouble knockout miceHeart failureActivation of p38Chronic insulin exposureActivation of p38αMetabolism gene expressionProtein kinaseRole of IRS1Cellular metabolismMolecular mechanismsInsulin receptorNeonatal rat ventricular cardiomyocytesP38α MAPKCause heart failureCellular dysfunctionIRS1Myocardial insulin resistanceClass OSerine Phosphorylation Sites on IRS2 Activated by Angiotensin II and Protein Kinase C To Induce Selective Insulin Resistance in Endothelial Cells
Park K, Li Q, Rask-Madsen C, Mima A, Mizutani K, Winnay J, Maeda Y, D'Aquino K, White M, Feener E, King G. Serine Phosphorylation Sites on IRS2 Activated by Angiotensin II and Protein Kinase C To Induce Selective Insulin Resistance in Endothelial Cells. Molecular And Cellular Biology 2013, 33: 3227-3241. PMID: 23775122, PMCID: PMC3753901, DOI: 10.1128/mcb.00506-13.Peer-Reviewed Original ResearchMeSH KeywordsAngiotensin IIAnimalsCattleCell LineEndothelial CellsEnzyme ActivationInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceMaleMiceMice, TransgenicPhosphatidylinositol 3-KinasesPhosphorylationProtein Kinase CProtein Kinase C betaRatsRats, ZuckerSerineTetradecanoylphorbol AcetateThreonineTyrosinePhosphatidylcholine Transfer Protein Interacts with Thioesterase Superfamily Member 2 to Attenuate Insulin Signaling
Ersoy B, Tarun A, D’Aquino K, Hancer N, Ukomadu C, White M, Michel T, Manning B, Cohen D. Phosphatidylcholine Transfer Protein Interacts with Thioesterase Superfamily Member 2 to Attenuate Insulin Signaling. Science Signaling 2013, 6: ra64. PMID: 23901139, PMCID: PMC3959124, DOI: 10.1126/scisignal.2004111.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsGlucoseHEK293 CellsHomeostasisHumansInhibitory Concentration 50InsulinLiverMechanistic Target of Rapamycin Complex 1MiceMice, TransgenicMultiprotein ComplexesPhospholipid Transfer ProteinsPhosphorylationSignal TransductionThiolester HydrolasesTOR Serine-Threonine KinasesTuberous Sclerosis Complex 2 ProteinTumor Suppressor ProteinsConceptsThioesterase superfamily member 2Insulin receptor substrate 2Phosphatidylcholine transfer proteinTSC1-TSC2 complexGenetic ablationRapamycin complex 1Transfer proteinSteady-state amountsMember 2Hepatic glucose homeostasisPhospholipid-binding proteinProtein exhibitInsulin signalingChemical inhibitionKey effectorsSubstrate 2Mammalian targetDiet-induced diabetesProteinTSC2KnockdownGlucose homeostasisPhospholipid-dependent mechanismsActivationComplexes 1