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 rateDownregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex
Xie L, Yuan Y, Xu S, Lu S, Gu J, Wang Y, Wang Y, Zhang X, Chen S, Li J, Lu J, Sun H, Hu R, Piao H, Wang W, Wang C, Wang J, Li N, White M, Han L, Jia W, Miao J, Liu J. Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex. Cell Reports 2022, 41: 111498. PMID: 36261001, PMCID: PMC10153649, DOI: 10.1016/j.celrep.2022.111498.Peer-Reviewed Original ResearchConceptsNon-alcoholic fatty liver diseaseFatty liver diseaseLipid metabolism diseasesLipid catabolismHepatic lipid catabolismFatty acid oxidationDetectable hepatotoxicityCopper deficiencyNAFLD developmentLiver diseaseMetabolic diseasesMetabolism diseasesNormal levelsDiseaseMitochondrial biogenesisAcid oxidationAMPK activityAMPKAblationDeficiencyCatabolismLKB1HepatotoxicityTAZ inhibits glucocorticoid receptor and coordinates hepatic glucose homeostasis in normal physiological states
Xu S, Liu Y, Hu R, Wang M, Stöhr O, Xiong Y, Chen L, Kang H, Zheng L, Cai S, He L, Wang C, Copps K, White M, Miao J. TAZ inhibits glucocorticoid receptor and coordinates hepatic glucose homeostasis in normal physiological states. ELife 2021, 10: e57462. PMID: 34622775, PMCID: PMC8555985, DOI: 10.7554/elife.57462.Peer-Reviewed Original ResearchConceptsGluconeogenic gene promotersBinding of GRGene promoterGlucocorticoid receptorGlucose homeostasisLigand-binding domainGlucose productionOverexpression of TAZHepatic glucose homeostasisWW domainsBlood glucose concentrationPhysiological fastingGluconeogenic genesGR response elementResponse elementNovel roleTAZNormal physiological stateGR transactivationPhysiological statePromoterMouse liverPericentral hepatocytesPathological statesGlucose concentration
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 advancesRoleSequenceYearsIrs2 deficiency alters hippocampus-associated behaviors during young adulthood
Tanokashira D, Wang W, Maruyama M, Kuroiwa C, White M, Taguchi A. Irs2 deficiency alters hippocampus-associated behaviors during young adulthood. Biochemical And Biophysical Research Communications 2021, 559: 148-154. PMID: 33940386, PMCID: PMC8361845, DOI: 10.1016/j.bbrc.2021.04.101.Peer-Reviewed Original ResearchConceptsYoung adult male miceAdult male miceMale miceAlzheimer's diseaseType 2 diabetes mellitusInsulin-like growth factor-1Brain energy metabolismGrowth factor-1Young adult malesCore body temperatureDiabetes mellitusInsulin resistanceInsulin/insulin-like growth factor-1Risk factorsBehavioral alterationsCognitive impairmentGenetic backgroundPremature deathHippocampusMiceYoung adulthoodAberrant alterationsFactor 1Abnormal changesBody temperatureFoxO1 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 toleranceInsulin receptor substrate 1, but not IRS2, plays a dominant role in regulating pancreatic alpha cell function in mice
Takatani T, Shirakawa J, Shibue K, Gupta M, Kim H, Lu S, Hu J, White M, Kennedy R, Kulkarni R. Insulin receptor substrate 1, but not IRS2, plays a dominant role in regulating pancreatic alpha cell function in mice. Journal Of Biological Chemistry 2021, 296: 100646. PMID: 33839150, PMCID: PMC8131928, DOI: 10.1016/j.jbc.2021.100646.Peer-Reviewed Original ResearchConceptsAKT Ser/Thr kinaseInsulin receptor substrate (IRS) proteinsSer/Thr kinaseAlpha-cell functionGlobal protein translationCell functionInsulin receptor substrate-1Pancreatic alpha-cell functionDownstream target genesReceptor substrate-1Alpha cellsAlpha-cell lineGlucagon secretionSubstrate proteinsProtein translationTarget genesSubstrate-1Downstream proteinsDominant regulatorPancreatic alpha cellsMitochondrial dysfunctionCognate receptorsIRS2Normal glucose toleranceCell lines
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 problemsDiabetesParaventricular, subparaventricular and periventricular hypothalamic IRS4-expressing neurons are required for normal energy balance
Sutton A, Gonzalez I, Sadagurski M, Rajala M, Lu C, Allison M, Adams J, Myers M, White M, Olson D. Paraventricular, subparaventricular and periventricular hypothalamic IRS4-expressing neurons are required for normal energy balance. Scientific Reports 2020, 10: 5546. PMID: 32218485, PMCID: PMC7099088, DOI: 10.1038/s41598-020-62468-z.Peer-Reviewed Original ResearchConceptsEnergy expenditureEnergy expenditure regulationAnti-obesity therapiesFeeding-related behaviorsNormal energy balanceInsulin receptor substrate 4Negative energy balancePVH neuronsHypothalamic circuitryHypothalamic sitesEnergy balance controlFeeding suppressionParaventricular nucleusSatiety responseSubstantial obesityNormal feedingPVHNeuronsViral toolsNeural componentsHindbrain regionsObesityRequisite roleBalance controlEnergy balanceInsulin 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
Hyperglycemia induces vascular smooth muscle cell dedifferentiation by suppressing insulin receptor substrate-1–mediated p53/KLF4 complex stabilization
Xi G, Shen X, Wai C, White M, Clemmons D. Hyperglycemia induces vascular smooth muscle cell dedifferentiation by suppressing insulin receptor substrate-1–mediated p53/KLF4 complex stabilization. Journal Of Biological Chemistry 2018, 294: 2407-2421. PMID: 30578299, PMCID: PMC6378959, DOI: 10.1074/jbc.ra118.005398.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtherosclerosisCell DifferentiationHumansHyperglycemiaInsulin Receptor Substrate ProteinsInsulin ResistanceKruppel-Like Factor 4Kruppel-Like Transcription FactorsMiceMice, KnockoutMultiprotein ComplexesMuscle, Smooth, VascularMyocytes, Smooth MuscleProtein StabilityProto-Oncogene MasProto-Oncogene Proteins c-mdm2SwineTumor Suppressor Protein p53ConceptsKrüppel-like factor 4Vascular smooth muscle cell dedifferentiationSmooth muscle cell dedifferentiationInsulin receptor substrate-1Muscle cell dedifferentiationNormoglycemic miceAtherosclerotic lesionsHigh glucoseVSMC differentiationInsulin resistance stateP53 levelsIRS-1 knockdownSmooth muscle protein 22P53 associationExpression of p21Cell dedifferentiationMarker protein expressionAccelerates AtherosclerosisNondiabetic pigsDiabetic pigsIRS-1 overexpressionNutlin-3 treatmentMDM2/p53Receptor substrate-1MDM2 proto-oncogeneInsulin 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 obesityExpressionDysregulationChromatinFOXO1Rho kinase/AMPK axis regulates hepatic lipogenesis during overnutrition
Huang H, Lee S, Sousa-Lima I, Kim S, Hwang W, Dagon Y, Yang W, Cho S, Kang M, Seo J, Shibata M, Cho H, Belew G, Bhin J, Desai B, Ryu M, Shong M, Li P, Meng H, Chung B, Hwang D, Kim M, Park K, Macedo M, White M, Jones J, Kim Y. Rho kinase/AMPK axis regulates hepatic lipogenesis during overnutrition. Journal Of Clinical Investigation 2018, 128: 5335-5350. PMID: 30226474, PMCID: PMC6264719, DOI: 10.1172/jci63562.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseFatty liver diseaseHepatic lipid accumulationLiver diseaseInsulin resistanceRisk factorsNovo lipogenesisObesity-related metabolic disordersLipid accumulationObesity-induced steatosisChronic liver diseaseObese diabetic miceDiet-induced obesityMajor risk factorSevere hepatic steatosisHigh-fat dietDe novo lipogenesisThermogenic gene expressionRho kinase 1Antidiabetes drugsDiabetic miceHepatic steatosisActivation of AMPKHepatocellular carcinomaMetabolic disordersInactivating hepatic follistatin alleviates hyperglycemia
Tao R, Wang C, Stöhr O, Qiu W, Hu Y, Miao J, Dong X, Leng S, Stefater M, Stylopoulos N, Lin L, Copps K, White M. Inactivating hepatic follistatin alleviates hyperglycemia. Nature Medicine 2018, 24: 1058-1069. PMID: 29867232, PMCID: PMC6039237, DOI: 10.1038/s41591-018-0048-0.Peer-Reviewed Original ResearchConceptsHepatic glucose productionAdipose tissue insulinGlucose toleranceTissue insulinSuppression of HGPGastric bypass surgeryFed obese miceHepatic insulin resistanceWhite adipose tissuePotential clinical significanceInsulin receptor substrate-1Bypass surgeryGlucose intoleranceHepatic inactivationObese miceInsulin resistanceObese individualsGlycated hemoglobinTranscription factor FOXO1Insulin sensitivityNormal suppressionClinical significanceReceptor substrate-1Adipose tissueExpression of FstAblation 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
Down-regulation of Insulin Receptor Substrate 1 during Hyperglycemia Induces Vascular Smooth Muscle Cell Dedifferentiation*
Xi G, Wai C, White M, Clemmons D. Down-regulation of Insulin Receptor Substrate 1 during Hyperglycemia Induces Vascular Smooth Muscle Cell Dedifferentiation*. Journal Of Biological Chemistry 2016, 292: 2009-2020. PMID: 28003360, PMCID: PMC5290970, DOI: 10.1074/jbc.m116.758987.Peer-Reviewed Original ResearchConceptsInsulin receptor substrate-1Receptor substrate-1IRS-1Differentiated stateSubstrate-1Aberrant signalingMetabolic stressVascular smooth muscle cell dedifferentiationIGF-I stimulationIRS-1 expressionVascular smooth muscle cell migrationScaffold proteinSHPS-1Transcription factorsSmooth muscle cell dedifferentiationSmooth muscle cell migrationMuscle cell dedifferentiationMuscle cell migrationReceptor signalsVSMC dedifferentiationCell migrationInsulin-like growth factor ICell dedifferentiationMajor risk factorDevelopment of atherosclerosisG protein-coupled receptors (GPCRs) That Signal via Protein Kinase A (PKA) Cross-talk at Insulin Receptor Substrate 1 (IRS1) to Activate the phosphatidylinositol 3-kinase (PI3K)/AKT Pathway*
Law N, White M, Hunzicker-Dunn M. G protein-coupled receptors (GPCRs) That Signal via Protein Kinase A (PKA) Cross-talk at Insulin Receptor Substrate 1 (IRS1) to Activate the phosphatidylinositol 3-kinase (PI3K)/AKT Pathway*. Journal Of Biological Chemistry 2016, 291: 27160-27169. PMID: 27856640, PMCID: PMC5207145, DOI: 10.1074/jbc.m116.763235.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCells, CulturedCyclic AMP-Dependent Protein KinasesFemaleGranulosa CellsHumansInsulin Receptor Substrate ProteinsOvarian FolliclePhosphatidylinositol 3-KinasePhosphorylationProto-Oncogene Proteins c-aktRatsRats, Sprague-DawleyReceptors, G-Protein-CoupledSignal TransductionThyroid NeoplasmsConceptsG protein-coupled receptorsInsulin receptor substrate-1PI3K/Akt cascadeProtein-coupled receptorsAkt cascadeSer/ThrReceptor substrate-1PI3K/Akt activationInsulin-like growth factor-1PI3K/Akt pathwayGranulosa cellsConserved mechanismPI3K/AktCellular functionsProtein kinaseSer residuesSubstrate-1Myosin phosphataseSubunit 1Akt activationCell survivalAutocrine/paracrine mannerViral oncoproteinsAkt pathwayPreantral granulosa cells