2021
FoxO1 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
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 obesityExpressionDysregulationChromatinFOXO1
2014
Insulin Receptor Substrates Are Essential for the Bioenergetic and Hypertrophic Response of the Heart to Exercise Training
Riehle C, Wende A, Zhu Y, Oliveira K, Pereira R, Jaishy B, Bevins J, Valdez S, Noh J, Kim B, Moreira A, Weatherford E, Manivel R, Rawlings T, Rech M, White M, Abel E. Insulin Receptor Substrates Are Essential for the Bioenergetic and Hypertrophic Response of the Heart to Exercise Training. Molecular And Cellular Biology 2014, 34: 3450-3460. PMID: 25002528, PMCID: PMC4135616, DOI: 10.1128/mcb.00426-14.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEnergy MetabolismGene Expression RegulationGlycogenHeartInsulin Receptor Substrate ProteinsMiceMice, Inbred C57BLMice, KnockoutMitochondriaPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaPhosphatidylinositol 3-KinasesProtein IsoformsSignal TransductionSwimmingTranscription FactorsConceptsInsulin receptor substrate-1IRS isoformsProtein phosphatase 2AReceptor substrate-1Insulin receptor substrateInsulin-like growth factor 1 receptorGrowth factor 1 receptorSynthase kinase-3βPeroxisome proliferator-activated receptor gamma coactivatorPhosphatase 2AProliferator-activated receptor gamma coactivatorFactor 1 receptorPGC-1α protein contentCardiomyocyte-specific deletionDevelopmental regulationProtein contentHypertrophic responseReceptor substrateReceptor gamma coactivatorFatty acid oxidationSubstrate-1Kinase-3βDivergent rolesMetabolic adaptationNonredundant role
2009
Foxo1 integrates insulin signaling with mitochondrial function in the liver
Cheng Z, Guo S, Copps K, Dong X, Kollipara R, Rodgers J, Depinho R, Puigserver P, White M. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nature Medicine 2009, 15: 1307-1311. PMID: 19838201, PMCID: PMC3994712, DOI: 10.1038/nm.2049.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsCells, CulturedElectron Transport Chain Complex ProteinsForkhead Box Protein O1Forkhead Transcription FactorsGene Expression RegulationHeme Oxygenase-1HepatocytesInsulinInsulin Receptor Substrate ProteinsLiverMembrane Potential, MitochondrialMembrane ProteinsMiceMice, KnockoutMicroscopy, Electron, TransmissionMitochondriaMutationNADPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaSignal TransductionTrans-ActivatorsTranscription FactorsThe Irs1 Branch of the Insulin Signaling Cascade Plays a Dominant Role in Hepatic Nutrient Homeostasis
Guo S, Copps K, Dong X, Park S, Cheng Z, Pocai A, Rossetti L, Sajan M, Farese R, White M. The Irs1 Branch of the Insulin Signaling Cascade Plays a Dominant Role in Hepatic Nutrient Homeostasis. Molecular And Cellular Biology 2009, 29: 5070-5083. PMID: 19596788, PMCID: PMC2738277, DOI: 10.1128/mcb.00138-09.Peer-Reviewed Original ResearchConceptsHigh-fat dietHepatic nutrient homeostasisIntracerebroventricular insulin infusionSuppression of HGPImpaired glucose toleranceHyperinsulinemic-euglycemic clampHepatic insulin actionHepatic glucose productionHepatic Irs1Cre-loxP approachLivers of controlGlucose toleranceInsulin infusionInsulin Signaling CascadeInsulin sensitivityPostprandial hyperglycemiaGlucose homeostasisInsulin actionPrincipal mediatorGlucose productionLipogenic genesMiceTyrosine phosphorylationLiverIRS2
2005
Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents
Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N, Neschen S, White MF, Bilz S, Sono S, Pypaert M, Shulman GI. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. Journal Of Clinical Investigation 2005, 115: 3587-3593. PMID: 16284649, PMCID: PMC1280967, DOI: 10.1172/jci25151.Peer-Reviewed Original ResearchMeSH KeywordsBiopsyBlood GlucoseBlotting, WesternBody Mass IndexBody WeightDiabetes Mellitus, Type 2DNA, MitochondrialFamily HealthFemaleGene Expression RegulationGlucose Clamp TechniqueGlucose Tolerance TestHumansHyperinsulinismImmunoprecipitationInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLipidsMaleMicroscopy, ElectronMicroscopy, Electron, TransmissionMitochondriaMusclesPhosphoproteinsPhosphorylationProtein Serine-Threonine KinasesReverse Transcriptase Polymerase Chain ReactionRNA, MessengerSerineSignal TransductionTime FactorsTranscription, GeneticTriglyceridesConceptsInsulin-resistant offspringIR offspringType 2 diabetesInsulin-stimulated muscle glucose uptakeType 2 diabetic parentsIntramyocellular lipid contentHyperinsulinemic-euglycemic clampMuscle glucose uptakeIRS-1 serine phosphorylationMuscle mitochondrial densityMitochondrial densityMuscle biopsy samplesSerine kinase cascadeInsulin-stimulated Akt activationDiabetic parentsInsulin resistanceControl subjectsBiopsy samplesGlucose uptakeLipid accumulationMitochondrial dysfunctionInsulin signalingAkt activationEarly defectsMuscle
2004
Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes
Lin X, Taguchi A, Park S, Kushner J, Li F, Li Y, White M. Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes. Journal Of Clinical Investigation 2004, 114: 908-916. PMID: 15467829, PMCID: PMC518668, DOI: 10.1172/jci22217.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBody WeightBrainDiabetes Mellitus, Type 2DietEatingGene DeletionGene Expression RegulationGlucoseHomeostasisHumansHypothalamusInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsIslets of LangerhansMaleMiceMice, Inbred C57BLMice, KnockoutObesityPhosphoproteinsRandom AllocationSignal TransductionConceptsInsulin receptor substrate 2Beta cellsInsulin resistanceSufficient beta cell functionPancreas beta cellsBeta-cell failureBeta-cell functionFunctional beta cellsMonths of ageAdult beta cellsFat body massSubstrate 2Obese miceDiabetesΒ-cellsObesityPromotes RegenerationConditional knockoutCell functionMiceBrainBody massMolecular linkCell failureCells
2003
Upregulation of insulin receptor substrate-2 in pancreatic β cells prevents diabetes
Hennige A, Burks D, Ozcan U, Kulkarni R, Ye J, Park S, Schubert M, Fisher T, Dow M, Leshan R, Zakaria M, Mossa-Basha M, White M. Upregulation of insulin receptor substrate-2 in pancreatic β cells prevents diabetes. Journal Of Clinical Investigation 2003, 112: 1521-1532. PMID: 14617753, PMCID: PMC259126, DOI: 10.1172/jci18581.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCell SizeDiabetes Mellitus, ExperimentalDiabetes Mellitus, Type 2Dietary FatsGene Expression RegulationHumansInsulinInsulin Receptor Substrate ProteinsInsulin-Like Growth Factor IIntracellular Signaling Peptides and ProteinsIslets of LangerhansIslets of Langerhans TransplantationMaleMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicPhosphoproteinsReceptor, InsulinSignal TransductionSurvival RateUp-RegulationConceptsPancreatic beta-cell functionPeripheral insulin actionBeta-cell failureBeta-cell functionType 2 diabetesIrs2-/- miceInsulin receptor substrate 2Beta-cell growthBeta cell-specific expressionPrevents diabetesObese miceTransgenic isletsInsulin secretionWT isletsIRS2 expressionPharmacological approachesBeta cellsPhysiologic responsesInsulin actionRational treatmentDiabetesInsulin/IGFCell functionMiceCell-specific expressioncAMP promotes pancreatic β-cell survival via CREB-mediated induction of IRS2
Jhala U, Canettieri G, Screaton R, Kulkarni R, Krajewski S, Reed J, Walker J, Lin X, White M, Montminy M. cAMP promotes pancreatic β-cell survival via CREB-mediated induction of IRS2. Genes & Development 2003, 17: 1575-1580. PMID: 12842910, PMCID: PMC196130, DOI: 10.1101/gad.1097103.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCell LineCell SurvivalColforsinCyclic AMPCyclic AMP Response Element-Binding ProteinDiabetes MellitusGene Expression RegulationGlucagonGlucagon-Like Peptide 1GlucoseGlucose IntoleranceHumansInsulinInsulin Receptor Substrate ProteinsInsulin-Like Growth Factor IIntracellular Signaling Peptides and ProteinsIslets of LangerhansMiceMice, TransgenicPeptide FragmentsPhosphoproteinsPhosphorylationPromoter Regions, GeneticProtein PrecursorsProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktSignal TransductionTransfectionTransgenesTumor Cells, CulturedConceptsPancreatic β-cell survivalActivity of CREBSecond messenger cAMPSurvival kinase AktΒ-cell survivalKinase AktPathway componentsA-CREBCREB actionExpression of IRS2Cell survivalBeta-cell apoptosisDirect targetIslet cell survivalNovel mechanismCREBIRS2ExpressionCAMPInductionTransgeneAktIGF-1ApoptosisSurvival
1998
Insulin receptor substrate-2 amino acid polymorphisms are not associated with random type 2 diabetes among Caucasians.
Bernal D, Almind K, Yenush L, Ayoub M, Zhang Y, Rosshani L, Larsson C, Pedersen O, White M. Insulin receptor substrate-2 amino acid polymorphisms are not associated with random type 2 diabetes among Caucasians. Diabetes 1998, 47: 976-979. PMID: 9604879, DOI: 10.2337/diabetes.47.6.976.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceDiabetes Mellitus, Type 2ExonsFemaleFetusGene Expression RegulationHumansInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsMaleMolecular Sequence DataOrgan SpecificityPhosphoproteinsPolymorphism, GeneticReceptor, InsulinRNA, MessengerSequence AlignmentSequence Homology, Amino AcidTranscription, GeneticWhite People
1996
Insulin-induced egr-1 and c-fos Expression in 32D Cells Requires Insulin Receptor, Shc, and Mitogen-activated Protein Kinase, but Not Insulin Receptor Substrate-1 and Phosphatidylinositol 3-Kinase Activation*
Harada S, Smith R, Smith J, White M, Jarett L. Insulin-induced egr-1 and c-fos Expression in 32D Cells Requires Insulin Receptor, Shc, and Mitogen-activated Protein Kinase, but Not Insulin Receptor Substrate-1 and Phosphatidylinositol 3-Kinase Activation*. Journal Of Biological Chemistry 1996, 271: 30222-30226. PMID: 8939974, DOI: 10.1074/jbc.271.47.30222.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsCell LineCHO CellsCricetinaeDNA-Binding ProteinsEarly Growth Response Protein 1Enzyme ActivationEnzyme InhibitorsGene Expression RegulationGRB2 Adaptor ProteinImmediate-Early ProteinsInsulinInsulin Receptor Substrate ProteinsMicePhosphatidylinositol 3-KinasesPhosphoproteinsPhosphorylationPhosphotransferases (Alcohol Group Acceptor)Protein KinasesProteinsProto-Oncogene Proteins c-fosReceptor, InsulinRNA, MessengerTranscription FactorsTyrosineConceptsC-fos expressionInsulin receptor substrate-1Egr-1 expressionInsulin receptorReceptor substrate-1Mitogen-activated protein kinase activationEgr-1Protein kinase activationMultiple signal transduction pathwaysBlot analysisEffect of insulinSignal transduction pathwaysSubstrate-1Tyrosine phosphorylationImmediate early gene Egr-1Mitogen-activated protein kinase kinase inhibitorWestern blot analysisProtein kinase kinase inhibitorInsulin receptor tyrosine phosphorylationInsulin treatmentKinase activationIRS-1 phosphorylationTransduction pathwaysKinase kinase inhibitorGene Egr-1