2021
Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol – PKCε – insulin receptorT1160 phosphorylation
Lyu K, Zhang D, Song J, Li X, Perry RJ, Samuel VT, Shulman GI. Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol – PKCε – insulin receptorT1160 phosphorylation. JCI Insight 2021, 6: e139946. PMID: 33411692, PMCID: PMC7934919, DOI: 10.1172/jci.insight.139946.Peer-Reviewed Original ResearchConceptsInsulin resistanceInsulin actionAdipose tissue insulin resistanceTissue insulin resistanceWT control miceHyperinsulinemic-euglycemic clampShort-term HFDTissue insulin actionAdipose tissue insulin actionDiet-fed ratsPotential therapeutic targetHFD feedingControl miceInsulin sensitivityTherapeutic targetLipolysis suppressionImpairs insulinHFDPKCε activationGlucose uptakeΕ activationMiceDiacylglycerol accumulationRecent evidenceProtein kinase C
2020
Metabolic control analysis of hepatic glycogen synthesis in vivo
Nozaki Y, Petersen MC, Zhang D, Vatner DF, Perry RJ, Abulizi A, Haedersdal S, Zhang XM, Butrico GM, Samuel VT, Mason GF, Cline GW, Petersen KF, Rothman DL, Shulman GI. Metabolic control analysis of hepatic glycogen synthesis in vivo. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 8166-8176. PMID: 32188779, PMCID: PMC7149488, DOI: 10.1073/pnas.1921694117.Peer-Reviewed Original Research
2019
Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production
Gassaway BM, Cardone RL, Padyana AK, Petersen MC, Judd ET, Hayes S, Tong S, Barber KW, Apostolidi M, Abulizi A, Sheetz JB, Kshitiz, Aerni HR, Gross S, Kung C, Samuel VT, Shulman GI, Kibbey RG, Rinehart J. Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production. Cell Reports 2019, 29: 3394-3404.e9. PMID: 31825824, PMCID: PMC6951436, DOI: 10.1016/j.celrep.2019.11.009.Peer-Reviewed Original ResearchConceptsCyclin-dependent kinasesMetabolic control pointPhosphorylation sitesNuclear retentionCDK activityPKL activityDays high-fat dietKinase phosphorylationImportant enzymePyruvate kinaseHigh-fat dietS113KinaseEnzyme kineticsPhosphorylationAdditional control pointsRegulationGlucose productionHepatic glucose productionInsulin resistanceGlycolysisEnzymePKAPathwayActivity
2018
Ectopic lipid deposition mediates insulin resistance in adipose specific 11β-hydroxysteroid dehydrogenase type 1 transgenic mice
Abulizi A, Camporez JP, Zhang D, Samuel VT, Shulman GI, Vatner DF. Ectopic lipid deposition mediates insulin resistance in adipose specific 11β-hydroxysteroid dehydrogenase type 1 transgenic mice. Metabolism 2018, 93: 1-9. PMID: 30576689, PMCID: PMC6401251, DOI: 10.1016/j.metabol.2018.12.003.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceEctopic lipid depositionInsulin resistanceHepatic lipid contentGlucocorticoid actionTransgenic miceLipid depositionSevere hepatic insulin resistanceTissue-specific insulin actionHepatic triglyceride contentHigh-fat dietHyperinsulinemic-euglycemic clampGlucocorticoid excessAkt serine phosphorylationGlucocorticoid activityHepatic steatosisFat dietLittermate controlsHepatic insulinInsulin actionTriglyceride contentPKCε activationDevelopment of lipidLipid contentMicePEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats
Beddow SA, Gattu AK, Vatner DF, Paolella L, Alqarzaee A, Tashkandi N, Popov V, Church C, Rodeheffer M, Cline G, Geisler J, Bhanot S, Samuel VT. PEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats. Endocrinology 2018, 160: 205-219. PMID: 30445425, PMCID: PMC6307100, DOI: 10.1210/en.2018-00630.Peer-Reviewed Original ResearchMeSH KeywordsAdipose Tissue, WhiteAdiposityAnimalsDiabetes Mellitus, Type 2Diet, High-FatGlucokinaseHumansInsulinIntracellular Signaling Peptides and ProteinsLipogenesisLiverLiver GlycogenMaleMiceMice, Inbred C57BLOligonucleotides, AntisensePhosphoenolpyruvate Carboxykinase (GTP)RatsRats, Sprague-DawleyConceptsHepatic glycogen synthesisAdipose tissueAntisense oligonucleotideType 2 diabetes mellitusWhite adipose tissue massIncreased hepatic gluconeogenesisChow fed ratsHepatic insulin sensitivityMale Sprague-DawleyAdipose tissue massHepatic insulin resistanceWhite adipose tissueHepatic glucose productionDe novo lipogenesisHepatic glucokinase expressionControl antisense oligonucleotideGlycogen synthesisTranscription factor 3HFF ratsDiabetes mellitusHepatic steatosisInsulin resistanceHyperglycemic clampPlasma glucoseInsulin sensitivityPKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling
Gassaway BM, Petersen MC, Surovtseva YV, Barber KW, Sheetz JB, Aerni HR, Merkel JS, Samuel VT, Shulman GI, Rinehart J. PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: e8996-e9005. PMID: 30181290, PMCID: PMC6156646, DOI: 10.1073/pnas.1804379115.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, Genetically ModifiedDiabetes Mellitus, Type 2Diet, High-FatDisease Models, AnimalGene Knockdown TechniquesHumansInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLipid MetabolismLiverPhosphorylationProtein Kinase C-epsilonProteomicsRatsReceptor, InsulinRibosomal Protein S6Ribosomal Protein S6 Kinases, 70-kDaRNA, Small InterferingSignal TransductionConceptsHigh-fat diet-induced hepatic insulin resistanceDiet-induced hepatic insulin resistanceLipid-induced insulin resistanceProtein phosphorylationSiRNA-based screenProtein kinase C εSet of proteinsCross talkHepatic insulin resistanceQuantitative phosphoproteomicsMotif analysisUnknown regulatorKinase assaysPhosphoproteomic dataCanonical insulinP70S6KInsulin receptorImpact of lipidSystem-level approachPKCεDiacylglycerolPhosphorylationKey mediatorNew therapeutic approachesInsulin resistanceAngptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents
Vatner DF, Goedeke L, Camporez JG, Lyu K, Nasiri AR, Zhang D, Bhanot S, Murray SF, Still CD, Gerhard GS, Shulman GI, Samuel VT. Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents. Diabetologia 2018, 61: 1435-1446. PMID: 29497783, PMCID: PMC5940564, DOI: 10.1007/s00125-018-4579-1.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAngiopoietin-Like Protein 8Angiopoietin-like ProteinsAnimalsBody CompositionCalorimetry, IndirectDiet, High-FatGlucose Tolerance TestInsulin ResistanceLipid MetabolismMaleMiceMice, Inbred C57BLNon-alcoholic Fatty Liver DiseaseOligonucleotides, AntisensePeptide HormonesRatsRats, Sprague-DawleyConceptsHepatic insulin resistanceAdipose tissue lipoprotein lipaseInsulin resistanceEctopic lipid accumulationTissue lipoprotein lipaseAdipose tissueLipid uptakeTolerance testFed miceNon-alcoholic fatty liver diseaseAntisense oligonucleotideMixed meal tolerance testLipoprotein lipaseLipid accumulationDiet-induced NAFLDBariatric surgery patientsFatty liver diseaseHyperinsulinaemic euglycaemic clampMeal tolerance testSecond-generation antisense oligonucleotideAmeliorate insulin resistanceType 2 diabetesLipid-induced hepatic insulin resistanceLipoprotein lipase inhibitorWhite adipose tissue
2017
Mitochondrial Targeted Catalase Protects Against High-Fat Diet-Induced Muscle Insulin Resistance by Decreasing Intramuscular Lipid Accumulation
Lee HY, Lee JS, Alves T, Ladiges W, Rabinovitch PS, Jurczak MJ, Choi CS, Shulman GI, Samuel VT. Mitochondrial Targeted Catalase Protects Against High-Fat Diet-Induced Muscle Insulin Resistance by Decreasing Intramuscular Lipid Accumulation. Diabetes 2017, 66: db161334. PMID: 28476930, PMCID: PMC5521865, DOI: 10.2337/db16-1334.Peer-Reviewed Original ResearchConceptsHigh-fat dietMuscle insulin resistanceAcute lipid infusionInsulin resistanceRegular chowLipid infusionMCAT miceInsulin actionLipid-induced insulin resistanceDiet-induced insulin resistanceReactive oxygen speciesHyperinsulinemic-euglycemic clampWild-type miceMuscle fat oxidationIntramuscular lipid accumulationROS productionAcute infusionHFD-fedWT miceImpaired insulinPKCθ activationFat oxidationLipid emulsionMuscle insulinMice
2014
Targeting steroid receptor coactivator 1 with antisense oligonucleotides increases insulin-stimulated skeletal muscle glucose uptake in chow-fed and high-fat-fed male rats
Cantley JL, Vatner DF, Galbo T, Madiraju A, Petersen M, Perry RJ, Kumashiro N, Guebre-Egziabher F, Gattu AK, Stacy MR, Dione DP, Sinusas AJ, Ragolia L, Hall CE, Manchem VP, Bhanot S, Bogan JS, Samuel VT. Targeting steroid receptor coactivator 1 with antisense oligonucleotides increases insulin-stimulated skeletal muscle glucose uptake in chow-fed and high-fat-fed male rats. AJP Endocrinology And Metabolism 2014, 307: e773-e783. PMID: 25159329, PMCID: PMC4216948, DOI: 10.1152/ajpendo.00148.2014.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAnimalsBiological TransportDiet, High-FatEnzyme InhibitorsGene Expression Regulation, EnzymologicGlucose IntoleranceGlucose Transporter Type 4Insulin ResistanceIntracellular Signaling Peptides and ProteinsIntramolecular OxidoreductasesLipocalinsLiverMaleMuscle, SkeletalNuclear Receptor Coactivator 1Oligodeoxyribonucleotides, AntisensePhosphoenolpyruvate Carboxykinase (GTP)Prostaglandin D2Protein Interaction Domains and MotifsProteolysisRats, Sprague-DawleyConceptsMuscle glucose uptakeSteroid receptor coactivator-1Endogenous glucose productionInsulin-stimulated muscle glucose uptakeReceptor coactivator-1Glucose uptakeGlucose homeostasisInsulin-stimulated skeletal muscle glucose uptakeAntisense oligonucleotideBasal endogenous glucose productionInsulin-stimulated whole-body glucose disposalCoactivator-1Whole-body glucose disposalSkeletal muscle glucose uptakeLipocalin-type prostaglandin D2 synthaseSprage-Dawley ratsGluconeogenic enzymes