2023
Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis
Luukkonen P, Sakuma I, Gaspar R, Mooring M, Nasiri A, Kahn M, Zhang X, Zhang D, Sammalkorpi H, Penttilä A, Orho-Melander M, Arola J, Juuti A, Zhang X, Yimlamai D, Yki-Järvinen H, Petersen K, Shulman G. Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2217543120. PMID: 36669104, PMCID: PMC9942818, DOI: 10.1073/pnas.2217543120.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseLiver fibrosisLiver diseaseCommon chronic liver diseaseChronic liver diseaseFatty liver diseaseRisk of fibrosisDistinct mouse modelsPyrimidine catabolismNonalcoholic steatohepatitisMouse modelTherapeutic targetFibrosisDihydropyrimidine dehydrogenaseHuman liverA variantCommon variantsMetabolomics approachDiseaseMiceInhibitionCatabolismKnockdownSteatohepatitisGimeracil
2022
Distinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice
Gaspar R, Lyu K, Hubbard B, Leitner B, Luukkonen P, Hirabara S, Sakuma I, Nasiri A, Zhang D, Kahn M, Cline G, Pauli J, Perry R, Petersen K, Shulman G. Distinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice. Diabetologia 2022, 66: 567-578. PMID: 36456864, PMCID: PMC11194860, DOI: 10.1007/s00125-022-05838-8.Peer-Reviewed Original ResearchConceptsProtein kinase CsSubcellular compartmentsDistinct subcellular localisationMuscle insulin sensitivityMultiple subcellular compartmentsInsulin receptor kinaseNovel protein kinase CsActivation of PKCεSubcellular localisationPKCθ translocationReceptor kinasePlasma membraneSubcellular distributionTriacylglycerol contentCrucial pathwaysIntramuscular triacylglycerol contentRC miceDiacylglycerolConclusions/interpretationThese resultsPKCεPM compartmentPhosphorylationMuscle triacylglycerol contentSkeletal muscleRecent findingsDyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice
Bhat N, Narayanan A, Fathzadeh M, Kahn M, Zhang D, Goedeke L, Neogi A, Cardone RL, Kibbey RG, Fernandez-Hernando C, Ginsberg HN, Jain D, Shulman G, Mani A. Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice. Journal Of Clinical Investigation 2022, 132: e153724. PMID: 34855620, PMCID: PMC8803348, DOI: 10.1172/jci153724.Peer-Reviewed Original ResearchConceptsDe novo lipogenesisNonalcoholic steatohepatitisInsulin resistanceHepatic lipogenesisElevated de novo lipogenesisNonalcoholic fatty liver diseaseFatty liver diseaseLiver of patientsHepatic glycogen storageHigh-sucrose dietHepatic insulin resistanceFatty acid uptakeMetabolic syndromeLiver diseaseHepatic steatosisTriacylglycerol secretionNovo lipogenesisHepatic insulinTherapeutic targetImpaired activationAcid uptakeGlycogen storageMouse liverLiverLipogenesis
2020
Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice
Abulizi A, Vatner DF, Ye Z, Wang Y, Camporez JP, Zhang D, Kahn M, Lyu K, Sirwi A, Cline GW, Hussain MM, Aspichueta P, Samuel VT, Shulman GI. Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice. Journal Of Lipid Research 2020, 61: 1565-1576. PMID: 32907986, PMCID: PMC7707176, DOI: 10.1194/jlr.ra119000586.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceInsulin resistanceHepatic insulin sensitivityHepatic steatosisLipid-induced hepatic insulin resistancePKCε activationInsulin sensitivityKnockout miceNormal hepatic insulin sensitivityWild-type control miceHepatic ceramide contentHyperinsulinemic-euglycemic clampComprehensive metabolic phenotypingLipid dropletsHepatic DAG contentDAG contentGlucose intoleranceControl miceMTTP activityHepatic insulinAnimal modelsSteatosisAKT Ser/ThrMiceMetabolic phenotyping
2018
In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia.
Qiu Y, Perry RJ, Camporez JG, Zhang XM, Kahn M, Cline GW, Shulman GI, Vatner DF. In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia. Biochemical Journal 2018, 475: 1063-1074. PMID: 29483297, PMCID: PMC5884121, DOI: 10.1042/bcj20180063.Peer-Reviewed Original Research
2015
Hepatic insulin resistance and increased hepatic glucose production in mice lacking Fgf21
Camporez JP, Asrih M, Zhang D, Kahn M, Samuel VT, Jurczak MJ, Jornayvaz FR. Hepatic insulin resistance and increased hepatic glucose production in mice lacking Fgf21. Journal Of Endocrinology 2015, 226: 207-217. PMID: 26203166, DOI: 10.1530/joe-15-0136.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceFGF21 KO miceInsulin resistanceHepatic glucose productionKetogenic dietKO miceHepatic glucoseLipid metabolismGlucose productionFibroblast growth factor 21Littermate WT controlsRole of FGF21Growth factor 21Plasma glucagon levelsType 2 diabetesPotential pharmacological agentsFGF21 resistanceGlucagon levelsFactor 21Fat massMale miceWT littermatesPharmacological agentsWT controlsInsulin action
2014
Muscle-specific activation of Ca2+/calmodulin-dependent protein kinase IV increases whole-body insulin action in mice
Lee HY, Gattu AK, Camporez JP, Kanda S, Guigni B, Kahn M, Zhang D, Galbo T, Birkenfeld AL, Jornayvaz FR, Jurczak MJ, Choi CS, Yan Z, Williams RS, Shulman GI, Samuel VT. Muscle-specific activation of Ca2+/calmodulin-dependent protein kinase IV increases whole-body insulin action in mice. Diabetologia 2014, 57: 1232-1241. PMID: 24718953, PMCID: PMC5634138, DOI: 10.1007/s00125-014-3212-1.Peer-Reviewed Original ResearchConceptsMitochondrial contentDependent protein kinaseDependent protein kinase IVSkeletal muscleInsulin actionMuscle mitochondrial contentInsulin-stimulated glucose uptakeMuscle-specific activationΓ coactivator 1αGlucose uptakePhosphorylation of AktSkeletal muscle insulin actionProtein kinaseOxidative type IMitochondrial biogenesisKinase IVMuscle insulin actionGLUT4 proteinGlucose metabolismInsulin-stimulated whole-body glucose uptakePleiotropic effectsWhole-body glucose uptakeCAMK4Coactivator 1αWhole-body insulin action
2013
Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo
Galbo T, Perry RJ, Jurczak MJ, Camporez J, Alves TC, Kahn M, Guigni BA, Serr J, Zhang D, Bhanot S, Samuel VT, Shulman GI. Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 12780-12785. PMID: 23840067, PMCID: PMC3732992, DOI: 10.1073/pnas.1311176110.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceFat-induced hepatic insulin resistanceInsulin resistanceToll-like receptor 4 receptorTLR-4 knockout miceFat-induced insulin resistanceTLR-4 activationTLR-4 signalingType 2 diabetesImpairment of insulinInhibition of insulinCeramide synthesisActivation of PKCεTLR-4Hepatic steatosisHepatic accumulationKnockout miceIRS-2 signalingReceptor signalingCeramide accumulationAntisense oligonucleotideInsulinPrimary eventImpairmentFatty acidsCellular Mechanisms by Which FGF21 Improves Insulin Sensitivity in Male Mice
Camporez JP, Jornayvaz FR, Petersen MC, Pesta D, Guigni BA, Serr J, Zhang D, Kahn M, Samuel VT, Jurczak MJ, Shulman GI. Cellular Mechanisms by Which FGF21 Improves Insulin Sensitivity in Male Mice. Endocrinology 2013, 154: 3099-3109. PMID: 23766126, PMCID: PMC3749479, DOI: 10.1210/en.2013-1191.Peer-Reviewed Original ResearchMeSH KeywordsAdipose Tissue, BrownAnimalsCells, CulturedDiet, High-FatDrug ImplantsEnergy MetabolismFibroblast Growth FactorsGlucose IntoleranceHumansInfusions, SubcutaneousInsulin ResistanceIsoenzymesLipectomyLipid MetabolismLiverMaleMiceMice, Inbred C57BLMuscle, SkeletalProtein Kinase CProtein Kinase C-epsilonProtein Kinase C-thetaRecombinant ProteinsConceptsType 2 diabetesInsulin resistanceRegular chowInsulin sensitivityInsulin actionNonalcoholic fatty liver diseaseFibroblast growth factor 21Fatty liver diseasePeripheral insulin sensitivityEffects of FGF21HFD-fed miceGrowth factor 21High-fat dietCellular mechanismsWild-type miceWhite adipose tissueMuscle insulin resistanceMuscle ceramide contentProtein kinase Cε activationFGF21 administrationLiver diseaseFactor 21Male miceNovel therapiesAdipose tissueCellular Mechanism by Which Estradiol Protects Female Ovariectomized Mice From High-Fat Diet-Induced Hepatic and Muscle Insulin Resistance
Camporez JP, Jornayvaz FR, Lee HY, Kanda S, Guigni BA, Kahn M, Samuel VT, Carvalho CR, Petersen KF, Jurczak MJ, Shulman GI. Cellular Mechanism by Which Estradiol Protects Female Ovariectomized Mice From High-Fat Diet-Induced Hepatic and Muscle Insulin Resistance. Endocrinology 2013, 154: 1021-1028. PMID: 23364948, PMCID: PMC3578999, DOI: 10.1210/en.2012-1989.Peer-Reviewed Original ResearchConceptsEstrogen replacement therapyOVX miceMuscle insulin sensitivityMuscle insulin resistanceInsulin resistanceInsulin sensitivityReplacement therapyHigh-fat diet feedingWhole-body insulin resistanceWhole-body insulin sensitivityFemale ovariectomized miceEctopic lipid depositionWhole-body energy expenditureType 2 diabetesEnergy expenditureWeeks of ageWhole-body energy homeostasisProtein kinase Cε activationHepatic DAG contentLivers of shamPostmenopausal womenSham miceOvariectomized miceGlucose toleranceE2 treatmentCGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance
Cantley JL, Yoshimura T, Camporez JP, Zhang D, Jornayvaz FR, Kumashiro N, Guebre-Egziabher F, Jurczak MJ, Kahn M, Guigni BA, Serr J, Hankin J, Murphy RC, Cline GW, Bhanot S, Manchem VP, Brown JM, Samuel VT, Shulman GI. CGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 1869-1874. PMID: 23302688, PMCID: PMC3562813, DOI: 10.1073/pnas.1219456110.Peer-Reviewed Original ResearchMeSH Keywords1-Acylglycerol-3-Phosphate O-AcyltransferaseAdipose Tissue, WhiteAnimalsCell MembraneDiet, High-FatDiglyceridesEndoplasmic ReticulumGene ExpressionGene Knockdown TechniquesHumansImmunoblottingInjections, IntraperitonealInsulin ResistanceLipidsLiverMaleMiceMice, Inbred C57BLOligonucleotides, AntisenseProtein Kinase C-epsilonProtein TransportReverse Transcriptase Polymerase Chain ReactionConceptsHepatic insulin resistanceInsulin resistanceHepatic steatosisCGI-58 knockdownHigh-fat fed miceHyperinsulinemic-euglycemic clamp studiesSevere hepatic steatosisCGI-58 expressionFat-fed miceLipid-induced hepatic insulin resistanceChanarin-Dorfman syndromeComparative gene identification-58Lipid droplet-associated proteinAdipose triglyceride lipaseDroplet-associated proteinAntisense oligonucleotide treatmentInsulin sensitivityASO treatmentClamp studiesLipotoxic conditionsKnockdown miceCGI-58PKCε activationMiceTriglyceride lipase
2012
Fatty acid amide hydrolase ablation promotes ectopic lipid storage and insulin resistance due to centrally mediated hypothyroidism
Brown WH, Gillum MP, Lee HY, Camporez JP, Zhang XM, Jeong JK, Alves TC, Erion DM, Guigni BA, Kahn M, Samuel VT, Cravatt BF, Diano S, Shulman GI. Fatty acid amide hydrolase ablation promotes ectopic lipid storage and insulin resistance due to centrally mediated hypothyroidism. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 14966-14971. PMID: 22912404, PMCID: PMC3443187, DOI: 10.1073/pnas.1212887109.Peer-Reviewed Original ResearchMeSH KeywordsAmidesAmidohydrolasesAnalysis of VarianceAnimalsArachidonic AcidsChromatography, LiquidEndocannabinoidsEnergy MetabolismEthanolaminesHypothyroidismImmunoblottingInsulin ResistanceMiceMice, KnockoutPalmitic AcidsPolymerase Chain ReactionPolyunsaturated AlkamidesPPAR gammaTandem Mass SpectrometryThyrotropinThyrotropin-Releasing HormoneThyroxineTriiodothyronineConceptsEctopic lipid storageHepatic insulin resistanceInsulin resistanceEnergy expenditureDiet-induced hepatic insulin resistanceHypothalamic thyrotropin-releasing hormoneFatty acid amide hydrolase knockout miceThyroid-stimulating hormoneThyrotropin-releasing hormoneLipid storageDeiodinase 2 expressionReduced mRNA expressionProtein kinase Cε activationHepatic diacylglycerol contentPituitary thyroid-stimulating hormoneExcess energy storageFAAH deletionKnockout miceReceptor γThyroid axisThyroxine concentrationsMRNA expressionMiceHypothyroidismFAAH
2011
Dissociation of Inositol-requiring Enzyme (IRE1α)-mediated c-Jun N-terminal Kinase Activation from Hepatic Insulin Resistance in Conditional X-box-binding Protein-1 (XBP1) Knock-out Mice*
Jurczak MJ, Lee AH, Jornayvaz FR, Lee HY, Birkenfeld AL, Guigni BA, Kahn M, Samuel VT, Glimcher LH, Shulman GI. Dissociation of Inositol-requiring Enzyme (IRE1α)-mediated c-Jun N-terminal Kinase Activation from Hepatic Insulin Resistance in Conditional X-box-binding Protein-1 (XBP1) Knock-out Mice*. Journal Of Biological Chemistry 2011, 287: 2558-2567. PMID: 22128176, PMCID: PMC3268415, DOI: 10.1074/jbc.m111.316760.Peer-Reviewed Original ResearchAnimalsDNA-Binding ProteinsEndoplasmic ReticulumEndoplasmic Reticulum Chaperone BiPEndoplasmic Reticulum StressEndoribonucleasesEukaryotic Initiation Factor-2Heat-Shock ProteinsInsulin Receptor Substrate ProteinsInsulin ResistanceJNK Mitogen-Activated Protein KinasesLipid MetabolismLiverMiceMice, KnockoutPhosphorylationProtein Serine-Threonine KinasesRegulatory Factor X Transcription FactorsSignal TransductionTranscription FactorsX-Box Binding Protein 1Influence of the Hepatic Eukaryotic Initiation Factor 2α (eIF2α) Endoplasmic Reticulum (ER) Stress Response Pathway on Insulin-mediated ER Stress and Hepatic and Peripheral Glucose Metabolism*
Birkenfeld AL, Lee HY, Majumdar S, Jurczak MJ, Camporez JP, Jornayvaz FR, Frederick DW, Guigni B, Kahn M, Zhang D, Weismann D, Arafat AM, Pfeiffer AF, Lieske S, Oyadomari S, Ron D, Samuel VT, Shulman GI. Influence of the Hepatic Eukaryotic Initiation Factor 2α (eIF2α) Endoplasmic Reticulum (ER) Stress Response Pathway on Insulin-mediated ER Stress and Hepatic and Peripheral Glucose Metabolism*. Journal Of Biological Chemistry 2011, 286: 36163-36170. PMID: 21832042, PMCID: PMC3196114, DOI: 10.1074/jbc.m111.228817.Peer-Reviewed Original ResearchConceptsHepatic glucose productionInsulin sensitivityInsulin resistanceCaloric excessER stressHigh-fat diet-fed miceBasal plasma glucose concentrationsGlucose productionIGFBP-3 levelsHepatic ERPeripheral glucose metabolismTissue insulin sensitivityDiet-fed miceHepatic lipid accumulationHigh-fat dietHyperinsulinemic-euglycemic clampHepatic insulin sensitivityInfusion of insulinPlasma glucose concentrationEndoplasmic reticulum stress response pathwayEndoplasmic reticulum stressInsulin-stimulated muscleIGFBP-3Fat dietMuscle glucose
2009
Prevention of Hepatic Steatosis and Hepatic Insulin Resistance by Knockdown of cAMP Response Element-Binding Protein
Erion DM, Ignatova ID, Yonemitsu S, Nagai Y, Chatterjee P, Weismann D, Hsiao JJ, Zhang D, Iwasaki T, Stark R, Flannery C, Kahn M, Carmean CM, Yu XX, Murray SF, Bhanot S, Monia BP, Cline GW, Samuel VT, Shulman GI. Prevention of Hepatic Steatosis and Hepatic Insulin Resistance by Knockdown of cAMP Response Element-Binding Protein. Cell Metabolism 2009, 10: 499-506. PMID: 19945407, PMCID: PMC2799933, DOI: 10.1016/j.cmet.2009.10.007.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceNonalcoholic fatty liver diseaseCAMP response element-binding proteinInsulin resistanceResponse element-binding proteinASO treatmentElement-binding proteinCREB expressionType 2 diabetes mellitusOb/ob miceFatty liver diseaseHepatic triglyceride contentPlasma glucose concentrationFed rat modelAttractive therapeutic targetAntisense oligonucleotideDiabetes mellitusLiver diseaseZDF ratsHepatic steatosisOb micePostprandial hyperglycemiaPlasma cholesterolRat modelTriglyceride concentrationsMAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice
Roth RJ, Le AM, Zhang L, Kahn M, Samuel VT, Shulman GI, Bennett AM. MAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice. Journal Of Clinical Investigation 2009, 119: 3817-3829. PMID: 19920356, PMCID: PMC2786792, DOI: 10.1172/jci39054.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceDietary FatsDNA PrimersDual Specificity Phosphatase 1Energy MetabolismMAP Kinase Signaling SystemMiceMice, Inbred C57BLMice, KnockoutModels, BiologicalMuscle Fibers, Slow-TwitchObesityP38 Mitogen-Activated Protein KinasesPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaRNA, MessengerTrans-ActivatorsTranscription FactorsUp-RegulationSensitivity of Lipid Metabolism and Insulin Signaling to Genetic Alterations in Hepatic Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α Expression
Estall JL, Kahn M, Cooper MP, Fisher FM, Wu MK, Laznik D, Qu L, Cohen DE, Shulman GI, Spiegelman BM. Sensitivity of Lipid Metabolism and Insulin Signaling to Genetic Alterations in Hepatic Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α Expression. Diabetes 2009, 58: 1499-1508. PMID: 19366863, PMCID: PMC2699879, DOI: 10.2337/db08-1571.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAnimalsBlood GlucoseBody CompositionCell Culture TechniquesCrosses, GeneticFatty LiverFemaleGene Expression RegulationHepatocytesHomeostasisInsulinInsulin ResistanceIntegrasesKetonesLipidsLiverMiceMice, TransgenicPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaRNA, Small InterferingTrans-ActivatorsTranscription FactorsTriglyceridesConceptsPGC-1alpha levelsCre/lox systemExpression of genesKey metabolic enzymesKey metabolic pathwaysPGC-1alpha activityPGC-1alpha expressionPeroxisome proliferator-activated receptor gamma coactivatorReceptor γ coactivatorLipid metabolismProliferator-activated receptor gamma coactivatorComplete genetic ablationTranscriptional coactivatorNutrient deprivationReceptor gamma coactivatorPGC-1alphaFatty acid oxidationOxidative phosphorylationMetabolic enzymesLox systemCoactivatorLipid homeostasisMetabolic pathwaysGenetic ablationGenetic alterations
2007
Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance
Choi CS, Fillmore JJ, Kim JK, Liu ZX, Kim S, Collier EF, Kulkarni A, Distefano A, Hwang YJ, Kahn M, Chen Y, Yu C, Moore IK, Reznick RM, Higashimori T, Shulman GI. Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance. Journal Of Clinical Investigation 2007, 117: 1995-2003. PMID: 17571165, PMCID: PMC1888566, DOI: 10.1172/jci13579.Peer-Reviewed Original ResearchMeSH KeywordsAgingAMP-Activated Protein KinasesAnimalsEnzyme ActivationGene Expression RegulationHormonesHumansInsulinInsulin ResistanceIon ChannelsIsoenzymesLipid MetabolismMaleMiceMice, TransgenicMitochondrial ProteinsMultienzyme ComplexesMuscle, SkeletalProtein Kinase CProtein Kinase C-thetaProtein Serine-Threonine KinasesProto-Oncogene Proteins c-aktUncoupling Protein 3Weight GainConceptsFat-induced insulin resistanceInsulin resistanceSkeletal muscleType 2 diabetes mellitusProtein 3IRS-2-associated PI3K activityHigh-fat dietType 2 diabetesHepatic insulin resistanceWild-type miceInsulin-stimulated glucose uptakeExcellent therapeutic targetInsulin-stimulated insulin receptor substrate 1Fatty acid metabolitesSerine kinase cascadeInsulin receptor substrate-1Intramyocellular fatDiabetes mellitusSkeletal muscle protectsReceptor substrate-1Therapeutic targetTransgenic miceAcid metabolitesPI3K activityGlucose uptake