2024
High-fat-diet-induced hepatic insulin resistance per se attenuates murine de novo lipogenesis
Goedeke L, Strober J, Suh R, Paolella L, Li X, Rogers J, Petersen M, Nasiri A, Casals G, Kahn M, Cline G, Samuel V, Shulman G, Vatner D. High-fat-diet-induced hepatic insulin resistance per se attenuates murine de novo lipogenesis. IScience 2024, 27: 111175. PMID: 39524330, PMCID: PMC11550620, DOI: 10.1016/j.isci.2024.111175.Peer-Reviewed Original ResearchDuration of high-fat dietAttenuated insulin signalingHigh-fat dietHepatic insulin resistanceInsulin signalingInsulin stimulationLipogenic substrateStimulation of de novo lipogenesisReduced lipogenesisHFD feedingReduce DNLInsulin resistanceResistance per seLipogenesisInsulin resistance per sePathway selectionGlucose metabolismHepatic IRMiceFat dietSREBP1cINSRCeramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway
Xu W, Zhang D, Ma Y, Gaspar R, Kahn M, Nasiri A, Murray S, Samuel V, Shulman G. Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway. Cell Reports 2024, 43: 114746. PMID: 39302831, DOI: 10.1016/j.celrep.2024.114746.Peer-Reviewed Original ResearchLipid-induced hepatic insulin resistanceHepatic insulin resistancePhosphorylation pathwayAntisense oligonucleotidesCeramide synthesis inhibitorsLipid-induced insulin resistanceMyriocin treatmentCeramide synthesisDihydroceramide desaturaseInsulin resistanceHepatic ceramideMyriocinCeramideCeramide contentInsulin-sensitizing effectsPhosphorylationHepatic insulin sensitivityPathwaySynthetic pathwayDES1Glucose productionSynthesis inhibitorDGAT2DesaturaseInhibition
2022
Dyrk1b 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 phenotypingA Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance
Lyu K, Zhang Y, Zhang D, Kahn M, Ter Horst KW, Rodrigues MRS, Gaspar RC, Hirabara SM, Luukkonen PK, Lee S, Bhanot S, Rinehart J, Blume N, Rasch MG, Serlie MJ, Bogan JS, Cline GW, Samuel VT, Shulman GI. A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance. Cell Metabolism 2020, 32: 654-664.e5. PMID: 32882164, PMCID: PMC7544641, DOI: 10.1016/j.cmet.2020.08.001.Peer-Reviewed Original ResearchConceptsPlasma membraneEndoplasmic reticulumHigh-fat diet-induced hepatic insulin resistanceSubcellular fractionation methodInsulin receptor kinaseKey lipid speciesHepatic insulin resistanceDiet-induced hepatic insulin resistanceReceptor kinaseDiacylglycerol acyltransferase 2Molecular mechanismsAcute knockdownPhosphorylationLipid dropletsLipid speciesAcyltransferase 2KnockdownLiver-specific overexpressionDAG accumulationPKCϵDAG contentMembraneFractionation methodKinaseMitochondria
2019
Hepatic insulin sensitivity is improved in high‐fat diet‐fed Park2 knockout mice in association with increased hepatic AMPK activation and reduced steatosis
Edmunds LR, Huckestein BR, Kahn M, Zhang D, Chu Y, Zhang Y, Wendell SG, Shulman GI, Jurczak MJ. Hepatic insulin sensitivity is improved in high‐fat diet‐fed Park2 knockout mice in association with increased hepatic AMPK activation and reduced steatosis. Physiological Reports 2019, 7: e14281. PMID: 31724300, PMCID: PMC6854109, DOI: 10.14814/phy2.14281.Peer-Reviewed Original ResearchConceptsPark2 KO miceHepatic insulin sensitivityKO miceInsulin sensitivityInsulin resistanceShort-term HFD feedingDiet-induced hepatic insulin resistanceWhole-body insulin sensitivityPark2 knockout miceImproved hepatic insulin sensitivityDiet-induced obesityHigh-fat dietBioactive lipid speciesTumor necrosis factorHepatic insulin resistanceHepatic AMPK activationNegative energy balanceEndoplasmic reticulum stress responseRegular chowCytokine levelsHFD feedingReduced steatosisChronic HFDInterleukin-6Necrosis factor266-OR: Plasma Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance
LYU K, ZHANG Y, ZHANG D, KAHN M, NOZAKI Y, BHANOT S, BOGAN J, CLINE G, SAMUEL V, SHULMAN G. 266-OR: Plasma Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance. Diabetes 2019, 68 DOI: 10.2337/db19-266-or.Peer-Reviewed Original ResearchHepatic insulin resistanceInsulin resistanceExogenous fatty acidsInsulin actionLipid dropletsHepatic ceramide contentHyperinsulinemic-euglycemic clampHepatic insulin actionBioactive lipid speciesHepatic glucose productionChow-fed ratsHepatic diacylglycerol contentAdvisory PanelFatty acidsHepatic steatosisImpaired suppressionSingle doseSpouse/partnerGlucose productionPKCε activationJanssen ResearchAcute knockdownCeramide contentNational InstituteReceptor kinase activation19-OR: Controlled-Release Mitochondrial Protonophore (CRMP) Reverses Hypertriglyceridemia and Hepatic Steatosis in Dysmetabolic Nonhuman Primates
GOEDEKE L, ROMERAL V, BUTRICO G, KAHN M, DUFOUR S, ZHANG X, CLINE G, PETERSEN K, CHNG K, SHULMAN G. 19-OR: Controlled-Release Mitochondrial Protonophore (CRMP) Reverses Hypertriglyceridemia and Hepatic Steatosis in Dysmetabolic Nonhuman Primates. Diabetes 2019, 68 DOI: 10.2337/db19-19-or.Peer-Reviewed Original ResearchControlled-release mitochondrial protonophoreSpouse/partnerCRMP treatmentInsulin resistanceDiet-induced rodent modelJanssen ResearchReversal of hypertriglyceridemiaNAFLD/NASHInflammation/fibrosisNonhuman primate modelMitochondrial protonophoreEndogenous glucose productionHepatic insulin resistanceHepatic acetyl-CoA contentAdvisory PanelMitochondrial fat oxidationMetabolic syndromeFatty liverHepatic steatosisAdverse reactionsHepatic triglyceridesAcetyl-CoA contentPrimate modelNovo Nordisk A/S.Food intake
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
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 acidsTargeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance
Kumashiro N, Beddow SA, Vatner DF, Majumdar SK, Cantley JL, Guebre-Egziabher F, Fat I, Guigni B, Jurczak MJ, Birkenfeld AL, Kahn M, Perler BK, Puchowicz MA, Manchem VP, Bhanot S, Still CD, Gerhard GS, Petersen KF, Cline GW, Shulman GI, Samuel VT. Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance. Diabetes 2013, 62: 2183-2194. PMID: 23423574, PMCID: PMC3712050, DOI: 10.2337/db12-1311.Peer-Reviewed Original ResearchConceptsPyruvate carboxylaseAntisense oligonucleotideHepatocyte fatty acid oxidationInsulin resistanceNonalcoholic fatty liver diseaseZucker diabetic fatty ratsHigh fat-fed ratsFatty liver diseaseLiver biopsy specimensDiabetic fatty ratsPlasma lipid concentrationsType 2 diabetesHepatic insulin sensitivityHuman liver biopsy specimensEndogenous glucose productionHepatic insulin resistancePlasma glucose concentrationPotential therapeutic approachSpecific antisense oligonucleotideFat-fed ratsCarboxylaseFatty acid oxidationDe novo fatty acid synthesisLiver diseaseTissue-specific inhibitionCGI-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
Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease
Kumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA, Chu X, Still CD, Gerhard GS, Han X, Dziura J, Petersen KF, Samuel VT, Shulman GI. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 16381-16385. PMID: 21930939, PMCID: PMC3182681, DOI: 10.1073/pnas.1113359108.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseFatty liver diseaseHepatic DAG contentInsulin resistanceHepatic insulin resistanceLiver diseaseHepatic steatosisCellular mechanismsHomeostatic model assessmentInsulin resistance indexMarkers of inflammationType 2 diabetesER stress markersLipid dropletsHepatic diacylglycerol contentEndoplasmic reticulum stressActivation of PKCεLiver biopsyNondiabetic individualsHepatocellular lipidsInsulin sensitivityCytoplasmic lipid dropletsDAG contentResistance indexAnimal modelsRegulation of hepatic fat and glucose oxidation in rats with lipid‐induced hepatic insulin resistance
Alves TC, Befroy DE, Kibbey RG, Kahn M, Codella R, Carvalho RA, Petersen K, Shulman GI. Regulation of hepatic fat and glucose oxidation in rats with lipid‐induced hepatic insulin resistance. Hepatology 2011, 53: 1175-1181. PMID: 21400553, PMCID: PMC3077048, DOI: 10.1002/hep.24170.Peer-Reviewed Original ResearchConceptsLipid-induced hepatic insulin resistanceHepatic insulin resistanceInsulin resistanceTricarboxylic acid fluxFatty acid oxidationPyruvate dehydrogenaseHyperinsulinemic-euglycemic clampHyperinsulinemic-hyperglycemic clampInfusion of somatostatinSubstrate availabilityHigh-fat dietPlasma glucose concentrationRegulationCritical rolePyruvate dehydrogenase fluxHepatic fatHyperglycemic clampAcid oxidationAwake ratsBasal concentrations
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 concentrations
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 uptakeSuppression of Diacylglycerol Acyltransferase-2 (DGAT2), but Not DGAT1, with Antisense Oligonucleotides Reverses Diet-induced Hepatic Steatosis and Insulin Resistance*
Choi CS, Savage DB, Kulkarni A, Yu XX, Liu ZX, Morino K, Kim S, Distefano A, Samuel VT, Neschen S, Zhang D, Wang A, Zhang XM, Kahn M, Cline GW, Pandey SK, Geisler JG, Bhanot S, Monia BP, Shulman GI. Suppression of Diacylglycerol Acyltransferase-2 (DGAT2), but Not DGAT1, with Antisense Oligonucleotides Reverses Diet-induced Hepatic Steatosis and Insulin Resistance*. Journal Of Biological Chemistry 2007, 282: 22678-22688. PMID: 17526931, DOI: 10.1074/jbc.m704213200.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseHepatic insulin resistanceProtein kinase C epsilon activationInsulin resistanceASO treatmentFat-induced hepatic insulin resistanceDiet-induced nonalcoholic fatty liver diseaseDiacylglycerol acyltransferase 2Epsilon activationHigh fat-fed ratsTriglyceride synthesisFatty liver diseaseType 2 diabetesHepatic fatty acid oxidationHepatic insulin sensitivityFat-fed ratsFatty acid oxidationHepatic diacylglycerol contentLiver diseaseHepatic lipidsHepatic steatosisControl ratsInsulin sensitivityPharmacological reductionParadoxical reductionInhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease
Samuel VT, Liu ZX, Wang A, Beddow SA, Geisler JG, Kahn M, Zhang XM, Monia BP, Bhanot S, Shulman GI. Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease. Journal Of Clinical Investigation 2007, 117: 739-745. PMID: 17318260, PMCID: PMC1797607, DOI: 10.1172/jci30400.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceNonalcoholic fatty liver diseaseFatty liver diseaseInsulin resistanceHigh-fat feedingLiver diseaseFat-induced hepatic insulin resistanceType 2 diabetes mellitusType 2 diabetesHepatic fat accumulationNovel therapeutic targetInsulin receptor kinase activityDiabetes mellitusHepatic steatosisFat accumulationRats resultsTherapeutic targetHepatic insulinReceptor kinase activityProtein kinase CεInsulin receptorCausal roleIsoforms of PKCAntisense oligonucleotideRats