2023
Lysophosphatidic acid triggers inflammation in the liver and white adipose tissue in rat models of 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 deficiency and overnutrition
Sakuma I, Gaspar R, Luukkonen P, Kahn M, Zhang D, Zhang X, Murray S, Golla J, Vatner D, Samuel V, Petersen K, Shulman G. Lysophosphatidic acid triggers inflammation in the liver and white adipose tissue in rat models of 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 deficiency and overnutrition. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2312666120. PMID: 38127985, PMCID: PMC10756285, DOI: 10.1073/pnas.2312666120.Peer-Reviewed Original Research
2020
A 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
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
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 inhibitionRole of patatin‐like phospholipase domain‐containing 3 on lipid‐induced hepatic steatosis and insulin resistance in rats
Kumashiro N, Yoshimura T, Cantley JL, Majumdar SK, Guebre‐Egziabher F, Kursawe R, Vatner DF, Fat I, Kahn M, Erion DM, Zhang X, Zhang D, Manchem VP, Bhanot S, Gerhard GS, Petersen KF, Cline GW, Samuel VT, Shulman GI. Role of patatin‐like phospholipase domain‐containing 3 on lipid‐induced hepatic steatosis and insulin resistance in rats. Hepatology 2013, 57: 1763-1772. PMID: 23175050, PMCID: PMC3597437, DOI: 10.1002/hep.26170.Peer-Reviewed Original Research
2012
The Role of the Carbohydrate Response Element-Binding Protein in Male Fructose-Fed Rats
Erion DM, Popov V, Hsiao JJ, Vatner D, Mitchell K, Yonemitsu S, Nagai Y, Kahn M, Gillum MP, Dong J, Murray SF, Manchem VP, Bhanot S, Cline GW, Shulman GI, Samuel VT. The Role of the Carbohydrate Response Element-Binding Protein in Male Fructose-Fed Rats. Endocrinology 2012, 154: 36-44. PMID: 23161873, PMCID: PMC3529388, DOI: 10.1210/en.2012-1725.Peer-Reviewed Original ResearchConceptsDe novo lipogenesisResponse element-binding proteinCarbohydrate response element-binding proteinASO treatmentHepatic expressionNovo lipogenesisElement-binding proteinInsulin-stimulated peripheral glucose uptakeNonalcoholic fatty liver diseaseAntisense oligonucleotideMale Sprague-Dawley ratsHepatic de novo lipogenesisFructose-fed groupHepatic insulin responsivenessFatty liver diseaseFructose fed ratsPeripheral glucose uptakeHyperinsulinemic-euglycemic clampHigh-fat dietHepatic lipid contentHepatic triglyceride secretionHepatic insulin sensitivitySprague-Dawley ratsPlasma triglyceride concentrationsPlasma uric acid
2011
Regulation 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
2010
Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor-γ (PPAR-γ) activation in a rat model of insulin resistance
Weismann D, Erion DM, Ignatova-Todorava I, Nagai Y, Stark R, Hsiao JJ, Flannery C, Birkenfeld AL, May T, Kahn M, Zhang D, Yu XX, Murray SF, Bhanot S, Monia BP, Cline GW, Shulman GI, Samuel VT. Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor-γ (PPAR-γ) activation in a rat model of insulin resistance. Diabetologia 2010, 54: 935-944. PMID: 21190014, PMCID: PMC4061906, DOI: 10.1007/s00125-010-1984-5.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzhydryl CompoundsDiabetes Mellitus, Type 2Disease Models, AnimalEpoxy CompoundsGlucose Clamp TechniqueImmunoblottingInsulin ResistanceMaleOligonucleotides, AntisensePPAR gammaProtein KinasesProtein Serine-Threonine KinasesRatsRats, Sprague-DawleyReverse Transcriptase Polymerase Chain ReactionConceptsTribbles homologue 3Euglycaemic hyperinsulinaemic clampWhite adipose tissueInsulin sensitivityAdipose tissueAntisense oligonucleotideInsulin-stimulated whole-body glucose uptakeWhole-body glucose uptakeConclusions/interpretationThese dataTissue-specific insulin sensitivityGlucose uptakeSkeletal muscle glucose uptakeWhite adipose tissue massPlasma HDL cholesterolRole of PPARAdipose tissue massMuscle glucose uptakeEndogenous glucose productionExpression of PPARInsulin-sensitising effectsDependent mannerViral proto-oncogeneHDL cholesterolAkt2 activityInsulin resistance
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
Suppression 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