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
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
Dissociation of Muscle Insulin Resistance from Alterations in Mitochondrial Substrate Preference
Song JD, Alves TC, Befroy DE, Perry RJ, Mason GF, Zhang XM, Munk A, Zhang Y, Zhang D, Cline GW, Rothman DL, Petersen KF, Shulman GI. Dissociation of Muscle Insulin Resistance from Alterations in Mitochondrial Substrate Preference. Cell Metabolism 2020, 32: 726-735.e5. PMID: 33035493, PMCID: PMC8218871, DOI: 10.1016/j.cmet.2020.09.008.Peer-Reviewed Original ResearchA 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 methodKinaseMitochondriaMetabolic 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 ResearchLeptin mediates postprandial increases in body temperature through hypothalamus–adrenal medulla–adipose tissue crosstalk
Perry RJ, Lyu K, Rabin-Court A, Dong J, Li X, Yang Y, Qing H, Wang A, Yang X, Shulman GI. Leptin mediates postprandial increases in body temperature through hypothalamus–adrenal medulla–adipose tissue crosstalk. Journal Of Clinical Investigation 2020, 130: 2001-2016. PMID: 32149734, PMCID: PMC7108915, DOI: 10.1172/jci134699.Peer-Reviewed Original ResearchConceptsBrown adipose tissueLeptin concentrationsBody temperatureAdrenomedullary catecholamine secretionPlasma leptin concentrationsAdipose tissue lipolysisFasting-induced reductionFeeding-induced increaseMeal ingestionPlasma catecholaminesPostprandial increaseCatecholamine secretionObese ratsTissue lipolysisLean ratsAdrenergic activationAdipose tissueTissue crosstalkWeight gainIntragastric infusionRatsLeptinBolusLipolysisFatty acids
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
2014
Leptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis
Perry RJ, Zhang XM, Zhang D, Kumashiro N, Camporez JP, Cline GW, Rothman DL, Shulman GI. Leptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis. Nature Medicine 2014, 20: 759-763. PMID: 24929951, PMCID: PMC4344321, DOI: 10.1038/nm.3579.Peer-Reviewed Original ResearchMetformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase
Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ, Jurczak MJ, Camporez JP, Lee HY, Cline GW, Samuel VT, Kibbey RG, Shulman GI. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014, 510: 542-546. PMID: 24847880, PMCID: PMC4074244, DOI: 10.1038/nature13270.Peer-Reviewed Original Research
2013
Reversal of Hypertriglyceridemia, Fatty Liver Disease, and Insulin Resistance by a Liver-Targeted Mitochondrial Uncoupler
Perry RJ, Kim T, Zhang XM, Lee HY, Pesta D, Popov VB, Zhang D, Rahimi Y, Jurczak MJ, Cline GW, Spiegel DA, Shulman GI. Reversal of Hypertriglyceridemia, Fatty Liver Disease, and Insulin Resistance by a Liver-Targeted Mitochondrial Uncoupler. Cell Metabolism 2013, 18: 740-748. PMID: 24206666, PMCID: PMC4104686, DOI: 10.1016/j.cmet.2013.10.004.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseFatty liver diseaseInsulin resistanceLiver diseaseMetabolic syndromeFatty liverSystemic toxicityWhole-body insulin resistanceMajor predisposing conditionReversal of hypertriglyceridemiaTreatment of hypertriglyceridemiaType 2 diabetesMuscle insulin resistanceWide therapeutic indexPredisposing conditionRat modelProtein kinase C epsilonHypertriglyceridemiaTherapeutic indexFed ratsBeneficial effectsLiverPKCθ activitySyndromeMitochondrial uncoupler
2008
N-acylphosphatidylethanolamine, a Gut- Derived Circulating Factor Induced by Fat Ingestion, Inhibits Food Intake
Gillum MP, Zhang D, Zhang XM, Erion DM, Jamison RA, Choi C, Dong J, Shanabrough M, Duenas HR, Frederick DW, Hsiao JJ, Horvath TL, Lo CM, Tso P, Cline GW, Shulman GI. N-acylphosphatidylethanolamine, a Gut- Derived Circulating Factor Induced by Fat Ingestion, Inhibits Food Intake. Cell 2008, 135: 813-824. PMID: 19041747, PMCID: PMC2643061, DOI: 10.1016/j.cell.2008.10.043.Peer-Reviewed Original ResearchConceptsFood intakeInhibits food intakeTreatment of obesityNovel therapeutic targetCentral nervous systemUnknown physiological significanceFat ingestionCirculating factorsN-acylphosphatidylethanolaminePlasma lipidsIntracerebroventricular infusionPhysiologic dosesSystemic administrationTherapeutic targetBody weightNervous systemIngested fatSmall intestineIntakeTaste aversionInfusionPhysiological significanceNanomolar amountsObesityHypothalamus
2001
Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis
Bergeron R, Ren J, Cadman K, Moore I, Perret P, Pypaert M, Young L, Semenkovich C, Shulman G. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. AJP Endocrinology And Metabolism 2001, 281: e1340-e1346. PMID: 11701451, DOI: 10.1152/ajpendo.2001.281.6.e1340.Peer-Reviewed Original ResearchMeSH Keywords5-Aminolevulinate SynthetaseAdenylate KinaseAnimalsBlotting, NorthernCell NucleusCytochrome c GroupDNA-Binding ProteinsEnergy MetabolismEnzyme ActivationMaleMicroscopy, ElectronMitochondria, MuscleMuscle, SkeletalNF-E2-Related Factor 1Nuclear Respiratory Factor 1Nuclear Respiratory FactorsRatsRats, Sprague-DawleyRNA, MessengerTrans-ActivatorsNMR Spectroscopy in β Cell Engineering and Islet Transplantation
PAPAS K, COLTON C, GOUNARIDES J, ROOS E, JAREMA M, SHAPIRO M, CHENG L, CLINE G, SHULMAN G, WU H, BONNER‐WEIR S, WEIR G. NMR Spectroscopy in β Cell Engineering and Islet Transplantation. Annals Of The New York Academy Of Sciences 2001, 944: 96-119. PMID: 11797699, DOI: 10.1111/j.1749-6632.2001.tb03826.x.Peer-Reviewed Original ResearchConceptsIslet transplantationGlucose metabolismBeta cellsLong-term complicationsIrreversible damageTerm complicationsOxidative glucose metabolismAcute ischemiaTransplantationVivo efficacyHuman isletsIslet preparationsC-myc oncogeneSecreting tissueCell damageSuch exposureGenetic alterationsBcl-2Overnight incubationIslet transportationIsletsPrevention of fat-induced insulin resistance by salicylate
Kim J, Kim Y, Fillmore J, Chen Y, Moore I, Lee J, Yuan M, Li Z, Karin M, Perret P, Shoelson S, Shulman G. Prevention of fat-induced insulin resistance by salicylate. Journal Of Clinical Investigation 2001, 108: 437-446. PMID: 11489937, PMCID: PMC209353, DOI: 10.1172/jci11559.Peer-Reviewed Original ResearchConceptsType 2 diabetesLipid infusionInsulin resistanceGlucose uptakeInsulin actionWhole-body glucose uptakeFat-induced insulin resistanceSkeletal muscleHigh-dose salicylatesHyperinsulinemic-euglycemic clampWild-type miceInsulin-stimulated glucose uptakeSkeletal muscle insulinIRS-1-associated PISerine kinase cascadeLipid-induced effectsAwake ratsAwake miceKnockout miceMuscle insulinInfusionTherapeutic agentsSalicylate actionKinase cascadeIKK betaEffect of 5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside Infusion on In Vivo Glucose and Lipid Metabolism in Lean and Obese Zucker Rats
Bergeron R, Previs S, Cline G, Perret P, Russell III R, Young L, Shulman G. Effect of 5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside Infusion on In Vivo Glucose and Lipid Metabolism in Lean and Obese Zucker Rats. Diabetes 2001, 50: 1076-1082. PMID: 11334411, DOI: 10.2337/diabetes.50.5.1076.Peer-Reviewed Original ResearchMeSH KeywordsAdenylate KinaseAminoimidazole CarboxamideAnimalsBlood GlucoseBody WeightFatty Acids, NonesterifiedGlucoseGlycerolInfusions, IntravenousInjections, IntravenousInsulinInsulin ResistanceLactatesMaleModels, AnimalMuscle, SkeletalObesityRatsRats, ZuckerReference ValuesRibonucleotidesTriglyceridesConceptsWhole-body glucose disposalInsulin-resistant rat modelObese ratsEndogenous glucose productionObese Zucker ratsRed gastrocnemius muscleInsulin infusion rateLean ratsGlucose disposalInsulin infusionRat modelInfusion rateGastrocnemius muscleZucker ratsLipid metabolismGlucose productionEndogenous glucose production rateGlucose transport activitySkeletal muscle glucose transport activityType 2 diabetesWhole-body carbohydrateInsulin-stimulated glucose uptakeInsulin-independent pathwaySkeletal muscle AMPKGlucose production rate
2000
13C/31P NMR Assessment of Mitochondrial Energy Coupling in Skeletal Muscle of Awake Fed and Fasted Rats RELATIONSHIP WITH UNCOUPLING PROTEIN 3 EXPRESSION*
Jucker B, Ren J, Dufour S, Cao X, Previs S, Cadman K, Shulman G. 13C/31P NMR Assessment of Mitochondrial Energy Coupling in Skeletal Muscle of Awake Fed and Fasted Rats RELATIONSHIP WITH UNCOUPLING PROTEIN 3 EXPRESSION*. Journal Of Biological Chemistry 2000, 275: 39279-39286. PMID: 10995775, DOI: 10.1074/jbc.m007760200.Peer-Reviewed Original ResearchAdenosine TriphosphateAlbuminsAnimalsBlotting, NorthernBlotting, WesternCarnitine O-PalmitoyltransferaseCarrier ProteinsEnzyme InhibitorsEpoxy CompoundsFatty AcidsFood DeprivationGlutamic AcidIon ChannelsKineticsMagnetic Resonance SpectroscopyMitochondriaMitochondrial ProteinsModels, BiologicalModels, ChemicalMuscle, SkeletalOxygenPalmitatesRatsRats, Sprague-DawleyRNA, MessengerTime FactorsTricarboxylic AcidsUncoupling Protein 3Regulation of myocardial [13C]glucose metabolism in conscious rats
McNulty P, Cline G, Whiting J, Shulman G. Regulation of myocardial [13C]glucose metabolism in conscious rats. AJP Heart And Circulatory Physiology 2000, 279: h375-h381. PMID: 10899078, DOI: 10.1152/ajpheart.2000.279.1.h375.Peer-Reviewed Original ResearchAssessment of mitochondrial energy coupling in vivo by 13C/31P NMR
Jucker B, Dufour S, Ren J, Cao X, Previs S, Underhill B, Cadman K, Shulman G. Assessment of mitochondrial energy coupling in vivo by 13C/31P NMR. Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 97: 6880-6884. PMID: 10823916, PMCID: PMC18769, DOI: 10.1073/pnas.120131997.Peer-Reviewed Original ResearchPersistent Changes in Myocardial Glucose Metabolism In Vivo During Reperfusion of a Limited-Duration Coronary Occlusion
McNulty P, Jagasia D, Cline G, Ng C, Whiting J, Garg P, Shulman G, Soufer R. Persistent Changes in Myocardial Glucose Metabolism In Vivo During Reperfusion of a Limited-Duration Coronary Occlusion. Circulation 2000, 101: 917-922. PMID: 10694532, DOI: 10.1161/01.cir.101.8.917.Peer-Reviewed Original ResearchConceptsCoronary occlusionGlucose metabolismPostischemic stunningAnterolateral left ventricleHeart glucose metabolismCoronary artery occlusionRegional glucose metabolismMyocardial glucose metabolismRegional myocardial ischemiaRegional mechanical functionRapid reperfusionReversible coronary occlusionArtery occlusionMyocardial ischemiaIntact ratsPreferential shuntingBlood flowReperfusionTracer uptakeLeft ventricleGlycogen depletionMetabolic signaturesOcclusionPersistent changesSustained changes
1999
Metabolic control analysis of insulin-stimulated glucose disposal in rat skeletal muscle
Jucker B, Barucci N, Shulman G. Metabolic control analysis of insulin-stimulated glucose disposal in rat skeletal muscle. American Journal Of Physiology 1999, 277: e505-e512. PMID: 10484363, DOI: 10.1152/ajpendo.1999.277.3.e505.Peer-Reviewed Original ResearchConceptsInsulin-stimulated glucose disposalGlucose transport/phosphorylationGlucose disposalHyperinsulinemic clampAwake ratsInfusion protocolGlycogen synthesisSkeletal muscleGlucose infusion rateMuscle glucose disposalSkeletal muscle glucose disposalProtocol IRat skeletal muscleRate of glycolysisInfusion rateHindlimb musclesMajority of controls