2023
O-linked N-acetylglucosamine modification is essential for physiological adipose expansion induced by high-fat feeding
Nakamoto A, Ohashi N, Sugawara L, Morino K, Ida S, Perry R, Sakuma I, Yanagimachi T, Fujita Y, Ugi S, Kume S, Shulman G, Maegawa H. O-linked N-acetylglucosamine modification is essential for physiological adipose expansion induced by high-fat feeding. AJP Endocrinology And Metabolism 2023, 325: e46-e61. PMID: 37224467, PMCID: PMC10292976, DOI: 10.1152/ajpendo.00263.2022.Peer-Reviewed Original ResearchConceptsFKO miceAdipose tissueBody weight gainPrimary cultured adipocytesAdipose expansionFree fatty acidsInflammatory genesWeight gainFree fatty acid effluxCultured adipocytesDiet-induced obesityHigh-fat dietHigh-fat feedingLess body weightDe novo lipogenesisAdipose tissue physiologyDe novo lipogenesis genesFatty acid effluxWeeks of ageAdipose inflammationGlucose intoleranceRAW 264.7 macrophagesControl miceFatty acidsSevere fibrosis
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 phenotypingMON-635 FDXR Regulates Iron Metabolism and Glucose Metabolism in Liver
Sakuma I, Yokoyama M, Yamagata K, Hashimoto N, Nakayama A, Shulman G, Tanaka T. MON-635 FDXR Regulates Iron Metabolism and Glucose Metabolism in Liver. Journal Of The Endocrine Society 2020, 4: mon-635. PMCID: PMC7207756, DOI: 10.1210/jendso/bvaa046.1557.Peer-Reviewed Original ResearchNon-alcoholic fatty liver diseaseForkhead box protein O1Iron metabolismFoxO1 nuclear exclusionOxidative stressFatty liver diseaseSerum ferritin levelsMouse liverHigh-fat dietType 2 diabetesPathogenesis of diabetesNovel therapeutic targetIron regulatory genesHepatic iron contentTreatment of diabetesHepG2 cellsBox protein O1Glucose intoleranceMost patientsFerritin levelsLiver diseaseClinical studiesGluconeogenesis activationFDXR expressionGlucose metabolismGlucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis
Perry RJ, Zhang D, Guerra MT, Brill AL, Goedeke L, Nasiri AR, Rabin-Court A, Wang Y, Peng L, Dufour S, Zhang Y, Zhang XM, Butrico GM, Toussaint K, Nozaki Y, Cline GW, Petersen KF, Nathanson MH, Ehrlich BE, Shulman GI. Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis. Nature 2020, 579: 279-283. PMID: 32132708, PMCID: PMC7101062, DOI: 10.1038/s41586-020-2074-6.Peer-Reviewed Original ResearchConceptsHepatic steatosisType 2Nonalcoholic fatty liver diseaseDiet-induced hepatic steatosisFatty liver diseasePlasma glucagon concentrationsHepatic adipose triglyceride lipaseHepatic acetyl-CoA contentHepatic glucose productionRatio of insulinHepatic glucose metabolismInositol triphosphate receptorAdipose triglyceride lipaseMitochondrial oxidationMitochondrial fat oxidationGlucose intoleranceLiver diseaseGlucagon concentrationsInsulin resistancePortal veinAcetyl-CoA contentHepatic lipolysisGlucagon biologyGlucose metabolismKnockout mice
2018
Mechanisms by Which Glucagon Acutely Stimulates Hepatic Mitochondrial Oxidation and Gluconeogenesis
PERRY R, WANG Y, BRILL A, PENG L, ZHANG D, DUFOUR S, ZHANG Y, ZHANG X, NOZAKI Y, CLINE G, EHRLICH B, PETERSEN K, SHULMAN G. Mechanisms by Which Glucagon Acutely Stimulates Hepatic Mitochondrial Oxidation and Gluconeogenesis. Diabetes 2018, 67 DOI: 10.2337/db18-146-or.Peer-Reviewed Original ResearchSpouse/partnerHigh-fat diet-induced hepatic steatosisNonalcoholic fatty liver diseaseDiet-induced hepatic steatosisGilead SciencesFatty liver diseasePlasma glucagon concentrationsType 2 diabetesHepatic acetyl-CoA contentLiver-specific knockdownIntracellular calcium signalingMitochondrial oxidationGlucose intoleranceAdipocyte triglyceride lipaseLiver diseaseWT miceGlucagon concentrationsHepatic steatosisGlucagon infusionAcetyl-CoA contentChronic increaseHepatic mitochondrial oxidationGlucagon biologyGlucagon stimulationKnockout mice
2001
Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver
Abel E, Peroni O, Kim J, Kim Y, Boss O, Hadro E, Minnemann T, Shulman G, Kahn B. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 2001, 409: 729-733. PMID: 11217863, DOI: 10.1038/35055575.Peer-Reviewed Original ResearchConceptsInsulin-stimulated glucose uptakeType 2 diabetesInsulin resistanceGlucose uptakeAdipose tissueGLUT4 expressionInsulin-resistant statesDownregulation of GLUT4Glucose intoleranceGlucose transportAdipose massIntracellular storage sitesGlucose homeostasisInsulin actionDiabetesPhosphoinositide-3-OH kinaseImpaired activationSkeletal muscleMuscleMicePlasma membrane4Early defectsLiverMain siteAdipocytes
2000
Loss of Insulin Signaling in Hepatocytes Leads to Severe Insulin Resistance and Progressive Hepatic Dysfunction
Michael M, Kulkarni R, Postic C, Previs S, Shulman G, Magnuson M, Kahn C. Loss of Insulin Signaling in Hepatocytes Leads to Severe Insulin Resistance and Progressive Hepatic Dysfunction. Molecular Cell 2000, 6: 87-97. PMID: 10949030, DOI: 10.1016/s1097-2765(05)00015-8.Peer-Reviewed Original ResearchConceptsInsulin resistanceGlucose homeostasisInsulin receptor knockout miceLiver-specific insulin receptor knockout miceDirect insulin actionNormal hepatic functionProgressive hepatic dysfunctionReceptor knockout miceSevere glucose intoleranceSevere insulin resistanceHepatic glucose productionFailure of insulinLoss of insulinHepatic gene expressionHepatic dysfunctionGlucose intoleranceMarked hyperinsulinemiaCre-loxP systemInsulin clearanceHepatic functionInsulin secretionInsulin receptor geneKnockout miceInsulin actionGlucose production