2023
Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis
Mooring M, Yeung G, Luukkonen P, Liu S, Akbar M, Zhang G, Balogun O, Yu X, Mo R, Nejak-Bowen K, Poyurovsky M, Booth C, Konnikova L, Shulman G, Yimlamai D. Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis. Science Translational Medicine 2023, 15: eade3157. PMID: 37756381, PMCID: PMC10874639, DOI: 10.1126/scitranslmed.ade3157.Peer-Reviewed Original ResearchConceptsNonalcoholic steatohepatitisLiver inflammationNonalcoholic fatty liver diseaseProgression of NASHCysteine-rich angiogenic inducer 61Fatty liver diseaseLiver-specific knockout miceImproved glucose toleranceType 2 diabetesGlucose toleranceLiver diseaseNASH progressionProfibrotic macrophagesProinflammatory propertiesReduced fibrosisCardiovascular diseaseProfibrotic phenotypeFibrotic developmentKnockout miceNF-κBMetabolic diseasesNASH dietPDGFB expressionFibrosisProfibrotic program
2021
IL-27 signalling promotes adipocyte thermogenesis and energy expenditure
Wang Q, Li D, Cao G, Shi Q, Zhu J, Zhang M, Cheng H, Wen Q, Xu H, Zhu L, Zhang H, Perry RJ, Spadaro O, Yang Y, He S, Chen Y, Wang B, Li G, Liu Z, Yang C, Wu X, Zhou L, Zhou Q, Ju Z, Lu H, Xin Y, Yang X, Wang C, Liu Y, Shulman GI, Dixit VD, Lu L, Yang H, Flavell RA, Yin Z. IL-27 signalling promotes adipocyte thermogenesis and energy expenditure. Nature 2021, 600: 314-318. PMID: 34819664, DOI: 10.1038/s41586-021-04127-5.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesAnimalsBariatric SurgeryDisease Models, AnimalEnergy MetabolismFemaleHumansInsulin ResistanceInterleukin-27MaleMiceObesityP38 Mitogen-Activated Protein KinasesPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaReceptors, InterleukinSignal TransductionThermogenesisUncoupling Protein 1ConceptsIL-27Beige adipose tissueAdipose tissueSerum IL-27Diet-induced obesityBariatric surgeryMetabolic morbidityImmunological factorsInsulin resistanceObesity showTherapeutic administrationMetabolic disordersMouse modelObesityPromising targetEnergy expenditureSignaling promotesThermogenesisBody temperatureMetabolic programsImportant roleTissueCritical roleImmunotherapyMorbidity
2020
Metabolic 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 Research
2017
Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms
Ferrandino G, Kaspari RR, Spadaro O, Reyna-Neyra A, Perry RJ, Cardone R, Kibbey RG, Shulman GI, Dixit VD, Carrasco N. Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: e9172-e9180. PMID: 29073114, PMCID: PMC5664516, DOI: 10.1073/pnas.1707797114.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseDe novo lipogenesisAdipose tissue lipolysisHepatic insulin resistanceThyroid hormonesHypothyroid miceImpaired suppressionInsulin resistanceTissue lipolysisInsulin secretionHigh thyroid-stimulating hormone levelsRegulation of THThyroid-stimulating hormone levelsLipid utilizationFatty liver diseaseSerum glucose levelsEndogenous glucose productionLow thyroid hormoneFatty acidsHepatic lipid utilizationLiver diseaseSevere hypothyroidismHormone levelsProfound suppressionGlucose levels
2015
Macrophage-specific de Novo Synthesis of Ceramide Is Dispensable for Inflammasome-driven Inflammation and Insulin Resistance in Obesity*
Camell CD, Nguyen KY, Jurczak MJ, Christian BE, Shulman GI, Shadel GS, Dixit VD. Macrophage-specific de Novo Synthesis of Ceramide Is Dispensable for Inflammasome-driven Inflammation and Insulin Resistance in Obesity*. Journal Of Biological Chemistry 2015, 290: 29402-29413. PMID: 26438821, PMCID: PMC4705943, DOI: 10.1074/jbc.m115.680199.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAnimalsBone Marrow CellsCarrier ProteinsCeramidesDiet, High-FatDisease Models, AnimalFatty AcidsFemaleInflammasomesInflammationInsulin ResistanceLipidsMacrophagesMaleMiceMice, TransgenicMitochondriaNLR Family, Pyrin Domain-Containing 3 ProteinObesityOxidative StressSerine C-PalmitoyltransferaseConceptsDe novo synthesisNovo synthesisOverexpression of catalaseDietary lipid overloadSynthesis machineryTissue homeostasisCell-specific deletionInflammasome activationAdipose tissue homeostasisNLRP3 inflammasome activationMyeloid cell-specific deletionMetabolic pathwaysCeramide synthesisAlternate metabolic pathwaysCaspase-1 cleavageEnergy homeostasisLipid overloadCeramideLipid metabolismInflammasome-dependent mannerOxidative stressDanger signalsFat diet-induced obesityHomeostasisFatty acids
2001
Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4
Kim J, Zisman A, Fillmore J, Peroni O, Kotani K, Perret P, Zong H, Dong J, Kahn C, Kahn B, Shulman G. Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4. Journal Of Clinical Investigation 2001, 108: 153-160. PMID: 11435467, PMCID: PMC353719, DOI: 10.1172/jci10294.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAge of OnsetAnimalsDepression, ChemicalDiabetes Mellitus, Type 2Disease Models, AnimalGlucoseGlucose Transporter Type 4HyperglycemiaInsulinInsulin Infusion SystemsInsulin ResistanceKidney TubulesLiverMaleMiceMice, KnockoutMonosaccharide Transport ProteinsMuscle ProteinsMuscle, SkeletalPhlorhizinPrediabetic StateProtein TransportConceptsDevelopment of diabetesMuscle glucose uptakeKO miceHepatic glucose productionInsulin-stimulated glucose uptakeGlucose toxicityMuscle-specific inactivationGlucose uptakeAdipose tissueInsulin-stimulated muscle glucose uptakeGlucose productionWhole-body glucose uptakeSkeletal muscle glucose uptakeAdipose tissue glucose uptakeSuppress hepatic glucose productionTissue glucose uptakeHyperinsulinemic-euglycemic clampMuscle glucose transportInsulin resistanceTransgenic miceDiabetes phenotypeInsulin actionPhloridzin treatmentInsulin's abilityDiabetesUncoupling Protein-2 Negatively Regulates Insulin Secretion and Is a Major Link between Obesity, β Cell Dysfunction, and Type 2 Diabetes
Zhang C, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig A, Boss O, Kim Y, Zheng X, Wheeler M, Shulman G, Chan C, Lowell B. Uncoupling Protein-2 Negatively Regulates Insulin Secretion and Is a Major Link between Obesity, β Cell Dysfunction, and Type 2 Diabetes. Cell 2001, 105: 745-755. PMID: 11440717, DOI: 10.1016/s0092-8674(01)00378-6.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsBlood GlucoseBody WeightDiabetes MellitusDiabetes Mellitus, Type 2Disease Models, AnimalGene TargetingHomeostasisHumansHyperglycemiaInsulinInsulin SecretionIon ChannelsIslets of LangerhansMaleMembrane Transport ProteinsMiceMice, KnockoutMice, ObeseMitochondrial ProteinsModels, BiologicalObesityProteinsRNA, MessengerThermogenesisUncoupling AgentsUncoupling Protein 2ConceptsOb/ob miceInsulin secretionOb miceCell dysfunctionFirst-phase insulin secretionIslet ATP levelsGlucose-stimulated insulin secretionLevel of glycemiaSerum insulin levelsBeta-cell dysfunctionType 2 diabetesObesity-induced diabetesΒ-cell dysfunctionBeta-cell glucose sensingProtein 2UCP2-deficient miceInsulin levelsPathophysiologic significanceBeta cellsType 2SecretionMiceObesityATP levelsDiabetes