2022
Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance
Huang Y, Zhou JH, Zhang H, Canfrán-Duque A, Singh AK, Perry RJ, Shulman G, Fernandez-Hernando C, Min W. Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance. Journal Of Clinical Investigation 2022, 132 PMID: 35202005, PMCID: PMC9057632, DOI: 10.1172/jci148852.Peer-Reviewed Original ResearchConceptsBrown adipose tissueBAT inflammationInsulin resistanceMitochondrial reactive oxygen speciesReactive oxygen speciesAberrant innate immune responsesDiet-induced insulin resistanceSystematic metabolismDiet-induced obesityNLRP3 inflammasome pathwayWhole-body energy metabolismCGAS/STINGInnate immune responseFatty acid oxidationExcessive mitochondrial reactive oxygen speciesMetabolic benefitsImmune responseInflammasome pathwayAdipose tissueInflammationInhibition reversesLipid uptakeLipid metabolismThioredoxin 2Adaptive thermogenesis
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 roleImmunotherapyMorbidityInsulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake
Habtemichael EN, Li DT, Camporez JP, Westergaard XO, Sales CI, Liu X, López-Giráldez F, DeVries SG, Li H, Ruiz DM, Wang KY, Sayal BS, González Zapata S, Dann P, Brown SN, Hirabara S, Vatner DF, Goedeke L, Philbrick W, Shulman GI, Bogan JS. Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake. Nature Metabolism 2021, 3: 378-393. PMID: 33686286, PMCID: PMC7990718, DOI: 10.1038/s42255-021-00359-x.Peer-Reviewed Original ResearchConceptsTUG cleavageGlucose uptakeProtein degradation pathwaysGLUT4 glucose transportersCoactivator PGC-1αC-terminal cleavage productInsulin-stimulated glucose uptakeAte1 arginyltransferaseGene expressionPhysiological relevanceWhole-body energy expenditureGlucose transporterPeroxisome proliferator-activated receptorCell surfacePGC-1αProtein 1Proliferator-activated receptorDegradation pathwayEffect of insulinCleavage pathwayAdipose cellsCleavage productsPathwayCleavageEnergy expenditureAn update on brown adipose tissue biology: a discussion of recent findings
Gaspar RC, Pauli JR, Shulman GI, Muñoz VR. An update on brown adipose tissue biology: a discussion of recent findings. AJP Endocrinology And Metabolism 2021, 320: e488-e495. PMID: 33459179, PMCID: PMC7988785, DOI: 10.1152/ajpendo.00310.2020.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytes, WhiteAdipose Tissue, BrownAnimalsEnergy MetabolismGlucoseHumansThermogenesisConceptsBrown adipose tissueBAT thermogenesisBrown adipose tissue biologyEnergy expenditureBrown-like cellsWhole-body glucoseAdipose tissue biologyBAT metabolismAdrenergic drugsAdipose tissuePotential treatmentThermogenic activityWhite adipocytesBody glucoseFat metabolismEndocrine mechanismsBeneficial roleSecretory moleculesActivity capacityTissue biologyThermogenesisRecent findingsRecent studiesAdditional focusMetabolism
2020
A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21
Han MS, Perry RJ, Camporez JP, Scherer PE, Shulman GI, Gao G, Davis RJ. A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21. Genes & Development 2020, 35: 133-146. PMID: 33334822, PMCID: PMC7778269, DOI: 10.1101/gad.344556.120.Peer-Reviewed Original ResearchMitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance
He F, Huang Y, Song Z, Zhou HJ, Zhang H, Perry RJ, Shulman GI, Min W. Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance. Journal Of Experimental Medicine 2020, 218: e20201416. PMID: 33315085, PMCID: PMC7927432, DOI: 10.1084/jem.20201416.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesAdipose TissueAnimalsDiabetes Mellitus, Type 2Diet, High-FatEnergy MetabolismFatty LiverGene DeletionGene TargetingGluconeogenesisHomeostasisHumansHyperglycemiaInflammationInsulin ResistanceLipogenesisLiverMaleMice, Inbred C57BLMice, KnockoutMitochondriaMitophagyNF-kappa BOxidative StressPhenotypeReactive Oxygen SpeciesSequestosome-1 ProteinSignal TransductionThioredoxinsConceptsHepatic insulin resistanceWhite adipose tissueInsulin resistanceAdipose inflammationType 2 diabetes mellitusLipid metabolic disordersNF-κB inhibitorAdipose-specific deletionWhole-body energy homeostasisAltered fatty acid metabolismFatty acid metabolismT2DM progressionT2DM patientsDiabetes mellitusReactive oxygen species pathwayHepatic steatosisMetabolic disordersNF-κBP62/SQSTM1Adipose tissueHuman adipocytesEnergy homeostasisExcessive mitophagyOxygen species pathwayInflammationEffect of a Low-Fat Vegan Diet on Body Weight, Insulin Sensitivity, Postprandial Metabolism, and Intramyocellular and Hepatocellular Lipid Levels in Overweight Adults
Kahleova H, Petersen KF, Shulman GI, Alwarith J, Rembert E, Tura A, Hill M, Holubkov R, Barnard ND. Effect of a Low-Fat Vegan Diet on Body Weight, Insulin Sensitivity, Postprandial Metabolism, and Intramyocellular and Hepatocellular Lipid Levels in Overweight Adults. JAMA Network Open 2020, 3: e2025454. PMID: 33252690, PMCID: PMC7705596, DOI: 10.1001/jamanetworkopen.2020.25454.Peer-Reviewed Original ResearchMeSH KeywordsAbsorptiometry, PhotonAdultAgedBlood GlucoseBody CompositionBody WeightCholesterolCholesterol, HDLCholesterol, LDLC-PeptideDiet, Fat-RestrictedDiet, VeganEnergy IntakeEnergy MetabolismFemaleGlycated HemoglobinHepatocytesHumansInsulinInsulin ResistanceIntra-Abdominal FatLipid MetabolismLiverMaleMiddle AgedMuscle Fibers, SkeletalMuscle, SkeletalObesityOverweightPostprandial PeriodProton Magnetic Resonance SpectroscopyTriglyceridesConceptsLow-fat vegan dietHomeostasis model assessment indexIntramyocellular lipid levelsModel assessment indexIntervention groupLipid levelsBody weightInsulin resistancePostprandial metabolismVegan dietOverweight adultsDietary interventionInsulin sensitivityThermic effectControl groupPlant-based dietary interventionDual X-ray absorptiometryInsulin resistance leadExcess body weightInsulin sensitivity indexType 2 diabetesMajor health problemProton magnetic resonance spectroscopyX-ray absorptiometrySubset of participantsA MicroRNA Linking Human Positive Selection and Metabolic Disorders
Wang L, Sinnott-Armstrong N, Wagschal A, Wark AR, Camporez JP, Perry RJ, Ji F, Sohn Y, Oh J, Wu S, Chery J, Moud BN, Saadat A, Dankel SN, Mellgren G, Tallapragada DSP, Strobel SM, Lee MJ, Tewhey R, Sabeti PC, Schaefer A, Petri A, Kauppinen S, Chung RT, Soukas A, Avruch J, Fried SK, Hauner H, Sadreyev RI, Shulman GI, Claussnitzer M, Näär AM. A MicroRNA Linking Human Positive Selection and Metabolic Disorders. Cell 2020, 183: 684-701.e14. PMID: 33058756, PMCID: PMC8092355, DOI: 10.1016/j.cell.2020.09.017.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytes, BrownAdiposityAllelesAnimalsCell DifferentiationCell LineCells, CulturedDiet, High-FatEnergy MetabolismEpigenesis, GeneticGenetic LociGlucoseHomeostasisHumansHypertrophyInsulin ResistanceLeptinMaleMammalsMetabolic DiseasesMice, Inbred C57BLMice, ObeseMicroRNAsObesityOligonucleotidesSpecies SpecificityConceptsPositive selectionMiR-128Additional genetic elementsCrucial metabolic regulatorAncient adaptationEvolutionary adaptationGenetic elementsMetabolic regulatorGenetic ablationLociMetabolic maladaptationLactase geneAntisense targetingMetabolic disease modelsThrifty phenotypeDisease modelsDiet-induced obesityMetabolic diseasesAbility of adultsMammalsAdaptationGenesMicroRNAsRegulatorSelectionSlc20a1/Pit1 and Slc20a2/Pit2 are essential for normal skeletal myofiber function and survival
Chande S, Caballero D, Ho BB, Fetene J, Serna J, Pesta D, Nasiri A, Jurczak M, Chavkin NW, Hernando N, Giachelli CM, Wagner CA, Zeiss C, Shulman GI, Bergwitz C. Slc20a1/Pit1 and Slc20a2/Pit2 are essential for normal skeletal myofiber function and survival. Scientific Reports 2020, 10: 3069. PMID: 32080237, PMCID: PMC7033257, DOI: 10.1038/s41598-020-59430-4.Peer-Reviewed Original ResearchConceptsHyp miceMuscle functionSkeletal muscleMyofiber functionNormal body weightSkeletal muscle atrophyGene dose-dependent reductionConditional knockout miceReduced oxygen consumption rateStimulation of AMP kinaseKnockout miceHypophosphatemic disordersMuscle atrophyERK1/2 activationGrip strengthConditional deletionHormonal changesLow bloodBody weightC2C12 myoblastsMiceFurther evaluationBlood phosphateDependent reductionAMP kinase
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 factor
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-ActivatorsIn Vivo Effects of Uncoupling Protein-3 Gene Disruption on Mitochondrial Energy Metabolism*
Cline G, Vidal-Puig A, Dufour S, Cadman K, Lowell B, Shulman G. In Vivo Effects of Uncoupling Protein-3 Gene Disruption on Mitochondrial Energy Metabolism*. Journal Of Biological Chemistry 2001, 276: 20240-20244. PMID: 11274222, DOI: 10.1074/jbc.m102540200.Peer-Reviewed Original ResearchConceptsATP synthesisEnergy metabolismSkeletal muscleMitochondrial oxidative phosphorylationMitochondrial energy metabolismGene disruptionRatio of ATPOxidative phosphorylationATP productionTricarboxylic acid cycle fluxWhole-body levelUCP3KO miceWhole-body energy expenditureCellular levelProtein 3Cycle fluxLabeling experimentsFirst evidenceBody energy expenditureMetabolismVivoMeasurement of ratesPhosphorylationEnergy expenditureUCP3
2000
Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice
Klaman L, Boss O, Peroni O, Kim J, Martino J, Zabolotny J, Moghal N, Lubkin M, Kim Y, Sharpe A, Stricker-Krongrad A, Shulman G, Neel B, Kahn B. Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice. Molecular And Cellular Biology 2000, 20: 5479-5489. PMID: 10891488, PMCID: PMC85999, DOI: 10.1128/mcb.20.15.5479-5489.2000.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAnimalsBody WeightCarrier ProteinsEnergy MetabolismFemaleGlucoseGlucose Tolerance TestHomeostasisHyperinsulinismInsulin ResistanceIon ChannelsLeptinMaleMembrane ProteinsMembrane Transport ProteinsMiceMice, Inbred C57BLMice, Mutant StrainsMitochondrial ProteinsMuscle, SkeletalProtein Tyrosine Phosphatase, Non-Receptor Type 1Protein Tyrosine PhosphatasesProteinsRNA, MessengerUncoupling Protein 1Uncoupling Protein 2Uncoupling Protein 3ConceptsProtein tyrosine phosphatasePTP-1BMajor protein tyrosine phosphataseProtein tyrosine phosphatase 1BSignal transduction pathwaysTargeted gene disruptionInsulin-stimulated glucose uptakeGene disruptionTransduction pathwaysFat cell massPhosphatase 1BMajor regulatorProtein mRNA expressionCell massNull miceSkeletal muscleDeficient miceGlucose uptakeBasal metabolic rateInsulin actionMetabolic ratePhosphataseFat storesDiet-induced obesityAdipocyte numberAssessment 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 ResearchConceptsUCP3 mRNAPersistent 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