2023
Innate immune cell-intrinsic ketogenesis is dispensable for organismal metabolism and age-related inflammation
Goldberg E, Letian A, Dlugos T, Leveau C, Dixit V. Innate immune cell-intrinsic ketogenesis is dispensable for organismal metabolism and age-related inflammation. Journal Of Biological Chemistry 2023, 299: 103005. PMID: 36775129, PMCID: PMC10025153, DOI: 10.1016/j.jbc.2023.103005.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsGlucoseImmunity, InnateInflammasomesInflammationKetone BodiesMiceNLR Family, Pyrin Domain-Containing 3 ProteinConceptsAge-related inflammationKetone bodiesOrganismal metabolismMyeloid cellsChronic low-grade inflammationKetogenic diet feedingLow-grade inflammationHigh-fat dietAbundant ketone bodyGlucose toleranceNLRP3 inflammasomeDiet feedingGlucose homeostasisMouse modelBody weightInflammationMetabolic checkpointOnly organConditional ablationTerminal enzymeΒ-hydroxybutyrateFunctional targetingMethylglutaryl-CoA lyaseKetogenesisModest effect
2022
Caloric restriction in humans reveals immunometabolic regulators of health span
Spadaro O, Youm Y, Shchukina I, Ryu S, Sidorov S, Ravussin A, Nguyen K, Aladyeva E, Predeus AN, Smith SR, Ravussin E, Galban C, Artyomov MN, Dixit VD. Caloric restriction in humans reveals immunometabolic regulators of health span. Science 2022, 375: 671-677. PMID: 35143297, PMCID: PMC10061495, DOI: 10.1126/science.abg7292.Peer-Reviewed Original ResearchMeSH Keywords1-Alkyl-2-acetylglycerophosphocholine EsteraseAdipose TissueAdultAgingAnimalsCaloric RestrictionDown-RegulationEnergy MetabolismFemaleHumansImmune SystemInflammasomesInflammationLongevityLymphopoiesisMacrophagesMaleMiceMiddle AgedMitochondriaNLR Family, Pyrin Domain-Containing 3 ProteinThermogenesisThymus GlandTranscriptomeConceptsCaloric restrictionAge-related inflammationHealth spanAnti-inflammatory responseNLRP3 inflammasome activationEctopic lipidsMetabolic healthInflammasome activationHealthy humansAdipose tissueImmunometabolic effectsFactor acetyl hydrolaseImmune defenseInflammationAcetyl hydrolaseMitochondrial bioenergeticsHumansLife spanLipoatrophyPLA2G7ThymopoiesisMice
2021
Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice
Ryu S, Shchukina I, Youm YH, Qing H, Hilliard B, Dlugos T, Zhang X, Yasumoto Y, Booth CJ, Fernández-Hernando C, Suárez Y, Khanna K, Horvath TL, Dietrich MO, Artyomov M, Wang A, Dixit VD. Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice. ELife 2021, 10: e66522. PMID: 34151773, PMCID: PMC8245129, DOI: 10.7554/elife.66522.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAgingAnimalsCoronavirus InfectionsCOVID-19Diet, KetogenicDisease Models, AnimalGlycolysisHumansInflammasomesKetone BodiesMaleMiceMice, Inbred C57BLMurine hepatitis virusNLR Family, Pyrin Domain-Containing 3 ProteinSARS-CoV-2ConceptsΓδ T cellsKetogenic dietCoronavirus infectionAged miceT cellsHigher systemic inflammationInfected aged miceCOVID-19 severityCOVID-19 infectionActivation of ketogenesisMouse hepatitis virus strain A59Systemic inflammationInflammatory damageInfluenza infectionClinical hallmarkNLRP3 inflammasomeImmune surveillanceAdipose tissuePotential treatmentInfectionMiceStrongest predictorLungMortalityAge
2019
Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis
Camell CD, Günther P, Lee A, Goldberg EL, Spadaro O, Youm YH, Bartke A, Hubbard GB, Ikeno Y, Ruddle NH, Schultze J, Dixit VD. Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis. Cell Metabolism 2019, 30: 1024-1039.e6. PMID: 31735593, PMCID: PMC6944439, DOI: 10.1016/j.cmet.2019.10.006.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAgingAnimalsB-LymphocytesBody Temperature RegulationCold-Shock ResponseFemaleHomeostasisInflammasomesInterleukin-18Interleukin-1betaLipolysisMaleMiceNLR Family, Pyrin Domain-Containing 3 ProteinReceptors, Interleukin-1ConceptsAge-associated B cellsFat-associated lymphoid clustersB cellsAdipose tissue leukocytesB-cell depletionB cell accumulationBody temperature maintenanceFALC formationVisceral adiposityCell depletionNLRP3 inflammasomeFemale miceLymphoid clustersMetabolic dysfunctionIL-1Metabolic impairmentIL-1RTissue leukocytesCell accumulationMetabolic homeostasisUnique populationLipolysisCellsTemperature maintenanceAdiposity
2017
Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing
Camell CD, Sander J, Spadaro O, Lee A, Nguyen KY, Wing A, Goldberg EL, Youm YH, Brown CW, Elsworth J, Rodeheffer MS, Schultze JL, Dixit VD. Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature 2017, 550: 119-123. PMID: 28953873, PMCID: PMC5718149, DOI: 10.1038/nature24022.Peer-Reviewed Original ResearchAdipocytesAdipose TissueAgingAnimalsCaspase 1CatecholaminesGene Expression ProfilingGene Expression RegulationGrowth Differentiation Factor 3InflammasomesLipaseLipolysisMacrophagesMiceMonoamine OxidaseMonoamine Oxidase InhibitorsNLR Family, Pyrin Domain-Containing 3 ProteinNorepinephrineSterol Esteraseβ-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares
Goldberg EL, Asher JL, Molony RD, Shaw AC, Zeiss CJ, Wang C, Morozova-Roche LA, Herzog RI, Iwasaki A, Dixit VD. β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares. Cell Reports 2017, 18: 2077-2087. PMID: 28249154, PMCID: PMC5527297, DOI: 10.1016/j.celrep.2017.02.004.Peer-Reviewed Original ResearchMeSH Keywords3-Hydroxybutyric AcidAdolescentAdultAgedAnimalsDiet, KetogenicFemaleGoutHumansInflammasomesInflammationInterleukin-1betaMacrophagesMaleMiceMice, Inbred C57BLMiddle AgedNeutrophilsNLR Family, Pyrin Domain-Containing 3 ProteinRatsUric AcidYoung AdultConceptsKetogenic dietGouty flaresΒ-hydroxybutyrateMajor risk factorAnti-inflammatory moleculesNLRP3-dependent mannerAlternate metabolic fuelsGout flaresJoint destructionIL-1βIntense painInterleukin-1βNLRP3 inflammasomeRisk factorsInflammatory neutrophilsBacterial infectionsNeutrophilsNLRP3Immune defenseGoutMetabolic fuelsBHBS100A9 fibrilsDietPain
2016
Growth Hormone Receptor Deficiency Protects against Age-Related NLRP3 Inflammasome Activation and Immune Senescence
Spadaro O, Goldberg EL, Camell CD, Youm YH, Kopchick JJ, Nguyen KY, Bartke A, Sun LY, Dixit VD. Growth Hormone Receptor Deficiency Protects against Age-Related NLRP3 Inflammasome Activation and Immune Senescence. Cell Reports 2016, 14: 1571-1580. PMID: 26876170, PMCID: PMC5992590, DOI: 10.1016/j.celrep.2016.01.044.Peer-Reviewed Original ResearchMeSH KeywordsAgingAnimalsAutocrine CommunicationBone Marrow CellsCarrier ProteinsGene Expression RegulationHomeostasisImmunity, InnateImmunologic MemoryInflammasomesInterferon-gammaLongevityMacrophagesMiceMice, KnockoutNLR Family, Pyrin Domain-Containing 3 ProteinReceptor, IGF Type 1Receptors, SomatotropinSignal TransductionSpleenT-LymphocytesConceptsNLRP3 inflammasome activationInflammasome activationImmune senescenceAge-related immune senescenceGrowth hormone receptor deficiencyHigher IFNγ secretionNaive T lymphocytesImmune system homeostasisMyeloid lineage cellsEffector memoryIFNγ secretionInflammasome inhibitionEffector cellsChronic inflammationReceptor deficiencyAdvanced ageAge-related activationSystemic activationT lymphocytesGrowth hormone receptorNLRP3 ligandsInnate immuneSomatotropic axisSystem homeostasisNLRP3
2015
A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents
Kursawe R, Dixit VD, Scherer PE, Santoro N, Narayan D, Gordillo R, Giannini C, Lopez X, Pierpont B, Nouws J, Shulman GI, Caprio S. A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents. Diabetes 2015, 65: 610-618. PMID: 26718495, PMCID: PMC4764142, DOI: 10.2337/db15-1478.Peer-Reviewed Original ResearchMeSH KeywordsAbdomenAcetyl-CoA CarboxylaseAdipogenesisAdiponectinAdolescentCarrier ProteinsCaspase 1ChildDown-RegulationFatty Acid Synthase, Type IFemaleGene Expression ProfilingGlucose Transporter Type 4HumansInflammasomesInsulin ResistanceInterleukin-1betaIntra-Abdominal FatLeptinLipogenesisLipoprotein LipaseMacrophagesMagnetic Resonance ImagingMaleNLR Family, Pyrin Domain-Containing 3 ProteinObesityPPAR gammaSirtuin 1Sterol Regulatory Element Binding Protein 1Subcutaneous FatToll-Like Receptor 4ConceptsVisceral adipose tissueObese adolescentsInsulin resistanceTissue inflammationNLRP3 inflammasomeAdipose tissueInnate immune cell sensorsAbdominal subcutaneous adipose tissueAbdominal adipose depotsAbdominal fat partitioningAdipogenesis/lipogenesisAdipose tissue inflammationProinflammatory cytokines interleukinInfiltration of macrophagesExpression of CASP1Subcutaneous adipose tissueInflammation markersSAT biopsiesIL-18Macrophage infiltrationVisceral fatCytokines interleukinSAT ratioInsulin sensitivityAdipose depotsThe ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease
Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease. Nature Medicine 2015, 21: 263-269. PMID: 25686106, PMCID: PMC4352123, DOI: 10.1038/nm.3804.Peer-Reviewed Original ResearchMeSH Keywords3-Hydroxybutyric AcidAdultAgedAnimalsCarrier ProteinsCaspase 1Cryopyrin-Associated Periodic SyndromesDiet, KetogenicDisease Models, AnimalFemaleHumansInflammasomesInflammationInterleukin-18Interleukin-1betaMaleMiceMonocytesNLR Family, Pyrin Domain-Containing 3 ProteinPotassium
2014
Adipose Tissue Macrophages Promote Myelopoiesis and Monocytosis in Obesity
Nagareddy PR, Kraakman M, Masters SL, Stirzaker RA, Gorman DJ, Grant RW, Dragoljevic D, Hong ES, Abdel-Latif A, Smyth SS, Choi SH, Korner J, Bornfeldt KE, Fisher EA, Dixit VD, Tall AR, Goldberg IJ, Murphy AJ. Adipose Tissue Macrophages Promote Myelopoiesis and Monocytosis in Obesity. Cell Metabolism 2014, 19: 821-835. PMID: 24807222, PMCID: PMC4048939, DOI: 10.1016/j.cmet.2014.03.029.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAnimalsBone MarrowCarrier ProteinsCell ProliferationHumansInflammasomesInterleukin-1betaMacrophagesMaleMiceMice, Inbred C57BLMonocytesMyeloid Differentiation Factor 88MyelopoiesisNeutrophilsNLR Family, Pyrin Domain-Containing 3 ProteinObesityReceptors, Interleukin-1Toll-Like Receptor 4ConceptsAT macrophagesInsulin resistanceNLRP3 inflammasome-dependent IL-1β productionAdipose tissueMyeloid progenitorsTLR4/MyD88Infiltration of macrophagesBone marrow myeloid progenitorsIL-1β productionS100A8/A9IL-1 receptorMarrow myeloid progenitorsProduction of monocytesAT inflammationLean recipientsNLRP3-ILTLR4 ligandIL-1βMurine modelMyeloid progenitor proliferationProminent monocytosisObesityMonocytosisWeight lossProgenitor proliferation