Featured Publications
A precision medicine approach to metabolic therapy for breast cancer in mice
Akingbesote ND, Norman A, Zhu W, Halberstam AA, Zhang X, Foldi J, Lustberg MB, Perry RJ. A precision medicine approach to metabolic therapy for breast cancer in mice. Communications Biology 2022, 5: 478. PMID: 35595952, PMCID: PMC9122928, DOI: 10.1038/s42003-022-03422-9.Peer-Reviewed Original ResearchConceptsPrecision medicine approachBreast cancerSodium-glucose transport protein 2 inhibitorsBreast tumorsMedicine approachCanonical insulinSGLT2 inhibitor dapagliflozinEfficacy of paclitaxelBreast tumor-bearing miceTumor glucose uptakeTumor-bearing miceChemotherapy correlatesNeoadjuvant approachNeoadjuvant settingPaclitaxel chemotherapyInhibitor dapagliflozinSGLT2 inhibitorsProlonging survivalAntihyperglycemic drugsPotential adjuvantMetabolic therapyDapagliflozinTumorsDriver mutationsGlucose uptakeGene and protein expression and metabolic flux analysis reveals metabolic scaling in liver ex vivo and in vivo
Akingbesote N, Leitner B, Jovin D, Desrouleaux R, Owusu D, Zhu W, Li Z, Pollak M, Perry R. Gene and protein expression and metabolic flux analysis reveals metabolic scaling in liver ex vivo and in vivo. ELife 2023, 12: e78335. PMID: 37219930, PMCID: PMC10205083, DOI: 10.7554/elife.78335.Peer-Reviewed Original ResearchConceptsMetabolic scalingMetabolic fluxMetabolic processesBody sizeMitochondrial metabolic processesMultiple cellular compartmentsVivo metabolic fluxesLevel of genesKey metabolic pathwaysProtein expressionMetabolic flux analysisAspects of metabolismCellular compartmentsGene expressionDifferential expressionMetabolic pathwaysGenesFlux analysisOxidative damageEnzyme activitySubstrate supplyFold rangeSpeciesExpressionMetabolic rateDichloroacetate as a novel pharmaceutical treatment for cancer-related fatigue in melanoma
Zhang X, Lee W, Leitner B, Zhu W, Fosam A, Li Z, Gaspar R, Halberstam A, Robles B, Rabinowitz J, Perry R. Dichloroacetate as a novel pharmaceutical treatment for cancer-related fatigue in melanoma. AJP Endocrinology And Metabolism 2023, 325: e363-e375. PMID: 37646579, PMCID: PMC10642987, DOI: 10.1152/ajpendo.00105.2023.Peer-Reviewed Original ResearchConceptsCancer-related fatigueNovel pharmaceutical treatmentsPhysical functionPharmaceutical treatmentTumor growthCancer treatmentStandard cancer treatmentTumor-bearing miceLate-stage tumorsEffective pharmaceutical treatmentMurine cancer modelsNew metabolic targetsMultiple cancer typesAdjuvant therapyCommon complicationPatients' qualitySymptom managementClinical trialsMurine modelPotential therapyPharmaceutical therapySmall molecule inhibitorsCancer modelDCA treatmentLactate concentration
2024
A kidney-hypothalamus axis promotes compensatory glucose production in response to glycosuria
Faniyan T, Zhang X, Morgan D, Robles J, Bathina S, Brookes P, Rahmouni K, Perry R, Chhabra K. A kidney-hypothalamus axis promotes compensatory glucose production in response to glycosuria. ELife 2024, 12: rp91540. PMID: 39082939, PMCID: PMC11290820, DOI: 10.7554/elife.91540.Peer-Reviewed Original ResearchConceptsGlucose productionEndogenous glucose productionReabsorption of nutrientsLoss of glucoseHypothalamic-pituitary-adrenal axisNormal energy supplyProteomic analysisCompensatory increaseAfferent renal nervesAfferent renal denervationPlasma proteomic analysisDefense mechanismsAcute phase proteinsRenal denervationKO miceSGLT2 inhibitorsKnockout miceRenal nervesAfferent nervesEfficiency of drugsBody's defense mechanismsGlycosuriaGlucosePhase proteinsTreat hyperglycemiaFatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring
Sun J, Esplugues E, Bort A, Cardelo M, Ruz-Maldonado I, Fernández-Tussy P, Wong C, Wang H, Ojima I, Kaczocha M, Perry R, Suárez Y, Fernández-Hernando C. Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring. Nature Metabolism 2024, 6: 741-763. PMID: 38664583, DOI: 10.1038/s42255-024-01019-6.Peer-Reviewed Original ResearchConceptsFatty acid binding protein 5Tumor-associated macrophagesHepatocellular carcinomaImmunosuppressive phenotype of tumor-associated macrophagesIncreased CD8+ T cell activationCD8+ T cell activationPhenotype of tumor-associated macrophagesPro-inflammatory tumor microenvironmentCo-stimulatory molecules CD80T cell activationHepatocellular carcinoma burdenTransformation of hepatocytesBinding protein 5Potential therapeutic approachImmunosuppressive phenotypeTumor microenvironmentFerroptosis-induced cell deathMale miceEnhanced ferroptosisTherapeutic approachesPharmacological inhibitionGenetic ablationIncreased expressionSingle-cell atlasAnalysis of transformed cellsA New Mitochondrial Uncoupler Improves Metabolic Homeostasis in Mice.
Ramshankar G, Perry R. A New Mitochondrial Uncoupler Improves Metabolic Homeostasis in Mice. Diabetes 2024, 73: 357-358. PMID: 38377448, DOI: 10.2337/dbi23-0033.Commentaries, Editorials and Letters
2023
Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis
Leitner B, Lee W, Zhu W, Zhang X, Gaspar R, Li Z, Rabinowitz J, Perry R. Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis. PLOS ONE 2023, 18: e0286525. PMID: 37410734, PMCID: PMC10325078, DOI: 10.1371/journal.pone.0286525.Peer-Reviewed Original ResearchConceptsTCA cycle anaplerosisGlobal mitochondrial dysfunctionAromatic amino acid transportAmino acid transportTissue-specific metabolic responsesMurine polymicrobial sepsis modelMetabolic signaturesAntioxidant metabolismGlutathione biosynthesisMitochondrial metabolismTCA cycleGreat therapeutic interestEnergetic demandsPolymicrobial sepsis modelAntioxidant synthesisUnique metabolic signatureGlutamine metabolismMitochondrial dysfunctionAcid transportMuscle transcriptomicsGlutathione cyclingATP ratioIsotope tracingCritical illnessReduced expression
2022
An optimized method for tissue glycogen quantification
Schaubroeck KJ, Leitner BP, Perry RJ. An optimized method for tissue glycogen quantification. Physiological Reports 2022, 10: e15195. PMID: 35179318, PMCID: PMC8855679, DOI: 10.14814/phy2.15195.Peer-Reviewed Original Research
2020
Glucagon 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
Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer
Wang Y, Nasiri AR, Damsky WE, Perry CJ, Zhang XM, Rabin-Court A, Pollak MN, Shulman GI, Perry RJ. Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer. Cell Reports 2018, 24: 47-55. PMID: 29972790, PMCID: PMC6056247, DOI: 10.1016/j.celrep.2018.06.008.Peer-Reviewed Original ResearchConceptsControlled-release mitochondrial protonophoreTumor growthGlucose uptakeDiet-induced obesityMurine colon cancer modelColon cancer modelHepatic energy metabolismColon cancer pathogenesisHormonal milieuPlasma insulinFed miceInsulin infusionMurine modelColon cancerCancer modelCancer pathogenesisOxidative phosphorylationNeoplastic growthMitochondrial protonophoreHepatic oxidative phosphorylationObesityUnderlying mechanismEnergy metabolismCancerInsulinLeptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation
Perry RJ, Wang Y, Cline GW, Rabin-Court A, Song JD, Dufour S, Zhang XM, Petersen KF, Shulman GI. Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation. Cell 2018, 172: 234-248.e17. PMID: 29307489, PMCID: PMC5766366, DOI: 10.1016/j.cell.2017.12.001.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 levelsNon-invasive assessment of hepatic mitochondrial metabolism by positional isotopomer NMR tracer analysis (PINTA)
Perry RJ, Peng L, Cline GW, Butrico GM, Wang Y, Zhang XM, Rothman DL, Petersen KF, Shulman GI. Non-invasive assessment of hepatic mitochondrial metabolism by positional isotopomer NMR tracer analysis (PINTA). Nature Communications 2017, 8: 798. PMID: 28986525, PMCID: PMC5630596, DOI: 10.1038/s41467-017-01143-w.Peer-Reviewed Original ResearchConceptsMitochondrial metabolismHepatic mitochondrial metabolismPyruvate carboxylase fluxCitrate synthase fluxPyruvate cyclingMitochondrial uncouplerIntermediary metabolismSpectrometry analysisPhysiological conditionsChromatography-mass spectrometry analysisSynthase fluxCentral roleMetabolismHepatic mitochondriaGas chromatography-mass spectrometry analysisVivo NMR spectroscopyMitochondriaNMR spectroscopyRegulationUncouplerRoleTracer analysisVivoMaintenance of normoglycemiaWide range
2016
Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome
Perry RJ, Peng L, Barry NA, Cline GW, Zhang D, Cardone RL, Petersen KF, Kibbey RG, Goodman AL, Shulman GI. Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome. Nature 2016, 534: 213-217. PMID: 27279214, PMCID: PMC4922538, DOI: 10.1038/nature18309.Peer-Reviewed Original ResearchConceptsGut microbiotaMetabolic syndromeGlucose-stimulated insulin secretionAltered gut microbiotaParasympathetic nervous systemPossible therapeutic targetGhrelin secretionInsulin resistanceInsulin secretionParasympathetic activationTherapeutic targetNervous systemObesityMicrobiota interactionsSyndromeMicrobiotaSecretionActivationSequelaeHyperphagia
2015
Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats
Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science 2015, 347: 1253-1256. PMID: 25721504, PMCID: PMC4495920, DOI: 10.1126/science.aaa0672.Peer-Reviewed Original ResearchMeSH Keywords2,4-DinitrophenolAnimalsBlood GlucoseDelayed-Action PreparationsDiabetes Mellitus, Type 2Glucose Tolerance TestInsulin ResistanceLipid MetabolismLiver CirrhosisMaleMiceMitochondria, LiverMuscle, SkeletalNon-alcoholic Fatty Liver DiseaseOxidation-ReductionProton IonophoresRandom AllocationRatsRats, ZuckerConceptsNonalcoholic fatty liver diseaseNonalcoholic steatohepatitisInsulin resistanceRat modelControlled-release oral formulationsPlasma transaminase concentrationsFatty liver diseaseType 2 diabetesMitochondrial uncouplingProtein-synthetic functionChronic treatmentLiver diseaseMetabolic syndromeTransaminase concentrationsHepatic steatosisLiver fibrosisEffective therapyPreclinical modelsOral formulationSystemic toxicityClinical useRelated epidemicsBeneficial effectsSynthetic functionMitochondrial protonophoreHepatic Acetyl CoA Links Adipose Tissue Inflammation to Hepatic Insulin Resistance and Type 2 Diabetes
Perry RJ, Camporez JP, Kursawe R, Titchenell PM, Zhang D, Perry CJ, Jurczak MJ, Abudukadier A, Han MS, Zhang XM, Ruan HB, Yang X, Caprio S, Kaech SM, Sul HS, Birnbaum MJ, Davis RJ, Cline GW, Petersen KF, Shulman GI. Hepatic Acetyl CoA Links Adipose Tissue Inflammation to Hepatic Insulin Resistance and Type 2 Diabetes. Cell 2015, 160: 745-758. PMID: 25662011, PMCID: PMC4498261, DOI: 10.1016/j.cell.2015.01.012.Peer-Reviewed Original ResearchConceptsHepatic glucose productionWhite adipose tissueHepatic insulin resistanceInsulin resistanceImpaired insulin-mediated suppressionAdipose tissue inflammationIL-6 neutralizationIL-6 infusionType 2 diabetesInsulin-mediated suppressionSuppression of lipolysisAdipose triglyceride lipaseTissue inflammationAdipose tissueType 2Fed ratsGlucose productionGenetic ablationInsulin's abilityAcetyl CoATriglyceride lipaseInsulin signalingRatsMetabolomics approachInsulin