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 cells
2019
Obesity-associated, but not obesity-independent, tumors respond to insulin by increasing mitochondrial glucose oxidation
Rabin-Court A, Rodrigues MR, Zhang XM, Perry RJ. Obesity-associated, but not obesity-independent, tumors respond to insulin by increasing mitochondrial glucose oxidation. PLOS ONE 2019, 14: e0218126. PMID: 31188872, PMCID: PMC6561592, DOI: 10.1371/journal.pone.0218126.Peer-Reviewed Original ResearchMeSH KeywordsAlanineBreast NeoplasmsCell Line, TumorCitrate (si)-SynthaseColonic NeoplasmsFemaleGene Expression RegulationGlucoseGlutamic AcidHumansInsulinIsotope LabelingKetone OxidoreductasesLymphoma, B-CellMaleMelanomaMitochondriaObesityOrgan SpecificityOxidation-ReductionPhosphorylationProstatic NeoplasmsReceptor, InsulinSignal TransductionSkin NeoplasmsSmall Cell Lung CarcinomaConceptsCell divisionTumor cell linesCell linesMitochondrial glucose oxidationTumor typesObesity-driven insulin resistanceSubstrate preferenceMolecular mechanismsDose-dependent increaseGlucose oxidationPhysiologic insulinPyruvate dehydrogenase fluxWorse prognosisInsulin resistanceStable isotope methodObesityOxidative responsePhysiologic concentrationsSynthase fluxInsulinMetabolic signaturesTumor cellsTumorsDivisionLines
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
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