2023
Lysophosphatidic acid triggers inflammation in the liver and white adipose tissue in rat models of 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 deficiency and overnutrition
Sakuma I, Gaspar R, Luukkonen P, Kahn M, Zhang D, Zhang X, Murray S, Golla J, Vatner D, Samuel V, Petersen K, Shulman G. Lysophosphatidic acid triggers inflammation in the liver and white adipose tissue in rat models of 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 deficiency and overnutrition. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2312666120. PMID: 38127985, PMCID: PMC10756285, DOI: 10.1073/pnas.2312666120.Peer-Reviewed Original ResearchTime-restricted feeding combined with resistance exercise prevents obesity and improves lipid metabolism in the liver of mice fed a high-fat diet
Damasceno de Lima R, Fudoli Lins Vieira R, Rosetto Muñoz V, Chaix A, Azevedo Macedo A, Calheiros Antunes G, Felonato M, Rosseto Braga R, Castelo Branco Ramos Nakandakari S, Calais Gaspar R, Ramos da Silva A, Esper Cintra D, Pereira de Moura L, Mekary R, Rochete Ropelle E, Pauli J. Time-restricted feeding combined with resistance exercise prevents obesity and improves lipid metabolism in the liver of mice fed a high-fat diet. AJP Endocrinology And Metabolism 2023, 325: e513-e528. PMID: 37755454, DOI: 10.1152/ajpendo.00129.2023.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseResistance exercise trainingTime-restricted feedingFatty liver diseaseHigh-fat dietLiver diseaseExercise trainingWeight gainGlycemic homeostasisMetabolic disordersEffects of TRFCommon liver diseaseDiet-induced obesityMajor risk factorEnergy expenditureFatty acid oxidation genesLiver of miceAccumulation of fatBody weight gainRespiratory exchange rateAccumulation of lipidsLower mRNA expressionRT groupPrevents obesityRisk factorsMAD2-Dependent Insulin Receptor Endocytosis Regulates Metabolic Homeostasis.
Park J, Hall C, Hubbard B, LaMoia T, Gaspar R, Nasiri A, Li F, Zhang H, Kim J, Haeusler R, Accili D, Shulman G, Yu H, Choi E. MAD2-Dependent Insulin Receptor Endocytosis Regulates Metabolic Homeostasis. Diabetes 2023, 72: 1781-1794. PMID: 37725942, PMCID: PMC10658066, DOI: 10.2337/db23-0314.Peer-Reviewed Original ResearchConceptsIR endocytosisInsulin receptor endocytosisCell division regulatorsInsulin receptorProlongs insulin actionReceptor endocytosisTranscriptomic profilesInsulin stimulationEndocytosisMetabolic homeostasisCell surfaceGenetic ablationMetabolic functionsInsulin actionP31cometMad2BubR1DisruptionSignalingRegulatorHomeostasisAdipose tissueInteractionHepatic fat accumulationMetabolismDichloroacetate 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 concentrationTissue-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 expressionEffects of short-term endurance and strength exercise in the molecular regulation of skeletal muscle in hyperinsulinemic and hyperglycemic Slc2a4+/− mice
Muñoz V, Botezelli J, Gaspar R, da Rocha A, Vieira R, Crisol B, Braga R, Severino M, Nakandakari S, Antunes G, Brunetto S, Ramos C, Velloso L, Simabuco F, de Moura L, da Silva A, Ropelle E, Cintra D, Pauli J. Effects of short-term endurance and strength exercise in the molecular regulation of skeletal muscle in hyperinsulinemic and hyperglycemic Slc2a4+/− mice. Cellular And Molecular Life Sciences 2023, 80: 122. PMID: 37052684, PMCID: PMC11072257, DOI: 10.1007/s00018-023-04771-2.Peer-Reviewed Original ResearchConceptsWhole-body glucose homeostasisSkeletal muscle glucose uptakeMuscle glucose uptakeMitochondrial adaptationsMitochondrial activityPost-translational mechanismsSkeletal muscleGlucose uptakeC2C12 cell lineInsulin resistanceStrength exercisesGlucose homeostasisMouse modelPhysical exerciseProtein response markersShort-term physical activityMolecular regulationTranscriptomic modulationRNA sequencingImpact of hyperglycemiaC2C12 cellsStrength exercise trainingType 2 diabetesStrength training protocolsMitochondrial functionShort-term flaxseed oil, rich in omega 3, protects mice against metabolic damage caused by high-fat diet, but not inflammation
Nakandakari S, Gaspar R, Kuga G, Ramos C, Vieira R, Rios T, Muñoz V, Sant'ana M, Simabuco F, da Silva A, Moura L, Ropelle E, Pauli J, Cintra D. Short-term flaxseed oil, rich in omega 3, protects mice against metabolic damage caused by high-fat diet, but not inflammation. The Journal Of Nutritional Biochemistry 2023, 114: 109270. PMID: 36706930, DOI: 10.1016/j.jnutbio.2023.109270.Peer-Reviewed Original ResearchConceptsControl groupFood intakeAdipose tissueLong-term high-fat diet feedingHigh-fat diet feedingFlaxseed oilHigh-fat dietMesenteric adipose tissueFatty acid incorporationNeuronal signaling pathwaysInflammatory markersHF dietInflammatory effectsDiet feedingEarly inflammationHF groupLipid profileTNFα proteinProtective effectTriggers inflammationMetabolic disordersGlucose homeostasisBody weightInflammationHF consumptionInhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis
Luukkonen P, Sakuma I, Gaspar R, Mooring M, Nasiri A, Kahn M, Zhang X, Zhang D, Sammalkorpi H, Penttilä A, Orho-Melander M, Arola J, Juuti A, Zhang X, Yimlamai D, Yki-Järvinen H, Petersen K, Shulman G. Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2217543120. PMID: 36669104, PMCID: PMC9942818, DOI: 10.1073/pnas.2217543120.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseLiver fibrosisLiver diseaseCommon chronic liver diseaseChronic liver diseaseFatty liver diseaseRisk of fibrosisDistinct mouse modelsPyrimidine catabolismNonalcoholic steatohepatitisMouse modelTherapeutic targetFibrosisDihydropyrimidine dehydrogenaseHuman liverA variantCommon variantsMetabolomics approachDiseaseMiceInhibitionCatabolismKnockdownSteatohepatitisGimeracil
2022
Aging reduces ABHD5 protein content in the adipose tissue of mice: The reversal effect of exercise
Brícola R, Cordeiro A, Crisol B, Braga R, de Melo D, Rocha M, Gaspar R, Nakandakari S, Silva V, Anaruma C, Katashima C, Canciglieri R, Munõz V, Pavan I, Pinto A, Simabuco F, da Silva A, Moura L, Pauli J, Cintra D, Ropelle E. Aging reduces ABHD5 protein content in the adipose tissue of mice: The reversal effect of exercise. Cell Biochemistry And Function 2022, 41: 128-137. PMID: 36515301, DOI: 10.1002/cbf.3770.Peer-Reviewed Original ResearchConceptsAged miceAdipose tissueControl of lipolysisHigh-intensity interval trainingSubcutaneous white adipose tissueExperimental mouse modelAdipose tissue metabolismWhite adipose tissueMessenger RNA levelsInterval trainingMouse modelTissue metabolismLipolytic pathwayMiceRNA levelsProtein levelsScWATTranscriptomic analyzesReversal effectTissueExerciseSignificant hallmarkLipolysisABHD5Lipolytic activityQ-Flux: A method to assess hepatic mitochondrial succinate dehydrogenase, methylmalonyl-CoA mutase, and glutaminase fluxes in vivo
Hubbard B, LaMoia T, Goedeke L, Gaspar R, Galsgaard K, Kahn M, Mason G, Shulman G. Q-Flux: A method to assess hepatic mitochondrial succinate dehydrogenase, methylmalonyl-CoA mutase, and glutaminase fluxes in vivo. Cell Metabolism 2022, 35: 212-226.e4. PMID: 36516861, PMCID: PMC9887731, DOI: 10.1016/j.cmet.2022.11.011.Peer-Reviewed Original ResearchDistinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice
Gaspar R, Lyu K, Hubbard B, Leitner B, Luukkonen P, Hirabara S, Sakuma I, Nasiri A, Zhang D, Kahn M, Cline G, Pauli J, Perry R, Petersen K, Shulman G. Distinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice. Diabetologia 2022, 66: 567-578. PMID: 36456864, PMCID: PMC11194860, DOI: 10.1007/s00125-022-05838-8.Peer-Reviewed Original ResearchConceptsProtein kinase CsSubcellular compartmentsDistinct subcellular localisationMuscle insulin sensitivityMultiple subcellular compartmentsInsulin receptor kinaseNovel protein kinase CsActivation of PKCεSubcellular localisationPKCθ translocationReceptor kinasePlasma membraneSubcellular distributionTriacylglycerol contentCrucial pathwaysIntramuscular triacylglycerol contentRC miceDiacylglycerolConclusions/interpretationThese resultsPKCεPM compartmentPhosphorylationMuscle triacylglycerol contentSkeletal muscleRecent findingsShort-term physical exercise controls age-related hyperinsulinemia and improves hepatic metabolism in aged rodents
Muñoz V, Gaspar R, Mancini M, de Lima R, Vieira R, Crisol B, Antunes G, Trombeta J, Bonfante I, Simabuco F, da Silva A, Cavaglieri C, Ropelle E, Cintra D, Pauli J. Short-term physical exercise controls age-related hyperinsulinemia and improves hepatic metabolism in aged rodents. Journal Of Endocrinological Investigation 2022, 46: 815-827. PMID: 36318449, DOI: 10.1007/s40618-022-01947-8.Peer-Reviewed Original ResearchConceptsInsulin sensitivityHepatic metabolismPhysical exerciseInsulin resistanceAerobic exerciseMetabolic healthAged rodentsShort-term aerobic exerciseAge-related insulin resistanceShort-term exercise trainingSignificant metabolic impairmentType 2 diabetesHepatic fat accumulationWhole-body glucoseDevelopment/progressionHepatic fat metabolismExercise trainingGlucose toleranceInsulin secretionFat accumulationHigh prevalenceHyperinsulinemic ratsMetabolic impairmentElderly populationGlucose homeostasisMetformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis
LaMoia TE, Butrico GM, Kalpage HA, Goedeke L, Hubbard BT, Vatner DF, Gaspar RC, Zhang XM, Cline GW, Nakahara K, Woo S, Shimada A, Hüttemann M, Shulman GI. Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2122287119. PMID: 35238637, PMCID: PMC8916010, DOI: 10.1073/pnas.2122287119.Peer-Reviewed Original ResearchConceptsGlucose-lowering effectPlasma glucose concentrationComplex I activityHepatic gluconeogenesisType 2 diabetes mellitusGlucose concentrationGlycerol-3-phosphate dehydrogenase activityI activityDiabetes mellitusSelective inhibitionMetforminInhibitionRelevant concentrationsGluconeogenesisPhenforminVivoMost studiesDehydrogenase activityGalegineMellitus
2021
Exercise Counterbalances Rho/ROCK2 Signaling Impairment in the Skeletal Muscle and Ameliorates Insulin Sensitivity in Obese Mice
Muñoz V, Gaspar R, Severino M, Macêdo A, Simabuco F, Ropelle E, Cintra D, da Silva A, Kim Y, Pauli J. Exercise Counterbalances Rho/ROCK2 Signaling Impairment in the Skeletal Muscle and Ameliorates Insulin Sensitivity in Obese Mice. Frontiers In Immunology 2021, 12: 702025. PMID: 34234788, PMCID: PMC8256841, DOI: 10.3389/fimmu.2021.702025.Peer-Reviewed Original ResearchConceptsSkeletal muscleInsulin receptor substrate-1Protein tyrosine phosphatase 1BSkeletal muscle glucose uptakeGlucose uptakeProtein kinase BReceptor substrate-1Muscle glucose uptakePhosphatase 1BRho kinase isoformsSubstrate-1Kinase BMolecular mechanismsSystemic glucose homeostasisTensin homologC2C12 myotubesAkt phosphorylationHigher phosphorylationMolecular analysisMuscle insulinInhibitory regulatorPotential targetRhoA-ROCK2PhosphorylationROCK2 proteinTime‐restricted feeding combined with aerobic exercise training can prevent weight gain and improve metabolic disorders in mice fed a high‐fat diet
Vieira R, Muñoz V, Junqueira R, de Oliveira F, Gaspar R, Nakandakari S, de Oliveira Costa S, Torsoni M, da Silva A, Cintra D, de Moura L, Ropelle E, Zaghloul I, Mekary R, Pauli J. Time‐restricted feeding combined with aerobic exercise training can prevent weight gain and improve metabolic disorders in mice fed a high‐fat diet. The Journal Of Physiology 2021, 600: 797-813. PMID: 33450053, DOI: 10.1113/jp280820.Peer-Reviewed Original ResearchConceptsTime-restricted feedingHigh-fat dietAerobic exercise trainingMale Swiss miceHigh-fat diet feedingFatty acid oxidationSwiss miceExercise trainingMetabolic disordersDiet feedingLiver metabolismAE trainingAcid oxidationLower serum triglyceridesHepatic lipid accumulationHepatic lipid contentImproved hepatic metabolismLipogenic gene expressionSerum triglyceridesAdiposity gainBody adiposityGlycaemic homeostasisInsulin sensitivityHepatic metabolismGlucose metabolismAn 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 ResearchConceptsBrown 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
Acute physical exercise increases PI3K‐p110α protein content in the hypothalamus of obese mice
Gaspar R, Nakandakari S, Muñoz V, Vieira R, da Silva A, Cintra D, de Moura L, Ropelle E, Pauli J. Acute physical exercise increases PI3K‐p110α protein content in the hypothalamus of obese mice. Journal Of Anatomy 2020, 238: 743-750. PMID: 33094520, PMCID: PMC7855078, DOI: 10.1111/joa.13342.Peer-Reviewed Original ResearchConceptsObese miceAcute exerciseFood intakePhysical exerciseCumulative food intakeBlood-brain barrierAcute physical exerciseEnergy homeostasis controlSuppressor of cytokineMain adipokinesHypothalamic nucleiPeripheral organsObese animalsLeptin signalingHypothalamusInsulin actionCentral signalingLeptinProtein levelsActivation of phosphoinositideMiceInsulin pathwayExerciseIntakeHomeostasis controlEffects of short-term physical training on the interleukin-15 signalling pathway and glucose tolerance in aged rats
Minuzzi L, da Conceição L, Muñoz V, Vieira R, Gaspar R, da Silva A, Cintra D, Pereira de Moura L, Ropelle E, Teixeira A, Pauli J. Effects of short-term physical training on the interleukin-15 signalling pathway and glucose tolerance in aged rats. Cytokine 2020, 137: 155306. PMID: 33010727, DOI: 10.1016/j.cyto.2020.155306.Peer-Reviewed Original ResearchConceptsAerobic physical trainingInsulin sensitivityIL-15Physical trainingGlucose toleranceInterleukin-15Elderly ratsWhole-body insulin sensitivityShort-term physical trainingSkeletal muscleLast exercise sessionExercise training protocolMesenteric fat massPhysical exercise trainingPhysical exercise protocolSkeletal muscle alterationsFourteen Wistar ratsExpression of HIF1αExercise trainingExercise protocolExercise sessionsMuscle alterationsFat massWistar ratsSupraphysiological levelsA Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance
Lyu K, Zhang Y, Zhang D, Kahn M, Ter Horst KW, Rodrigues MRS, Gaspar RC, Hirabara SM, Luukkonen PK, Lee S, Bhanot S, Rinehart J, Blume N, Rasch MG, Serlie MJ, Bogan JS, Cline GW, Samuel VT, Shulman GI. A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance. Cell Metabolism 2020, 32: 654-664.e5. PMID: 32882164, PMCID: PMC7544641, DOI: 10.1016/j.cmet.2020.08.001.Peer-Reviewed Original ResearchConceptsPlasma membraneEndoplasmic reticulumHigh-fat diet-induced hepatic insulin resistanceSubcellular fractionation methodInsulin receptor kinaseKey lipid speciesHepatic insulin resistanceDiet-induced hepatic insulin resistanceReceptor kinaseDiacylglycerol acyltransferase 2Molecular mechanismsAcute knockdownPhosphorylationLipid dropletsLipid speciesAcyltransferase 2KnockdownLiver-specific overexpressionDAG accumulationPKCϵDAG contentMembraneFractionation methodKinaseMitochondriaAging is associated with increased TRB3, ER stress, and hepatic glucose production in the liver of rats
Gaspar R, Muñoz V, Nakandakari S, Vieira R, da Conceição L, de Oliveira F, Crisol B, da Silva A, Cintra D, de Moura L, Ropelle E, Zaghloul I, Mekary R, Pauli J. Aging is associated with increased TRB3, ER stress, and hepatic glucose production in the liver of rats. Experimental Gerontology 2020, 139: 111021. PMID: 32659331, DOI: 10.1016/j.exger.2020.111021.Peer-Reviewed Original ResearchConceptsER stressEukaryotic translation initiation factorProtein kinase RNA-like endoplasmic reticulum kinaseRNA-like endoplasmic reticulum kinaseTranslation initiation factorPhosphorylation of inositolStress response regulationEndoplasmic reticulum kinaseEndoplasmic reticulum stress pathwayMammalian homologDrosophila tribblesEndoplasmic reticulum stressInitiation factorsProtein contentTRB3Multiple tissuesStress pathwaysImmunoglobulin proteinEnzymes of gluconeogenesisReticulum stressHepatic glucose productionEnzyme 1Response regulationMolecular changesPyruvate challenge