2023
MAD2-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 ResearchMeSH KeywordsAnimalsEndocytosisGlucoseHomeostasisInsulinInsulin ResistanceLiverMad2 ProteinsMaleMiceReceptor, InsulinConceptsIR endocytosisInsulin receptor endocytosisCell division regulatorsInsulin receptorProlongs insulin actionReceptor endocytosisTranscriptomic profilesInsulin stimulationEndocytosisMetabolic homeostasisCell surfaceGenetic ablationMetabolic functionsInsulin actionP31cometMad2BubR1DisruptionSignalingRegulatorHomeostasisAdipose tissueInteractionHepatic fat accumulationMetabolismEffects 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 ResearchMeSH KeywordsAnimalsDiabetes Mellitus, Type 2GlucoseGlucose Transporter Type 4HyperglycemiaInsulin ResistanceMiceMuscle, SkeletalConceptsWhole-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 function
2022
Distinct 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 homeostasis
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 ResearchMeSH KeywordsAnimalsDiet, High-FatInsulin ResistanceLiverMaleMetabolic DiseasesMiceMice, Inbred C57BLObesityWeight GainConceptsTime-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 metabolism
2020
Effects 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 methodKinaseMitochondriaPhysical exercise increases ROCK activity in the skeletal muscle of middle-aged rats
Muñoz V, Gaspar R, Esteca M, Baptista I, Vieira R, da Silva A, de Moura L, Cintra D, Ropelle E, Pauli J. Physical exercise increases ROCK activity in the skeletal muscle of middle-aged rats. Mechanisms Of Ageing And Development 2020, 186: 111213. PMID: 32032622, DOI: 10.1016/j.mad.2020.111213.Peer-Reviewed Original ResearchConceptsMiddle-aged ratsSoleus musclePhysical exerciseGlucose homeostasisAge-related metabolic disordersSkeletal muscle glucose uptakeSkeletal muscleImpaired glucose homeostasisType 2 diabetesMuscle glucose uptakeInsulin receptor substrate-1 phosphorylationWhole-body glucose homeostasisROCK activitySkeletal muscle fiber typesMuscle fiber typesInsulin resistanceSedentary ratsHigh insulinDifferent skeletal muscle fiber typesMetabolic disordersMetabolism-related genesPharmacological inhibitionRatsGlucose uptakeMuscle
2019
Rho-kinase activity is upregulated in the skeletal muscle of aged exercised rats
Muñoz V, Gaspar R, Minuzzi L, Dos Santos Canciglieri R, da Silva A, de Moura L, Cintra D, Ropelle E, Pauli J. Rho-kinase activity is upregulated in the skeletal muscle of aged exercised rats. Experimental Gerontology 2019, 128: 110746. PMID: 31629802, DOI: 10.1016/j.exger.2019.110746.Peer-Reviewed Original ResearchShort-term Resistance Training Increases APPL1 Content in the Liver and the Insulin Sensitivity of Mice Fed a Long-term High-fat Diet
Minuzzi L, Kuga G, Breda L, Gaspar R, Muñoz V, Pereira R, Botezelli J, da Silva A, Cintra D, de Moura L, Ropelle E, Pauli J. Short-term Resistance Training Increases APPL1 Content in the Liver and the Insulin Sensitivity of Mice Fed a Long-term High-fat Diet. Experimental And Clinical Endocrinology & Diabetes 2019, 128: 30-37. PMID: 30991419, DOI: 10.1055/a-0885-9872.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsDietary FatsInsulin ResistanceLiverMicePhysical Conditioning, AnimalTime FactorsConceptsLong-term high-fat dietShort-term resistance trainingHigh-fat dietResistance trainingInsulin sensitivityHigh calorie intakeLiver of miceAdiponectin pathwayChow dietMice fedInsulin resistanceGlycemic homeostasisSwiss miceAdiponectin receptorsPhysical activityPhysical exerciseInsulin actionHepatic tissueMiceLiverDietAdiponectinInadequate levelsAdverse consequencesCritical regulator
2018
Unsaturated fatty acids from flaxseed oil and exercise modulate GPR120 but not GPR40 in the liver of obese mice: a new anti-inflammatory approach
Gaspar R, Veiga C, Bessi M, Dátilo M, Sant'Ana M, Rodrigues P, de Moura L, da Silva A, Santos G, Catharino R, Ropelle E, Pauli J, Cintra D. Unsaturated fatty acids from flaxseed oil and exercise modulate GPR120 but not GPR40 in the liver of obese mice: a new anti-inflammatory approach. The Journal Of Nutritional Biochemistry 2018, 66: 52-62. PMID: 30771734, DOI: 10.1016/j.jnutbio.2018.12.003.Peer-Reviewed Original ResearchConceptsHigh-fat dietPhysical exerciseObese miceNew anti-inflammatory approachesFlaxseed oilAnti-inflammatory approachesAnti-inflammatory propertiesChronic physical exerciseImpact of exerciseType 2 diabetesInflammatory markersInflammatory responseExercise performanceHepatic metabolismGPR120Fat depotsSources of ω3GPR40ObesityLiverΒ-arrestinMiceRelated cascadesExerciseInsulinAcute physical exercise increases the adaptor protein APPL1 in the hypothalamus of obese mice
Gaspar R, Muñoz V, Formigari G, Kuga G, Nakandakari S, Botezelli J, da Silva A, Cintra D, de Moura L, Ropelle E, Pauli J. Acute physical exercise increases the adaptor protein APPL1 in the hypothalamus of obese mice. Cytokine 2018, 110: 87-93. PMID: 29705396, DOI: 10.1016/j.cyto.2018.04.013.Peer-Reviewed Original ResearchConceptsAcute physical exerciseObese micePhysical exerciseFood intakeArcuate proopiomelanocortin neuronsSerum adiponectin levelsProtein-3 levelsEffects of leptinCentral nervous systemRole of APPL1Proopiomelanocortin neuronsAdiponectin levelsAcute exerciseNervous systemHypothalamusPathophysiological processesAdiponectinAdaptor protein APPL1MiceProtein kinase BLeucine zipper motif 1Kinase BExerciseIntakeProtein contentExercise decreases CLK2 in the liver of obese mice and prevents hepatic fat accumulation
Muñoz V, Gaspar R, Kuga G, Nakandakari S, Baptista I, Mekary R, da Silva A, de Moura L, Ropelle E, Cintra D, Pauli J. Exercise decreases CLK2 in the liver of obese mice and prevents hepatic fat accumulation. Journal Of Cellular Biochemistry 2018, 119: 5885-5892. PMID: 29575149, DOI: 10.1002/jcb.26780.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseObesity conditionsPrevention of NAFLDPhysical exerciseImpaired fat oxidationFatty liver diseaseMetabolic syndrome riskChronic physical exerciseHepatic fat accumulationAcid oxidationFatty acid oxidationObese groupLiver diseaseObese miceSwiss miceSyndrome riskFat accumulationObese animalsHepatic metabolismFat oxidationHepatic ketogenesisBeneficial effectsElevated levelsPotent strategyMiceImpaired insulin signaling and spatial learning in middle-aged rats: The role of PTP1B
Kuga G, Muñoz V, Gaspar R, Nakandakari S, da Silva A, Botezelli J, Leme J, Gomes R, de Moura L, Cintra D, Ropelle E, Pauli J. Impaired insulin signaling and spatial learning in middle-aged rats: The role of PTP1B. Experimental Gerontology 2018, 104: 66-71. PMID: 29421605, DOI: 10.1016/j.exger.2018.02.005.Peer-Reviewed Original ResearchConceptsMiddle-aged ratsBrain-derived neurotrophic factorΒ-amyloid contentAlzheimer's diseaseInsulin resistanceTau phosphorylationMorris water maze testMiddle-aged Wistar ratsInsulin tolerance testMain risk factorsAge-related changesNeurotrophic factorTolerance testRisk factorsMaze testImpaired insulinWistar ratsNew therapiesHippocampus regionBody weightCognitive declineRole of PTP1BSynaptic plasticityRatsSpatial learningExercise increases Rho‐kinase activity and insulin signaling in skeletal muscle
Muñoz V, Gaspar R, Kuga G, da Rocha A, Crisol B, Botezelli J, Baptista I, Mekary R, da Silva A, Cintra D, de Moura L, Ropelle E, Pauli J. Exercise increases Rho‐kinase activity and insulin signaling in skeletal muscle. Journal Of Cellular Physiology 2018, 233: 4791-4800. PMID: 29219181, DOI: 10.1002/jcp.26278.Peer-Reviewed Original Research
2017
High Dosage of Vitamin D Regulates the Energy Metabolism and Increases Insulin Sensitivity, but are Associated with High Levels of Kidney Damage
Gaspar R, Botezelli J, Kuga G, Muñoz V, Coope A, Pereira R, da Silva A, Cintra D, de Moura L, Ropelle E, Pauli J. High Dosage of Vitamin D Regulates the Energy Metabolism and Increases Insulin Sensitivity, but are Associated with High Levels of Kidney Damage. Drug Development Research 2017, 78: 203-209. PMID: 28718949, DOI: 10.1002/ddr.21394.Peer-Reviewed Original ResearchConceptsMetabolic disordersHigh dosesRole of VitDVitamin D deficiencyImportant therapeutic targetD deficiencyRenal damageObese miceC57BL/6J miceInsulin sensitivityMetabolic benefitsTherapeutic strategiesTherapeutic targetVitDMiceDosesBody massDisordersLarge proportionCalcitriolObeseKidneyDiseaseDoseAdministration