2023
Time-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 accumulationMetabolismInhibition 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
Q-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 ResearchShort-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
Time‐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 metabolism
2020
A 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
2019
Short-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 ResearchConceptsLong-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 cascadesExerciseInsulinPhysical training reverses changes in hepatic mitochondrial diameter of Alloxan-induced diabetic rats
Kuga G, Gaspar R, Muñoz V, Nakandakari S, Breda L, Sandoval B, Caetano F, de Almeida Leme J, Pauli J, Gomes R. Physical training reverses changes in hepatic mitochondrial diameter of Alloxan-induced diabetic rats. Einstein (São Paulo) 2018, 16: eao4353. PMID: 30088548, PMCID: PMC6110382, DOI: 10.1590/s1679-45082018ao4353.Peer-Reviewed Original ResearchConceptsDiabetic ratsBody weightDiabetic groupSedentary diabeticDiabetic animalsPhysical trainingSedentary diabetic animalsPhysical training protocolMitochondrial diameterDiabetes mellitusAlloxan administrationBlood insulinExercise protocolSerum glucoseSedentary controlsWistar ratsHepatic metabolismReverses changesLiver glycogenHepatic glycogenDiabeticsRatsMeasurements of glycogenLiver samplesTraining protocolExercise 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 strategyMice
2017
Physical exercise reduces pyruvate carboxylase (PCB) and contributes to hyperglycemia reduction in obese mice
Muñoz V, Gaspar R, Crisol B, Formigari G, Sant’Ana M, Botezelli J, Gaspar R, da Silva A, Cintra D, de Moura L, Ropelle E, Pauli J. Physical exercise reduces pyruvate carboxylase (PCB) and contributes to hyperglycemia reduction in obese mice. The Journal Of Physiological Sciences 2017, 68: 493-501. PMID: 28710665, PMCID: PMC10717866, DOI: 10.1007/s12576-017-0559-3.Peer-Reviewed Original ResearchConceptsDiet-induced obesityObesity-inducing dietInsulin tolerance testObese micePhysical exerciseDIO miceExercise trainingControl miceHepatic tissueStandard rodent chowDevelopment of hyperglycemiaExercise training protocolType 2 diabetesTreadmill running protocolPhysical exercise sessionGlucose homeostasis controlEXE miceHyperglycemia reductionObese conditionsRodent chowTolerance testSerum glucoseSwiss miceExercise sessionsEpididymal fat