2025
Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis
Sakuma I, Gaspar R, Nasiri A, Dufour S, Kahn M, Zheng J, LaMoia T, Guerra M, Taki Y, Kawashima Y, Yimlamai D, Perelis M, Vatner D, Petersen K, Huttasch M, Knebel B, Kahl S, Roden M, Samuel V, Tanaka T, Shulman G. Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2502978122. PMID: 40310463, DOI: 10.1073/pnas.2502978122.Peer-Reviewed Original ResearchConceptsCholine-deficient l-amino acid-defined high-fat dietBempedoic acidLiver fibrosisLiver diseaseL-amino acid-defined high-fat dietAdvanced liver diseaseCholesterol contentHSD17B13 variantsHigh-fat dietTotal liver cholesterol contentTreated miceActivate signaling pathwaysVariant rs738409Liver cholesterol contentLiver lipidsFibrotic responsePromote inflammationTherapeutic approachesSteatotic liver diseaseDietary cholesterol supplementationFibrosisHuman liver samplesI148MAntisense oligonucleotidesProgressive formNotch1 Signalling Is Downregulated by Aerobic Exercise, Leading to Improvement of Hepatic Metabolism in Obese Mice
Gaspar R, Macêdo A, Nakandakari S, Muñoz V, Abud G, Vieira R, de Sousa Neto I, Pavan I, da Silva L, Simabuco F, da Silva A, Salgado W, Marchini J, Nonino C, Cintra D, Ropelle E, Pajvani U, de Freitas E, Pauli J. Notch1 Signalling Is Downregulated by Aerobic Exercise, Leading to Improvement of Hepatic Metabolism in Obese Mice. Liver International 2025, 45: e70068. PMID: 40078075, DOI: 10.1111/liv.70068.Peer-Reviewed Original ResearchConceptsNotch1 signalingAerobic exerciseRegulation of hepatic glucoseObese miceImpact of aerobic exerciseEffects of Notch1 signalingAerobic exercise trainingMTORC1 pathway activationNotch1 pathwayObese individualsTissue of obese miceCross-sectional studyNotch1 mRNA levelsMitochondrial respirationExercise trainingLivers of obese individualsTreadmill runningGluconeogenic enzymesHepG2 cell lineLipid accumulationTraining groupHepatic glucoseHepatic metabolismNotch1 proteinPathway activationTime-restricted feeding reduces inflammatory markers and downregulates JAG1 and NICD protein levels in the liver of aged mice
Macêdo A, de Sousa Neto I, Antonio G, Gaspar R, de Lima R, Dias L, Vieira R, Muñoz V, Brunelli D, da Silva A, Cintra D, Ropelle E, Pauli J. Time-restricted feeding reduces inflammatory markers and downregulates JAG1 and NICD protein levels in the liver of aged mice. Nutrition 2025, 133: 112691. PMID: 39983606, DOI: 10.1016/j.nut.2025.112691.Peer-Reviewed Original ResearchConceptsRNA-seq datasetsNotch1 intracellular domainMitochondrial respirationTime-restricted feedingAged miceInflammatory markersAd libitum dietIntracellular domainHepatic mitochondrial respirationATP productionLiver mitochondrial respirationCellular longevityLiver of aged miceLibitum dietDisease Activity ScoreCompared to adult animalsNotch1 signalingProtein contentTime-restricted feeding protocolsUpregulation of Notch1Investigated metabolic parametersProtein levelsNotch1Adult miceCollagen fibers
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 factorsShort-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 ResearchMeSH KeywordsAdipose TissueAnimalsDiet, High-FatFatty Acids, Omega-3GlucoseInflammationLinseed OilMiceMice, Inbred C57BLConceptsControl 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 consumption
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 findings
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 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
2019
Tlr4 participates in the responses of markers of apoptosis, inflammation, and ER stress to different acute exercise intensities in mice hearts
de Vicente L, Pinto A, Muñoz V, Rovina R, da Rocha A, Gaspar R, da Silva L, Simabuco F, Frantz F, Pauli J, de Moura L, Cintra D, Ropelle E, da Silva A. Tlr4 participates in the responses of markers of apoptosis, inflammation, and ER stress to different acute exercise intensities in mice hearts. Life Sciences 2019, 240: 117107. PMID: 31785241, DOI: 10.1016/j.lfs.2019.117107.Peer-Reviewed Original ResearchConceptsAcute exercise intensityAcute physical exerciseLeft ventricleTLR4 deletionIL-17Serum levelsTNF-alphaPhysical exerciseExercise intensityER stressToll-like receptor 4Heart mRNA levelsSame exercise conditionTLR4 KO miceRole of TLR4Myocardium of miceExpression of inflammationResponse of markersEndoplasmic reticulum stressKO miceReceptor 4CK-MBImmune responseInflammationER stress genesNAD+ precursor increases aerobic performance in mice
Crisol B, Veiga C, Braga R, Lenhare L, Baptista I, Gaspar R, Muñoz V, Cordeiro A, da Silva A, Cintra D, Moura L, Pauli J, Ropelle E. NAD+ precursor increases aerobic performance in mice. European Journal Of Nutrition 2019, 59: 2427-2437. PMID: 31494696, DOI: 10.1007/s00394-019-02089-z.Peer-Reviewed Original ResearchMeSH KeywordsAerobiosisAnimalsCell RespirationMaleMiceMice, Inbred C57BLMitochondriaMuscle, SkeletalNADNiacinamidePyridinium CompoundsConceptsNR supplementationSkeletal muscleMitochondrial markersMitochondrial proteinsTranscriptomic analysisRate-limiting enzymePhysiological assaysMitochondrial metabolismMitochondrial biogenesisMitochondrial oxidative capacityBXD miceIsogenic strainsDifferent phenotypesProtein contentMolecular assaysAerobic performanceOxidative capacityMuscle metabolismMetabolismBiogenesisMTCO1AssaysLarge panelBiosynthesisGenesExhaustive acute exercise-induced ER stress is attenuated in IL-6-knockout mice
Pinto A, da Rocha A, Kohama E, Gaspar R, Simabuco F, Frantz F, de Moura L, Pauli J, Cintra D, Ropelle E, de Freitas E, da Silva A. Exhaustive acute exercise-induced ER stress is attenuated in IL-6-knockout mice. Journal Of Endocrinology 2019, 240: 181-193. PMID: 30400033, DOI: 10.1530/joe-18-0404.Peer-Reviewed Original ResearchConceptsIL-6 knockout miceExtensor digitorium longusPhysical exercise protocolAcute exercise protocolER stress proteinsExercise protocolIL-6WT groupIL-6 KO groupSerum levelsKO groupExercise-induced IL-6IL-6 concentrationsWild-type miceIntense physical exerciseER stressEndoplasmic reticulum stressStress proteinsIL-10Interleukin-6Knockout micePhysical exerciseSoleusHomeostatic functionsMice
2018
Exercise 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
The role of physical exercise on Sestrin1 and 2 accumulations in the skeletal muscle of mice
Crisol B, Lenhare L, Gaspar R, Gaspar R, Muñoz V, da Silva A, Cintra D, de Moura L, Pauli J, Ropelle E. The role of physical exercise on Sestrin1 and 2 accumulations in the skeletal muscle of mice. Life Sciences 2017, 194: 98-103. PMID: 29273527, DOI: 10.1016/j.lfs.2017.12.023.Peer-Reviewed Original ResearchConceptsStress-related proteinsThreonine phosphorylationBXD miceSkeletal muscleSesn2 mRNATranscriptomic analysisProtein contentBioinformatics analysisIsogenic strainsSestrin 1SestrinsSESN1Phenotypic patternsSestrin1Sestrin2 expressionPhosphorylationMRNA levelsWestern blotProteinNew insightsExperimental approachBasal levelsLarge panelAccumulationMice
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