Rafael Calais Gaspar, PhD, MSc
Postdoctoral AssociateAbout
Research
Publications
2025
Cideb knockdown in mice increases mitochondrial fat oxidation and reverses hepatic steatosis and insulin resistance by the plasma membrane sn-1,2-DAGs–PKCε–insulin receptor kinaseT1150 pathway
Zheng J, Gaspar R, Sakuma I, Hubbard B, Zhang D, Nasiri A, Kahn M, Perelis M, Samuel V, Petersen K, Shulman G. Cideb knockdown in mice increases mitochondrial fat oxidation and reverses hepatic steatosis and insulin resistance by the plasma membrane sn-1,2-DAGs–PKCε–insulin receptor kinaseT1150 pathway. Diabetologia 2025, 1-15. PMID: 40908405, DOI: 10.1007/s00125-025-06539-8.Peer-Reviewed Original ResearchMitochondrial fat oxidationWhole-body energy expenditureTricarboxylic acidIn vivo rateHFD-induced hepatic steatosisHigh-fat dietHFD-induced insulin resistanceSteatotic liver diseaseAntisense oligonucleotidesHepatic lipogenesisHepatic mitochondrial oxidationHepatic insulin resistanceCidebHepatic steatosisComprehensive Lab Animal Monitoring SystemHigh-fat diet mouse modelInsulin resistanceMitochondrial oxidationMethodsC57BL/6J male miceRadio-labelled isotopesHyperinsulinaemic–euglycaemic clamp studiesKnockdownASO treatmentLipogenesisConclusions/interpretationThese findings1647-P: Coenzyme A Synthase Knockdown Increases Hepatic Mitochondrial Fat Oxidation and Reduces Hepatic Steatosis and Hepatic Insulin Resistance
GASPAR R, SAKUMA I, HUBBARD B, LAMOIA T, ZHENG J, PARIKH S, KAHN M, SILVEIRA L, DUFOUR S, NASIRI A, PERELIS M, PETERSEN K, SAMUEL V, SHULMAN G. 1647-P: Coenzyme A Synthase Knockdown Increases Hepatic Mitochondrial Fat Oxidation and Reduces Hepatic Steatosis and Hepatic Insulin Resistance. Diabetes 2025, 74 DOI: 10.2337/db25-1647-p.Peer-Reviewed Original ResearchHFD-fed miceAcetyl-CoAHepatic insulin resistanceHFD-fedHepatic acetyl-CoA contentMalonyl-CoA levelsCoenzyme A synthaseFatty acid synthesisHepatic acetyl-CoAAcetyl-CoA contentSteatotic liver diseasePathogenesis of type 2 diabetesHigh-fat dietTCA cycleMitochondrial fat oxidationWhole-body energy expenditureCoA biosynthesisHepatic steatosisAcid synthesisMetabolic pathwaysInsulin resistanceReduced hepatic steatosisDecreased hepatic steatosisCOASYTriacylglycerol contentLiver 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, PMCID: PMC12067271, 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 fibersDeterminants of increased muscle insulin sensitivity of exercise-trained versus sedentary normal weight and overweight individuals
Pesta D, Anadol-Schmitz E, Sarabhai T, Kamp Y, Gancheva S, Trinks N, Zaharia O, Mastrototaro L, Lyu K, Habets I, Kamp-Bruls Y, Dewidar B, Weiss J, Schrauwen-Hinderling V, Zhang D, Gaspar R, Strassburger K, Kupriyanova Y, Al-Hasani H, Szendroedi J, Schrauwen P, Phielix E, Shulman G, Roden M. Determinants of increased muscle insulin sensitivity of exercise-trained versus sedentary normal weight and overweight individuals. Science Advances 2025, 11: eadr8849. PMID: 39742483, PMCID: PMC11691647, DOI: 10.1126/sciadv.adr8849.Peer-Reviewed Original ResearchConceptsOverweight-to-obeseNormal weightEndurance-trained humansMuscle mitochondrial contentAthlete's paradoxTrained athletesExercise-trainedOverweight individualsAthletesObesity subtypesObservational studyIntramyocellular triglyceride accumulationInsulin sensitivityHigher insulin sensitivityMitochondrial contentIncreased insulin sensitivityMuscleFemale individualsIndividualsInsulin resistanceObesityMitochondrial partitioningIncreased calpainNPKC activityProtein kinase C
2024
SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts
Goedeke L, Ma Y, Gaspar R, Nasiri A, Lee J, Zhang D, Galsgaard K, Hu X, Zhang J, Guerrera N, Li X, LaMoia T, Hubbard B, Haedersdal S, Wu X, Stack J, Dufour S, Butrico G, Kahn M, Perry R, Cline G, Young L, Shulman G. SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts. Journal Of Clinical Investigation 2024, 134: e176708. PMID: 39680452, PMCID: PMC11645152, DOI: 10.1172/jci176708.Peer-Reviewed Original ResearchConceptsSodium-glucose cotransporter type 2Heart failureKetone oxidationGas chromatography-mass spectrometryFatty acid oxidationLeft ventricular ejection fractionReduced myocardial oxidative stressVentricular ejection fractionKetone supplementationWeeks of treatmentMyocardial oxidative stressDecreased pyruvate oxidationInduce heart failurePlasma glucose levelsIn vivo effectsSGLT2i treatmentEjection fractionAssociated with improvementsAwake ratsSGLT2 inhibitionCardioprotective benefitsLiquid chromatography-tandem mass spectrometryPlasma ketonesRates of ketonizationChromatography-tandem mass spectrometryCeramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway
Xu W, Zhang D, Ma Y, Gaspar R, Kahn M, Nasiri A, Murray S, Samuel V, Shulman G. Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway. Cell Reports 2024, 43: 114746. PMID: 39302831, DOI: 10.1016/j.celrep.2024.114746.Peer-Reviewed Original ResearchLipid-induced hepatic insulin resistanceHepatic insulin resistancePhosphorylation pathwayAntisense oligonucleotidesCeramide synthesis inhibitorsLipid-induced insulin resistanceMyriocin treatmentCeramide synthesisDihydroceramide desaturaseInsulin resistanceHepatic ceramideMyriocinCeramideCeramide contentInsulin-sensitizing effectsPhosphorylationHepatic insulin sensitivityPathwaySynthetic pathwayDES1Glucose productionSynthesis inhibitorDGAT2DesaturaseInhibitionEffect of Weight Loss on Skeletal Muscle Bioactive Lipids in People With Obesity and Type 2 Diabetes.
Petersen M, Yoshino M, Smith G, Gaspar R, Kahn M, Samovski D, Shulman G, Klein S. Effect of Weight Loss on Skeletal Muscle Bioactive Lipids in People With Obesity and Type 2 Diabetes. Diabetes 2024, 73: 2055-2064. PMID: 39264820, PMCID: PMC11579410, DOI: 10.2337/db24-0083.Peer-Reviewed Original ResearchMuscle insulin sensitivitySkeletal muscle insulin sensitivityType 2 diabetesEffects of weight lossInsulin sensitivityWeight lossWeight loss-induced improvementWhole-body insulin sensitivityObesityGlucose tracer infusionAssociated with changesHyperinsulinemic-euglycemic clamp procedureCeramide contentSn-1,2-DAGMuscleSmall molecule inhibition of glycogen synthase I reduces muscle glycogen content and improves biomarkers in a mouse model of Pompe disease
Gaspar R, Sakuma I, Nasiri A, Hubbard B, LaMoia T, Leitner B, Tep S, Xi Y, Green E, Ullman J, Petersen K, Shulman G. Small molecule inhibition of glycogen synthase I reduces muscle glycogen content and improves biomarkers in a mouse model of Pompe disease. AJP Endocrinology And Metabolism 2024, 327: e524-e532. PMID: 39171753, PMCID: PMC11482269, DOI: 10.1152/ajpendo.00175.2024.Peer-Reviewed Original ResearchGAA-KO miceMouse model of Pompe diseaseModel of Pompe diseasePompe diseaseMetabolic dysregulationRegular chowMouse modelSmall molecule inhibitionInsulin sensitivityReduced spontaneous activityGroups of male miceEnzyme acid alpha-glucosidaseProgressive muscle weaknessImprove metabolic dysregulationSynthase IWhole-body insulin sensitivityAcid alpha-glucosidaseImproved glucose toleranceIncreased AMPK phosphorylationWT miceAbnormal accumulation of glycogenGlycogen storage disorderMale miceSpontaneous activityImproved biomarkers
News
News
- July 29, 2025
Study Reveals Cholesterol’s Role in Fibrotic Progression of Metabolic Liver Disease
- February 18, 2025
What Makes a Successful Heart Failure Drug Work?
- September 14, 2023
Organ Systems Respond Uniquely to Fight Sepsis
- April 04, 2023
Researchers Demonstrate New Protective Process Against Liver Fibrosis in NASH
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