2024
High-fat-diet-induced hepatic insulin resistance per se attenuates murine de novo lipogenesis
Goedeke L, Strober J, Suh R, Paolella L, Li X, Rogers J, Petersen M, Nasiri A, Casals G, Kahn M, Cline G, Samuel V, Shulman G, Vatner D. High-fat-diet-induced hepatic insulin resistance per se attenuates murine de novo lipogenesis. IScience 2024, 27: 111175. DOI: 10.1016/j.isci.2024.111175.Peer-Reviewed Original ResearchDuration of high-fat dietAttenuated insulin signalingHigh-fat dietHepatic insulin resistanceInsulin signalingInsulin stimulationLipogenic substrateStimulation of de novo lipogenesisReduced lipogenesisHFD feedingReduce DNLInsulin resistanceResistance per seLipogenesisInsulin resistance per sePathway selectionGlucose metabolismHepatic IRMiceFat dietSREBP1cINSRSmall molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation
Mutlu B, Sharabi K, Sohn J, Yuan B, Latorre-Muro P, Qin X, Yook J, Lin H, Yu D, Camporez J, Kajimura S, Shulman G, Hui S, Kamenecka T, Griffin P, Puigserver P. Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation. Cell Chemical Biology 2024, 31: 1772-1786.e5. PMID: 39341205, PMCID: PMC11500315, DOI: 10.1016/j.chembiol.2024.09.001.Peer-Reviewed Original ResearchPhosphoenolpyruvate carboxykinase 1Lysine acetylationTricarboxylic acidAnti-diabetic effectsAnaplerotic reactionsGluconeogenic reactionsLiver-specific expressionGluconeogenic metabolitesLactate oxidationSmall moleculesAnti-diabetic actionSuppressed gluconeogenesisHepatic glucose productionPGC-1aAcetylationOxaloacetateGluconeogenesisObese miceGlucose productionIncreased glucoseGlucose oxidationSubstrate oxidationOxidationGlucoseMutantsCeramide 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 PMID: 39264820, 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-DAGMuscleThe mouse metabolic phenotyping center (MMPC) live consortium: an NIH resource for in vivo characterization of mouse models of diabetes and obesity
Laughlin M, McIndoe R, Adams S, Araiza R, Ayala J, Kennedy L, Lanoue L, Lantier L, Macy J, Malabanan E, McGuinness O, Perry R, Port D, Qi N, Elias C, Shulman G, Wasserman D, Lloyd K. The mouse metabolic phenotyping center (MMPC) live consortium: an NIH resource for in vivo characterization of mouse models of diabetes and obesity. Mammalian Genome 2024, 35: 485-496. PMID: 39191872, PMCID: PMC11522164, DOI: 10.1007/s00335-024-10067-y.Peer-Reviewed Original ResearchMouse Metabolic Phenotyping CentersMouse model of diabetesModels of diabetesNational Institutes of HealthNational Institute for DiabetesDigestive and Kidney DiseasesBehavioral phenotyping testsRenal functionProcedure in vivoFood intakeIn vivo characterizationMouse modelHeterogeneity of diabetesKidney diseaseBody compositionPhenotyping CentersInstitutes of HealthMiceObesityDiabetesPhenotypic testsWhole-body carbohydrateInsulin actionLipid metabolismLiving miceSmall 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 biomarkersGlucagon promotes increased hepatic mitochondrial oxidation and pyruvate carboxylase flux in humans with fatty liver disease
Petersen K, Dufour S, Mehal W, Shulman G. Glucagon promotes increased hepatic mitochondrial oxidation and pyruvate carboxylase flux in humans with fatty liver disease. Cell Metabolism 2024 PMID: 39197461, DOI: 10.1016/j.cmet.2024.07.023.Peer-Reviewed Original ResearchCytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation
LaMoia T, Hubbard B, Guerra M, Nasiri A, Sakuma I, Kahn M, Zhang D, Goodman R, Nathanson M, Sancak Y, Perelis M, Mootha V, Shulman G. Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation. Cell Metabolism 2024, 36: 2329-2340.e4. PMID: 39153480, PMCID: PMC11446666, DOI: 10.1016/j.cmet.2024.07.016.Peer-Reviewed Original ResearchO-GlcNAc modification in endothelial cells modulates adiposity via fat absorption from the intestine in mice
Ohgaku S, Ida S, Ohashi N, Morino K, Ishikado A, Yanagimachi T, Murata K, Sato D, Ugi S, Nasiri A, Shulman G, Maegawa H, Kume S, Fujita Y. O-GlcNAc modification in endothelial cells modulates adiposity via fat absorption from the intestine in mice. Heliyon 2024, 10: e34490. PMID: 39130439, PMCID: PMC11315187, DOI: 10.1016/j.heliyon.2024.e34490.Peer-Reviewed Original ResearchEndothelial cellsHigh-fat dietControl miceLipid absorptionExpression of VEGFR3Body weightNitric oxide donorReduced body weightKnockout miceTherapeutic strategiesOxide donorDecreased expressionIntercellular junctionsMiceHigh-fatNutrient-sensing mechanismsFat absorptionO-GlcNAcylationGlucose metabolismVE-cadherinMorphological alterationsMetabolic regulatory mechanismsJunction morphologyLipid metabolismO-GlcNAc transferase1571-P: CIDEB and CGI-58 Regulate Liver Lipid Droplet Size with Cholesterol Content, Linking to Inflammation and Fibrosis in Metabolic Dysfunction–Associated Steatohepatitis
SAKUMA I, GASPAR R, NASIRI A, KAHN M, ZHENG J, GUERRA M, YIMLAMAI D, MURRAY S, PERELIS M, BARNES W, VATNER D, PETERSEN K, SAMUEL V, SHULMAN G. 1571-P: CIDEB and CGI-58 Regulate Liver Lipid Droplet Size with Cholesterol Content, Linking to Inflammation and Fibrosis in Metabolic Dysfunction–Associated Steatohepatitis. Diabetes 2024, 73 DOI: 10.2337/db24-1571-p.Peer-Reviewed Original ResearchLipid droplet sizeCGI-58Choline-deficient l-amino acid-defined high-fat dietGlycerol-3-phosphate acyltransferaseAntisense oligonucleotidesComparative gene identification-58Glycerol-3-phosphateLoss of function mutationsLipid droplet morphologyExpression of CGI-58Liver inflammationCidebCholesterol contentFunction mutationsL-amino acid-defined high-fat dietComplications of type 2 diabetesMolecular mechanismsDevelopment of liver inflammationMacrophage crown-like structuresType 2 diabetesHigh-fat dietCrown-like structuresASO treatmentGPAMKnockdown292-OR: Coenzyme A Synthase Knockdown Alleviates Metabolic Dysfunction–Associated Steatohepatitis via Decreasing Cholesterol in Liver Lipid Droplets
SAKUMA I, GASPAR R, NASIRI A, KAHN M, GUERRA M, YIMLAMAI D, MURRAY S, PERELIS M, BARNES W, VATNER D, PETERSEN K, SAMUEL V, SHULMAN G. 292-OR: Coenzyme A Synthase Knockdown Alleviates Metabolic Dysfunction–Associated Steatohepatitis via Decreasing Cholesterol in Liver Lipid Droplets. Diabetes 2024, 73 DOI: 10.2337/db24-292-or.Peer-Reviewed Original ResearchCholine-deficient l-amino acid-defined high-fat dietAccumulation of cholesterolMRNA expressionPlasma ALTL-amino acid-defined high-fat dietProtective effectLiver lipid dropletsType 2 diabetesPotential therapeutic approachHigh-fat dietDecreased plasma ALTFibrosis markersFree cholesterol accumulationLipid dropletsLiver inflammationDay 1Macrophage markersHepatic inflammationMouse modelMarker expressionTherapeutic approachesDay 2Day 3Day 7Fibrosis1577-P: CIDEB Knockdown Promotes Increased Hepatic Mitochondrial Fat Oxidation and Reverses Hepatic Steatosis and Hepatic Insulin Resistance by the PKCε-Insulin Receptor Kinase Pathway
ZHENG J, NASIRI A, GASPAR R, HUBBARD B, SAKUMA I, MA X, MURRAY S, PERELIS M, BARNES W, SAMUEL V, PETERSEN K, SHULMAN G. 1577-P: CIDEB Knockdown Promotes Increased Hepatic Mitochondrial Fat Oxidation and Reverses Hepatic Steatosis and Hepatic Insulin Resistance by the PKCε-Insulin Receptor Kinase Pathway. Diabetes 2024, 73 DOI: 10.2337/db24-1577-p.Peer-Reviewed Original ResearchReceptor kinase pathwaysMitochondrial fat oxidationHepatic insulin resistanceKinase pathwayExpression of cidebAmeliorated HFD-induced hepatic steatosisHFD-induced hepatic steatosisHFD-induced insulin resistanceSteatotic liver diseasePathogenesis of type 2 diabetesHepatic steatosisCidebHyperinsulinemic-euglycemic clamp studiesHepatic triglyceride accumulationInsulin resistanceReverse hepatic steatosisTriglyceride accumulationHepatic insulin sensitivityInsulin sensitivityPathwayHepatic expressionHigh-fatWhole-body insulin sensitivityLiver diseaseTranslocation899-P: Combinations of the Mitochondrial Protonophore TLC-6740 and/or the ACC2 Inhibitor TLC-3595 Provide Additive Glycemic Benefits to Semaglutide (SEMA) in db/db Mice
VIJAYAKUMAR A, SRODA N, MURAKAMI E, WENG S, MYERS R, SUBRAMANIAN M, SHULMAN G. 899-P: Combinations of the Mitochondrial Protonophore TLC-6740 and/or the ACC2 Inhibitor TLC-3595 Provide Additive Glycemic Benefits to Semaglutide (SEMA) in db/db Mice. Diabetes 2024, 73 DOI: 10.2337/db24-899-p.Peer-Reviewed Original ResearchOral glucose tolerance testGLP-1R agonistsDb/db miceIncremental AUCGlucose tolerance testMale db/db miceImproved glucose toleranceSemaglutide groupGlycemic parametersSemaglutideTolerance testFood intakeGlucose toleranceGLP-1RLiver-targeted mitochondrial uncouplerDb/dbMiceGlucose bolusVEHAgonistsEvaluation of combinationsHbA1cDiabetesMitochondrial uncouplingAssess effects1886-LB: Safety, PK, and Preliminary Efficacy of the Liver-Targeted Mitochondrial Protonophore TLC-6740—A Phase 1 Study
GANE E, HUSS R, SUR J, MURAKAMI E, WENG S, KIRBY B, SHAH A, SHULMAN G, SUBRAMANIAN M, VIJAYAKUMAR A, MYERS R. 1886-LB: Safety, PK, and Preliminary Efficacy of the Liver-Targeted Mitochondrial Protonophore TLC-6740—A Phase 1 Study. Diabetes 2024, 73 DOI: 10.2337/db24-1886-lb.Peer-Reviewed Original ResearchTreatment of obesityAdverse eventsSteady-state half-lifeEvaluate food effectsPhase 1 studyDose-dependent improvementDose-dependent reductionProportion of subjectsUnrelated to treatmentDose-dependent mannerMAD cohortsLab abnormalitiesSerum totalLDL-CFood effectHealthy subjectsClinical useWeight lossImpact of foodBody weightPreliminary efficacyObesityHalf-lifeTreatmentMitochondrial uncoupling1637-P: TLC-6740, a Liver-Targeted Mitochondrial Protonophore, Increases Energy Expenditure and Lipid Utilization in Obese Mice
SRODA N, VIJAYAKUMAR A, MURAKAMI E, WENG S, SHULMAN G, MYERS R, SUBRAMANIAN M. 1637-P: TLC-6740, a Liver-Targeted Mitochondrial Protonophore, Increases Energy Expenditure and Lipid Utilization in Obese Mice. Diabetes 2024, 73 DOI: 10.2337/db24-1637-p.Peer-Reviewed Original ResearchEnergy intakeWeight lossEnergy expenditureRespiratory exchange ratioMitochondrial protonophoreObese miceDose-dependent weight lossReduced oral intakeData support evaluationDays of dosingC57 BL/6 miceDiet-induced obese miceNegative energy balanceMale C57 BL/6 miceIncreased energy expenditureWhole-body lipid utilizationCompared to pre-treatmentHigh-fat dietOral intakePO BIDBL/6 miceIndirect calorimetryMetabolic benefitsLipid utilizationVEHCardiometabolic characteristics of people with metabolically healthy and unhealthy obesity
Petersen M, Smith G, Palacios H, Farabi S, Yoshino M, Yoshino J, Cho K, Davila-Roman V, Shankaran M, Barve R, Yu J, Stern J, Patterson B, Hellerstein M, Shulman G, Patti G, Klein S. Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity. Cell Metabolism 2024, 36: 745-761.e5. PMID: 38569471, PMCID: PMC11025492, DOI: 10.1016/j.cmet.2024.03.002.Peer-Reviewed Original ResearchConceptsUnhealthy obesityPlasma PAI-1 concentrationAbnormalities associated with obesityMetabolically healthy obesityMetabolically unhealthy obesityPAI-1 concentrationsMetabolic heterogeneity of obesityHeterogeneity of obesityMetabolically healthy leanSystemic metabolic functionCharacteristics of peopleDecreased oxidative stressHealthy obesityCardiometabolic characteristicsAdipose tissue biologyHealthy leanSkeletal muscle biologyPlasma adiponectinPlasma glucoseObesityMetabolic heterogeneityOxidative stressPotential mechanismsTissue biologyMuscle biologyInsulin Resistance in Type 2 Diabetes
Roden M, Petersen K, Shulman G. Insulin Resistance in Type 2 Diabetes. 2024, 238-249. DOI: 10.1002/9781119697473.ch17.Peer-Reviewed Original Research
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 ResearchAuthor Correction: Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner
Pajvani U, Shawber C, Samuel V, Birkenfeld A, Shulman G, Kitajewski J, Accili D. Author Correction: Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner. Nature Medicine 2023, 30: 604-604. PMID: 38041001, DOI: 10.1038/s41591-023-02695-9.Peer-Reviewed Original ResearchThe PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans
Luukkonen P, Porthan K, Ahlholm N, Rosqvist F, Dufour S, Zhang X, Lehtimäki T, Seppänen W, Orho-Melander M, Hodson L, Petersen K, Shulman G, Yki-Järvinen H. The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans. Cell Metabolism 2023, 35: 1887-1896.e5. PMID: 37909034, DOI: 10.1016/j.cmet.2023.10.008.Peer-Reviewed Original ResearchConceptsDe novo lipogenesisHepatic de novo lipogenesisPlasma β-hydroxybutyrate concentrationsΒ-hydroxybutyrate concentrationsLiver diseaseNovo lipogenesisPNPLA3 I148M variantHepatic mitochondrial redox stateMajor genetic risk factorI148M variantFatty liver diseaseGenetic risk factorsHepatic mitochondrial dysfunctionKetogenic dietMixed mealRisk factorsHepatic metabolismHomozygous carriersM carriersMitochondrial dysfunctionCitrate synthase fluxM variantKetogenesisMitochondrial redox stateMitochondrial function