2023
The 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
2022
Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice
Bhat N, Narayanan A, Fathzadeh M, Kahn M, Zhang D, Goedeke L, Neogi A, Cardone RL, Kibbey RG, Fernandez-Hernando C, Ginsberg HN, Jain D, Shulman G, Mani A. Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice. Journal Of Clinical Investigation 2022, 132: e153724. PMID: 34855620, PMCID: PMC8803348, DOI: 10.1172/jci153724.Peer-Reviewed Original ResearchConceptsDe novo lipogenesisNonalcoholic steatohepatitisInsulin resistanceHepatic lipogenesisElevated de novo lipogenesisNonalcoholic fatty liver diseaseFatty liver diseaseLiver of patientsHepatic glycogen storageHigh-sucrose dietHepatic insulin resistanceFatty acid uptakeMetabolic syndromeLiver diseaseHepatic steatosisTriacylglycerol secretionNovo lipogenesisHepatic insulinTherapeutic targetImpaired activationAcid uptakeGlycogen storageMouse liverLiverLipogenesis
2021
Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis
Jiang Z, Zhao M, Voilquin L, Jung Y, Aikio MA, Sahai T, Dou FY, Roche AM, Carcamo-Orive I, Knowles JW, Wabitsch M, Appel EA, Maikawa CL, Camporez JP, Shulman GI, Tsai L, Rosen ED, Gardner CD, Spiegelman BM, Svensson KJ. Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis. Cell Metabolism 2021, 33: 1836-1852.e11. PMID: 34348115, PMCID: PMC8429235, DOI: 10.1016/j.cmet.2021.07.010.Peer-Reviewed Original ResearchConceptsFatty liver diseaseAdipose glucose uptakeGlucose toleranceLiver diseaseHepatic steatosisGlucose uptakeDiet-induced obese miceImpaired glucose toleranceInsulin-like growth factor receptorType 2 diabetesHepatic lipid synthesisIsthmin 1Growth factor receptorObese miceInsulin sensitivityTherapeutic dosingMouse modelGlucoregulatory functionGlucose regulationUnmet needTherapeutic potentialDiabetesLipid accumulationPI3K-AktFactor receptor
2020
Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance
He F, Huang Y, Song Z, Zhou HJ, Zhang H, Perry RJ, Shulman GI, Min W. Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance. Journal Of Experimental Medicine 2020, 218: e20201416. PMID: 33315085, PMCID: PMC7927432, DOI: 10.1084/jem.20201416.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesAdipose TissueAnimalsDiabetes Mellitus, Type 2Diet, High-FatEnergy MetabolismFatty LiverGene DeletionGene TargetingGluconeogenesisHomeostasisHumansHyperglycemiaInflammationInsulin ResistanceLipogenesisLiverMaleMice, Inbred C57BLMice, KnockoutMitochondriaMitophagyNF-kappa BOxidative StressPhenotypeReactive Oxygen SpeciesSequestosome-1 ProteinSignal TransductionThioredoxinsConceptsHepatic insulin resistanceWhite adipose tissueInsulin resistanceAdipose inflammationType 2 diabetes mellitusLipid metabolic disordersNF-κB inhibitorAdipose-specific deletionWhole-body energy homeostasisAltered fatty acid metabolismFatty acid metabolismT2DM progressionT2DM patientsDiabetes mellitusReactive oxygen species pathwayHepatic steatosisMetabolic disordersNF-κBP62/SQSTM1Adipose tissueHuman adipocytesEnergy homeostasisExcessive mitophagyOxygen species pathwayInflammationHepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease.
Ter Horst KW, Vatner DF, Zhang D, Cline GW, Ackermans MT, Nederveen AJ, Verheij J, Demirkiran A, van Wagensveld BA, Dallinga-Thie GM, Nieuwdorp M, Romijn JA, Shulman GI, Serlie MJ. Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease. Diabetes Care 2020, 44: 489-498. PMID: 33293347, PMCID: PMC7818337, DOI: 10.2337/dc20-1644.Peer-Reviewed Original ResearchMeSH KeywordsDiabetes Mellitus, Type 2HumansInsulinInsulin ResistanceLipogenesisLiverNon-alcoholic Fatty Liver DiseaseConceptsNonalcoholic fatty liver diseaseDe novo lipogenesisFatty liver diseaseBariatric surgeryLiver diseaseImpaired insulin-mediated suppressionGlucose productionHepatic de novo lipogenesisPeripheral glucose metabolismHyperinsulinemic-euglycemic clampType 2 diabetesInsulin-mediated suppressionInsulin-resistant subjectsHepatic insulin resistanceLiver biopsy samplesSuppress glucose productionLipogenic transcription factorsInsulin-mediated regulationObese subjectsInsulin resistanceAcute increaseNovo lipogenesisGlucose metabolismBiopsy samplesParadoxical increase
2015
A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents
Kursawe R, Dixit VD, Scherer PE, Santoro N, Narayan D, Gordillo R, Giannini C, Lopez X, Pierpont B, Nouws J, Shulman GI, Caprio S. A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents. Diabetes 2015, 65: 610-618. PMID: 26718495, PMCID: PMC4764142, DOI: 10.2337/db15-1478.Peer-Reviewed Original ResearchMeSH KeywordsAbdomenAcetyl-CoA CarboxylaseAdipogenesisAdiponectinAdolescentCarrier ProteinsCaspase 1ChildDown-RegulationFatty Acid Synthase, Type IFemaleGene Expression ProfilingGlucose Transporter Type 4HumansInflammasomesInsulin ResistanceInterleukin-1betaIntra-Abdominal FatLeptinLipogenesisLipoprotein LipaseMacrophagesMagnetic Resonance ImagingMaleNLR Family, Pyrin Domain-Containing 3 ProteinObesityPPAR gammaSirtuin 1Sterol Regulatory Element Binding Protein 1Subcutaneous FatToll-Like Receptor 4ConceptsVisceral adipose tissueObese adolescentsInsulin resistanceTissue inflammationNLRP3 inflammasomeAdipose tissueInnate immune cell sensorsAbdominal subcutaneous adipose tissueAbdominal adipose depotsAbdominal fat partitioningAdipogenesis/lipogenesisAdipose tissue inflammationProinflammatory cytokines interleukinInfiltration of macrophagesExpression of CASP1Subcutaneous adipose tissueInflammation markersSAT biopsiesIL-18Macrophage infiltrationVisceral fatCytokines interleukinSAT ratioInsulin sensitivityAdipose depots
2014
The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes
Perry RJ, Samuel VT, Petersen KF, Shulman GI. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 2014, 510: 84-91. PMID: 24899308, PMCID: PMC4489847, DOI: 10.1038/nature13478.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsType 2 diabetesHepatic insulin resistanceNon-alcoholic fatty liver diseaseFatty liver diseaseInsulin resistanceLiver diseaseHepatic lipidsHealth care costsInflammatory signalingTherapeutic approachesMortality rateDiabetesRelated epidemicsProtein kinase CεDiseaseCellular modificationsEpidemicLipid speciesMorbidityLipidsDiacylglycerol activationMice