2023
Brain responses to nutrients are severely impaired and not reversed by weight loss in humans with obesity: a randomized crossover study
van Galen K, Schrantee A, ter Horst K, la Fleur S, Booij J, Constable R, Schwartz G, DiLeone R, Serlie M. Brain responses to nutrients are severely impaired and not reversed by weight loss in humans with obesity: a randomized crossover study. Nature Metabolism 2023, 5: 1059-1072. PMID: 37308722, DOI: 10.1038/s42255-023-00816-9.Peer-Reviewed Original ResearchConceptsDiet-induced weight lossCerebral neuronal activityStriatal dopamine releaseWeight lossCrossover studyDopamine releaseNeuronal activityIntragastric glucoseNeuronal responsesSuccessful weight lossHealthy body weightSignificant weight lossBrain responsesPathological feeding behaviorsWeight regainHunger scoresLipid infusionLean participantsCaloric intakePlasma hormonesObesityBody weightInfusionNutrient signalsHigh rate
2021
The response to prolonged fasting in hypothalamic serotonin transporter availability is blunted in obesity
van Galen KA, Booij J, Schrantee A, Adriaanse SM, Unmehopa UA, Fliers E, Schwartz GJ, DiLeone RJ, Horst K, la Fleur SE, Serlie MJ. The response to prolonged fasting in hypothalamic serotonin transporter availability is blunted in obesity. Metabolism 2021, 123: 154839. PMID: 34331964, PMCID: PMC8994212, DOI: 10.1016/j.metabol.2021.154839.Peer-Reviewed Original ResearchConceptsStriatal DAT availabilityLean menSERT availabilityDAT availabilityThalamic serotonin transportersSerotonin transporterDopaminergic systemTransporter availabilityStriatal dopamine transporter availabilityPeripheral metabolic signalsFree fatty acid concentrationsCross-over trialSerotonin transporter availabilityFasting-induced increaseDopamine transporter availabilitySystemic energy metabolismHypothalamus/thalamusLean subjectsPlasma insulinFatty acid concentrationsStriatal DATFood intakeObesityInter-individual variationHigh inter-individual variation
2020
Hepatic 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 ResearchConceptsNonalcoholic 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 increaseA 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 methodKinaseMitochondria
2018
Striatal dopamine regulates systemic glucose metabolism in humans and mice
Ter Horst KW, Lammers NM, Trinko R, Opland DM, Figee M, Ackermans MT, Booij J, van den Munckhof P, Schuurman PR, Fliers E, Denys D, DiLeone RJ, la Fleur SE, Serlie MJ. Striatal dopamine regulates systemic glucose metabolism in humans and mice. Science Translational Medicine 2018, 10 PMID: 29794060, DOI: 10.1126/scitranslmed.aar3752.Peer-Reviewed Original ResearchConceptsSystemic glucose metabolismDeep brain stimulationPeripheral insulin sensitivityGlucose metabolismInsulin sensitivityStriatal dopamineBilateral deep brain stimulationStriatal neuronal activityPeripheral glucose metabolismReceptor-expressing neuronsStriatal dopamine signalingObservational human studiesNondiabetic patientsInsulin requirementsDopamine depletionGlucose toleranceObsessive-compulsive disorderDiabetes patientsInternal capsuleStriatal areasDopamine releaseHealthy subjectsAnterior limbNucleus accumbensNeuronal activity
2017
Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans
Horst K, Gilijamse PW, Versteeg RI, Ackermans MT, Nederveen AJ, la Fleur SE, Romijn JA, Nieuwdorp M, Zhang D, Samuel VT, Vatner DF, Petersen KF, Shulman GI, Serlie MJ. Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans. Cell Reports 2017, 19: 1997-2004. PMID: 28591572, PMCID: PMC5469939, DOI: 10.1016/j.celrep.2017.05.035.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceInsulin resistanceHepatic steatosisObese subjectsPKCε activationTissue-specific insulin sensitivityHepatic ceramide contentPeripheral insulin resistanceHepatic lipid accumulationPathogenesis of NAFLDLiver biopsyIntrahepatic triglyceridesLiver fatInsulin sensitivityAdipose tissueTranslational evidenceSteatosisLipid accumulationCeramide contentPKCε translocationSubjectsMolecular mechanismsDiacylglycerol contentHumansActivation
2016
The vitamin D metabolites 25(OH)D and 1,25(OH)2D are not related to either glucose metabolism or insulin action in obese women
Horst K, Versteeg RI, Gilijamse PW, Ackermans MT, Heijboer AC, Romijn JA, la Fleur SE, Trinko R, DiLeone RJ, Serlie MJ. The vitamin D metabolites 25(OH)D and 1,25(OH)2D are not related to either glucose metabolism or insulin action in obese women. Diabetes & Metabolism 2016, 42: 416-423. PMID: 27262368, DOI: 10.1016/j.diabet.2016.04.011.Peer-Reviewed Original ResearchConceptsVitamin D deficiencyObese womenInsulin actionD deficiencyVitamin DInsulin resistanceInsulin sensitivityGlucose metabolismEuglycaemic–hyperinsulinaemic clamp studiesActive vitamin D metaboliteBasal endogenous glucose productionObesity-related insulin resistanceTissue-specific insulin actionObesity-induced metabolic diseasesTissue-specific insulin sensitivitySkeletal muscle insulin sensitivityBody mass indexVitamin D metabolitesTotal body fatMuscle insulin sensitivityEndogenous glucose productionBaseline characteristicsSerum levelsMass indexD levels