2025
286-OR: Spatial Regulation of Glucose and Lipid Metabolism by Hepatic Insulin Signaling
HE B, COPPS K, WHITE M, TAO R. 286-OR: Spatial Regulation of Glucose and Lipid Metabolism by Hepatic Insulin Signaling. Diabetes 2025, 74 DOI: 10.2337/db25-286-or.Peer-Reviewed Original ResearchInsulin signalingHepatic Insulin SignalingDisrupted insulin signalingRegulation of glucoseSpatial regulationLipid homeostasisMetabolic enzymesFunctional significanceGlycolytic metabolismSystemic glucoseLipid metabolismGlucose homeostasisHepatic insulin sensitivityExcessive lipogenesisLipogenesisHomeostasisElevated blood glucoseType 2 diabetesMetabolismMetabolic dysregulationGlucoseHepatosteatosisLiver-to-muscleInsulin resistanceLipidSpatial regulation of glucose and lipid metabolism by hepatic insulin signaling
He B, Copps K, Stöhr O, Liu B, Hu S, Joshi S, Haigis M, White M, Zhu H, Tao R. Spatial regulation of glucose and lipid metabolism by hepatic insulin signaling. Cell Metabolism 2025, 37: 1568-1583.e7. PMID: 40245868, DOI: 10.1016/j.cmet.2025.03.015.Peer-Reviewed Original ResearchInsulin signalingHepatic Insulin SignalingDisrupted insulin signalingRegulation of glucoseSpatial regulationLipid homeostasisElevated gluconeogenesisMetabolic enzymesFunctional significanceGlycolytic metabolismSystemic glucoseLipid metabolismGlucose homeostasisHepatic insulin sensitivityExcessive lipogenesisLipogenesisHomeostasisMetabolismMetabolic dysregulationHepatosteatosisHepatocytesGlucoseInsulin resistanceLipidType 2 diabetes
2024
Ceramide 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 inhibitorDGAT2DesaturaseInhibition1577-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 diseaseTranslocation
2021
Relation of glomerular filtration to insulin resistance and related risk factors in obese children
Magen D, Halloun R, Galderisi A, Caprio S, Weiss R. Relation of glomerular filtration to insulin resistance and related risk factors in obese children. International Journal Of Obesity 2021, 46: 374-380. PMID: 34725443, DOI: 10.1038/s41366-021-01001-2.Peer-Reviewed Original ResearchConceptsGlomerular filtration rateInsulin sensitivityObese childrenInsulin resistanceBlood pressureFiltration rateRisk factorsWhole-body insulin sensitivityChildhood insulin resistanceFuture kidney diseaseRelation of eGFRSignificant renal morbiditySpectrum of obesityCardiovascular risk factorsPresence of microalbuminuriaSystolic blood pressureRelated risk factorsHepatic insulin sensitivityBody insulin sensitivityObjectiveChildhood obesityRenal morbidityClinical outcomesGlucose toleranceMale sexKidney diseaseDeletion of the diabetes candidate gene Slc16a13 in mice attenuates diet-induced ectopic lipid accumulation and insulin resistance
Schumann T, König J, von Loeffelholz C, Vatner DF, Zhang D, Perry RJ, Bernier M, Chami J, Henke C, Kurzbach A, El-Agroudy NN, Willmes DM, Pesta D, de Cabo R, O´Sullivan J, Simon E, Shulman GI, Hamilton BS, Birkenfeld AL. Deletion of the diabetes candidate gene Slc16a13 in mice attenuates diet-induced ectopic lipid accumulation and insulin resistance. Communications Biology 2021, 4: 826. PMID: 34211098, PMCID: PMC8249653, DOI: 10.1038/s42003-021-02279-8.Peer-Reviewed Original ResearchMeSH KeywordsAMP-Activated Protein KinasesAnimalsDiabetes Mellitus, Type 2Diet, High-FatGene ExpressionGenetic Predisposition to DiseaseHumansInsulin ResistanceLipid MetabolismLiverMice, Inbred C57BLMice, KnockoutMitochondriaMonocarboxylic Acid TransportersNon-alcoholic Fatty Liver DiseaseObesityOxygen ConsumptionConceptsMitochondrial respirationGenome-wide association studiesNovel susceptibility genesLipid accumulationPlasma membraneAMPK activationAssociation studiesPhysiological functionsEctopic lipid accumulationReduced hepatic lipid accumulationSusceptibility genesLactate transporterMonocarboxylate transportersPotential targetGenesTransportersDeletionLipid contentHepatic lipid accumulationPotential importanceKnockout miceRespirationHepatic insulin sensitivityMCT13Accumulation
2020
Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice
Abulizi A, Vatner DF, Ye Z, Wang Y, Camporez JP, Zhang D, Kahn M, Lyu K, Sirwi A, Cline GW, Hussain MM, Aspichueta P, Samuel VT, Shulman GI. Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice. Journal Of Lipid Research 2020, 61: 1565-1576. PMID: 32907986, PMCID: PMC7707176, DOI: 10.1194/jlr.ra119000586.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceInsulin resistanceHepatic insulin sensitivityHepatic steatosisLipid-induced hepatic insulin resistancePKCε activationInsulin sensitivityKnockout miceNormal hepatic insulin sensitivityWild-type control miceHepatic ceramide contentHyperinsulinemic-euglycemic clampComprehensive metabolic phenotypingLipid dropletsHepatic DAG contentDAG contentGlucose intoleranceControl miceMTTP activityHepatic insulinAnimal modelsSteatosisAKT Ser/ThrMiceMetabolic phenotypingIntrahepatic fat, irrespective of ethnicity, is associated with reduced endogenous insulin clearance and hepatic insulin resistance in obese youths: A cross‐sectional and longitudinal study from the Yale Pediatric NAFLD cohort
Tricò D, Galderisi A, Mari A, Polidori D, Galuppo B, Pierpont B, Samuels S, Santoro N, Caprio S. Intrahepatic fat, irrespective of ethnicity, is associated with reduced endogenous insulin clearance and hepatic insulin resistance in obese youths: A cross‐sectional and longitudinal study from the Yale Pediatric NAFLD cohort. Diabetes Obesity And Metabolism 2020, 22: 1628-1638. PMID: 32363679, PMCID: PMC8174801, DOI: 10.1111/dom.14076.Peer-Reviewed Original ResearchConceptsHepatic insulin resistance indexNon-alcoholic fatty liver diseaseEndogenous insulin clearanceInsulin secretion rateInsulin clearanceHepatic insulin resistanceObese youthInsulin resistanceOral glucose tolerance testIntrahepatic fat accumulationIntrahepatic fat contentReduced insulin clearanceInsulin resistance indexFatty liver diseaseGlucose tolerance testWaist-hip ratioIntrahepatic lipid accumulationHepatic insulin sensitivityPlasma glucose levelsMulti-ethnic cohortC-peptide dataNAFLD cohortIntrahepatic fatLiver diseaseInsulin levels
2019
Hepatic insulin sensitivity is improved in high‐fat diet‐fed Park2 knockout mice in association with increased hepatic AMPK activation and reduced steatosis
Edmunds LR, Huckestein BR, Kahn M, Zhang D, Chu Y, Zhang Y, Wendell SG, Shulman GI, Jurczak MJ. Hepatic insulin sensitivity is improved in high‐fat diet‐fed Park2 knockout mice in association with increased hepatic AMPK activation and reduced steatosis. Physiological Reports 2019, 7: e14281. PMID: 31724300, PMCID: PMC6854109, DOI: 10.14814/phy2.14281.Peer-Reviewed Original ResearchConceptsPark2 KO miceHepatic insulin sensitivityKO miceInsulin sensitivityInsulin resistanceShort-term HFD feedingDiet-induced hepatic insulin resistanceWhole-body insulin sensitivityPark2 knockout miceImproved hepatic insulin sensitivityDiet-induced obesityHigh-fat dietBioactive lipid speciesTumor necrosis factorHepatic insulin resistanceHepatic AMPK activationNegative energy balanceEndoplasmic reticulum stress responseRegular chowCytokine levelsHFD feedingReduced steatosisChronic HFDInterleukin-6Necrosis factorOR31-6 Insulin Sensitivity and Pancreatic Beta-Cell Function in Patients with Primary Aldosteronism
Grewal S, Fosam A, Chalk L, Deven A, Suzuki M, Demidowich A, Correa R, Blau J, Stratakis C, Muniyappa R. OR31-6 Insulin Sensitivity and Pancreatic Beta-Cell Function in Patients with Primary Aldosteronism. Journal Of The Endocrine Society 2019, 3: or31-6. PMCID: PMC6554914, DOI: 10.1210/js.2019-or31-6.Peer-Reviewed Original ResearchOral glucose tolerance testΒ-cell functionBeta-cell functionHepatic insulin resistance indexPancreatic beta-cell functionPrimary aldosteronismHepatic insulin sensitivityInsulin sensitivityInsulinogenic indexDisposition indexGlucose tolerancePA groupPancreatic β-cell functionIslet β-cell functionInsulin resistance indexMean arterial pressureGlucose tolerance testOral disposition indexType 2 diabetesSimilar glucose toleranceMinimal model analysisExcess aldosteronePA cohortElevated aldosteroneRenin levels
2018
PEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats
Beddow SA, Gattu AK, Vatner DF, Paolella L, Alqarzaee A, Tashkandi N, Popov V, Church C, Rodeheffer M, Cline G, Geisler J, Bhanot S, Samuel VT. PEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats. Endocrinology 2018, 160: 205-219. PMID: 30445425, PMCID: PMC6307100, DOI: 10.1210/en.2018-00630.Peer-Reviewed Original ResearchMeSH KeywordsAdipose Tissue, WhiteAdiposityAnimalsDiabetes Mellitus, Type 2Diet, High-FatGlucokinaseHumansInsulinIntracellular Signaling Peptides and ProteinsLipogenesisLiverLiver GlycogenMaleMiceMice, Inbred C57BLOligonucleotides, AntisensePhosphoenolpyruvate Carboxykinase (GTP)RatsRats, Sprague-DawleyConceptsHepatic glycogen synthesisAdipose tissueAntisense oligonucleotideType 2 diabetes mellitusWhite adipose tissue massIncreased hepatic gluconeogenesisChow fed ratsHepatic insulin sensitivityMale Sprague-DawleyAdipose tissue massHepatic insulin resistanceWhite adipose tissueHepatic glucose productionDe novo lipogenesisHepatic glucokinase expressionControl antisense oligonucleotideGlycogen synthesisTranscription factor 3HFF ratsDiabetes mellitusHepatic steatosisInsulin resistanceHyperglycemic clampPlasma glucoseInsulin sensitivityPredictive Accuracy of Surrogate Indices for Hepatic and Skeletal Muscle Insulin Sensitivity
Muniyappa R, Tella S, Sortur S, Mszar R, Grewal S, Abel B, Auh S, Chang D, Krakoff J, Skarulis M. Predictive Accuracy of Surrogate Indices for Hepatic and Skeletal Muscle Insulin Sensitivity. Journal Of The Endocrine Society 2018, 3: 108-118. PMID: 30675598, PMCID: PMC6299271, DOI: 10.1210/js.2018-00206.Peer-Reviewed Original ResearchOral glucose tolerance testInsulin sensitivitySurrogate indexGlucose clampDegrees of glucose toleranceInsulin sensitivity/resistance indicesHyperinsulinemic-euglycemic glucose clampGlucose tolerance testTritiated glucose infusionCross-sectional studyOGTT-derivedHepatic insulin sensitivityClinical studiesTolerance testGlucose tolerancePredicting insulin sensitivityMuscle insulin sensitivityGlucose infusionSkeletal muscle insulin sensitivityIndices of muscleSurrogate indicatorClampThe rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/Type 2 Diabetes in Obese Adolescents by Impairing beta-Cell Function and Hepatic Insulin Sensitivity
C C, N S, L G, C D, C C, A G, R K, B P, M G, S C. The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/Type 2 Diabetes in Obese Adolescents by Impairing beta-Cell Function and Hepatic Insulin Sensitivity. 2018 DOI: 10.1530/ey.15.12.3.Peer-Reviewed Original ResearchMembrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance In Vivo
LYU K, ZHANG D, NOZAKI Y, ZHANG Y, BHANOT S, CLINE G, SAMUEL V, SHULMAN G. Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance In Vivo. Diabetes 2018, 67 DOI: 10.2337/db18-243-lb.Peer-Reviewed Original ResearchHepatic insulin resistanceLipid-induced hepatic insulin resistanceDiglyceride acyltransferase 2Hepatic DAG contentInsulin resistanceHepatic insulin sensitivityInsulin sensitivityImpaired insulin-mediated suppressionActivation/translocationDGAT2 inhibitionAntisense oligonucleotideRegular chow dietInsulin-mediated suppressionHepatic insulin actionHepatic glucose productionInsulin receptor kinaseDAG contentChow dietASO treatmentIonis PharmaceuticalsInsulin actionGlucose productionPKCε activationSREBP-1cGilead Sciences
2017
A Branched-Chain Amino Acid-Related Metabolic Signature Characterizes Obese Adolescents with Non-Alcoholic Fatty Liver Disease
Goffredo M, Santoro N, Tricò D, Giannini C, D’Adamo E, Zhao H, Peng G, Yu X, Lam TT, Pierpont B, Caprio S, Herzog RI. A Branched-Chain Amino Acid-Related Metabolic Signature Characterizes Obese Adolescents with Non-Alcoholic Fatty Liver Disease. Nutrients 2017, 9: 642. PMID: 28640216, PMCID: PMC5537762, DOI: 10.3390/nu9070642.Peer-Reviewed Original ResearchConceptsNon-alcoholic fatty liver diseaseMagnetic resonance imagingBranched-chain amino acidsFatty liver diseaseHepatic fat contentObese adolescentsInsulin resistanceLiver diseaseTwo-step hyperinsulinemic-euglycemic clampOral glucose tolerance testSecond magnetic resonance imagingSubset of patientsGlucose tolerance testHyperinsulinemic-euglycemic clampHigher plasma levelsHepatic insulin sensitivityChain amino acidsPlasma levelsTolerance testInsulin sensitivityMetabolomic signaturePlasma metabolitesResonance imagingValine levelsLipid metabolism
2015
Second‐generation antisense oligonucleotides against β‐catenin protect mice against diet‐induced hepatic steatosis and hepatic and peripheral insulin resistance
Popov VB, Jornayvaz FR, Akgul EO, Kanda S, Jurczak MJ, Zhang D, Abudukadier A, Majumdar SK, Guigni B, Petersen KF, Manchem VP, Bhanot S, Shulman GI, Samuel VT. Second‐generation antisense oligonucleotides against β‐catenin protect mice against diet‐induced hepatic steatosis and hepatic and peripheral insulin resistance. The FASEB Journal 2015, 30: 1207-1217. PMID: 26644352, PMCID: PMC4750414, DOI: 10.1096/fj.15-271999.Peer-Reviewed Original ResearchConceptsHepatic steatosisInsulin resistanceAntisense oligonucleotideDiet-induced hepatic steatosisWhole-body glucose metabolismLipid-induced insulin resistanceMale C57BL/6 micePeripheral insulin resistanceHyperinsulinemic-euglycemic clampType 2 diabetesHepatic insulin sensitivityΒ-cateninHepatic lipid compositionWhite adipose tissueWnt/β-cateninΒ-catenin expressionMetabolic syndromeProtect miceC57BL/6 miceΒ-catenin mRNAFed miceHepatic triglyceridesInsulin sensitivityAwake miceGlucose metabolism
2013
Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance
Kumashiro N, Beddow SA, Vatner DF, Majumdar SK, Cantley JL, Guebre-Egziabher F, Fat I, Guigni B, Jurczak MJ, Birkenfeld AL, Kahn M, Perler BK, Puchowicz MA, Manchem VP, Bhanot S, Still CD, Gerhard GS, Petersen KF, Cline GW, Shulman GI, Samuel VT. Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance. Diabetes 2013, 62: 2183-2194. PMID: 23423574, PMCID: PMC3712050, DOI: 10.2337/db12-1311.Peer-Reviewed Original ResearchConceptsPyruvate carboxylaseAntisense oligonucleotideHepatocyte fatty acid oxidationInsulin resistanceNonalcoholic fatty liver diseaseZucker diabetic fatty ratsHigh fat-fed ratsFatty liver diseaseLiver biopsy specimensDiabetic fatty ratsPlasma lipid concentrationsType 2 diabetesHepatic insulin sensitivityHuman liver biopsy specimensEndogenous glucose productionHepatic insulin resistancePlasma glucose concentrationPotential therapeutic approachSpecific antisense oligonucleotideFat-fed ratsCarboxylaseFatty acid oxidationDe novo fatty acid synthesisLiver diseaseTissue-specific inhibitionThyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways
Vatner DF, Weismann D, Beddow SA, Kumashiro N, Erion DM, Liao XH, Grover GJ, Webb P, Phillips KJ, Weiss RE, Bogan JS, Baxter J, Shulman GI, Samuel VT. Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways. AJP Endocrinology And Metabolism 2013, 305: e89-e100. PMID: 23651850, PMCID: PMC3725564, DOI: 10.1152/ajpendo.00573.2012.Peer-Reviewed Original ResearchMeSH KeywordsAcetatesAnilidesAnimalsDietary FatsFatty LiverGene ExpressionGluconeogenesisGlucose Transporter Type 4HyperglycemiaHyperinsulinismInsulin ResistanceMaleMuscle, SkeletalNon-alcoholic Fatty Liver DiseasePhenolsRatsRats, Sprague-DawleySignal TransductionThyroid Hormone Receptors betaTriglyceridesConceptsEndogenous glucose productionHepatic insulin sensitivityInsulin sensitivityHepatic steatosisFat-fed ratsInsulin-stimulated peripheral glucose disposalTRβ agonistsInsulin-stimulated skeletal muscle glucose uptakePotent lipid-lowering drugsNonalcoholic fatty liver diseaseWhite adipose tissue lipolysisMale Sprague-Dawley ratsSkeletal muscle glucose uptakeGC-1 treatmentPeripheral glucose disposalFatty liver diseaseImpairs insulin sensitivityLipid-lowering drugsHepatic triglyceride contentAdipose tissue lipolysisMuscle glucose uptakeSprague-Dawley ratsHepatic insulin resistanceSkeletal muscle insulinPotential adverse effects
2012
The Role of the Carbohydrate Response Element-Binding Protein in Male Fructose-Fed Rats
Erion DM, Popov V, Hsiao JJ, Vatner D, Mitchell K, Yonemitsu S, Nagai Y, Kahn M, Gillum MP, Dong J, Murray SF, Manchem VP, Bhanot S, Cline GW, Shulman GI, Samuel VT. The Role of the Carbohydrate Response Element-Binding Protein in Male Fructose-Fed Rats. Endocrinology 2012, 154: 36-44. PMID: 23161873, PMCID: PMC3529388, DOI: 10.1210/en.2012-1725.Peer-Reviewed Original ResearchConceptsDe novo lipogenesisResponse element-binding proteinCarbohydrate response element-binding proteinASO treatmentHepatic expressionNovo lipogenesisElement-binding proteinInsulin-stimulated peripheral glucose uptakeNonalcoholic fatty liver diseaseAntisense oligonucleotideMale Sprague-Dawley ratsHepatic de novo lipogenesisFructose-fed groupHepatic insulin responsivenessFatty liver diseaseFructose fed ratsPeripheral glucose uptakeHyperinsulinemic-euglycemic clampHigh-fat dietHepatic lipid contentHepatic triglyceride secretionHepatic insulin sensitivitySprague-Dawley ratsPlasma triglyceride concentrationsPlasma uric acidLow Density Lipoprotein (LDL) Receptor-related Protein 6 (LRP6) Regulates Body Fat and Glucose Homeostasis by Modulating Nutrient Sensing Pathways and Mitochondrial Energy Expenditure*
Liu W, Singh R, Choi CS, Lee HY, Keramati AR, Samuel VT, Lifton RP, Shulman GI, Mani A. Low Density Lipoprotein (LDL) Receptor-related Protein 6 (LRP6) Regulates Body Fat and Glucose Homeostasis by Modulating Nutrient Sensing Pathways and Mitochondrial Energy Expenditure*. Journal Of Biological Chemistry 2012, 287: 7213-7223. PMID: 22232553, PMCID: PMC3293520, DOI: 10.1074/jbc.m111.286724.Peer-Reviewed Original ResearchMeSH KeywordsAdipose Tissue, BrownAdiposityAllelesAnimalsDiabetes Mellitus, Type 2Dietary FatsEnergy MetabolismForkhead Box Protein O1Forkhead Transcription FactorsGluconeogenesisGlucoseGlucose-6-PhosphataseHomeostasisInsulin ResistanceLow Density Lipoprotein Receptor-Related Protein-6Mechanistic Target of Rapamycin Complex 1MiceMice, KnockoutMitochondriaMultiprotein ComplexesObesityProteinsReceptors, LeptinTOR Serine-Threonine KinasesWnt Signaling PathwayConceptsLow-density lipoprotein receptor-related protein 6Type 2 diabetesInsulin resistanceInsulin sensitivityBody fatAdipose tissue insulin sensitivityLipoprotein receptor-related protein 6Tissue insulin resistanceTissue insulin sensitivityDiet-induced obesityHigh-fat dietLeptin receptor expressionHepatic insulin sensitivityHepatic glucose outputWild-type littermatesFoxo1-dependent expressionMitochondrial energy expenditureMetabolic syndromeFat dietReduced adiposityReceptor expressionPharmacological interventionsGlucose outputGlucose homeostasisKey gluconeogenic enzymes
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