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 dietSREBP1cINSR
2022
Sex‐ and strain‐specific effects of mitochondrial uncoupling on age‐related metabolic diseases in high‐fat diet‐fed mice
Goedeke L, Murt KN, Di Francesco A, Camporez JP, Nasiri AR, Wang Y, Zhang X, Cline GW, de Cabo R, Shulman GI. Sex‐ and strain‐specific effects of mitochondrial uncoupling on age‐related metabolic diseases in high‐fat diet‐fed mice. Aging Cell 2022, 21: e13539. PMID: 35088525, PMCID: PMC8844126, DOI: 10.1111/acel.13539.Peer-Reviewed Original ResearchConceptsControlled-release mitochondrial protonophoreAge-related metabolic diseasesHepatocellular carcinomaMetabolic diseasesHigh-fat diet-fed miceProtein kinase C epsilon activationDiet-induced obese miceWhole-body energy expenditureC57BL/6J male miceDiet-fed miceHigh-fat dietHepatic lipid peroxidationHepatic lipid contentMitochondrial uncouplingHepatic insulin resistanceHigh therapeutic indexHepatic mitochondrial biogenesisStrain-specific effectsSex-specific mannerCRMP treatmentHFD feedingUnwanted side effectsObese miceInsulin resistanceChronic ingestion
2021
335-OR: Lipid-Induced Insulin Resistance in the Renal Cortex Is Associated with Plasma Membrane Sn-1,2-diacylglycerol Accumulation and PKCe Translocation
HUBBARD B, GASPAR R, ZHANG D, KAHN M, NASIRI A, ZHANG X, CLINE G, SHULMAN G. 335-OR: Lipid-Induced Insulin Resistance in the Renal Cortex Is Associated with Plasma Membrane Sn-1,2-diacylglycerol Accumulation and PKCe Translocation. Diabetes 2021, 70 DOI: 10.2337/db21-335-or.Peer-Reviewed Original ResearchHigh-fat dietInsulin receptorInsulin resistanceLipid-Induced Insulin ResistanceRC miceProtein kinase CεRegular chowHFD miceRenal cortexCitrate synthase fluxHyperinsulinemic-euglycemic clamp conditionsAktS473 phosphorylationFatty acid fluxPyruvate oxidationPKCε translocationPyruvate dehydrogenase fluxPhosphorylationDiacylglycerol accumulationHFD feedingFat dietSpouse/partnerFold increaseSynthase fluxTranslocationIonis PharmaceuticalsShort-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol – PKCε – insulin receptorT1160 phosphorylation
Lyu K, Zhang D, Song J, Li X, Perry RJ, Samuel VT, Shulman GI. Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol – PKCε – insulin receptorT1160 phosphorylation. JCI Insight 2021, 6: e139946. PMID: 33411692, PMCID: PMC7934919, DOI: 10.1172/jci.insight.139946.Peer-Reviewed Original ResearchConceptsInsulin resistanceInsulin actionAdipose tissue insulin resistanceTissue insulin resistanceWT control miceHyperinsulinemic-euglycemic clampShort-term HFDTissue insulin actionAdipose tissue insulin actionDiet-fed ratsPotential therapeutic targetHFD feedingControl miceInsulin sensitivityTherapeutic targetLipolysis suppressionImpairs insulinHFDPKCε activationGlucose uptakeΕ activationMiceDiacylglycerol accumulationRecent evidenceProtein kinase C
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 factor