2025
Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis
Sakuma I, Gaspar R, Nasiri A, Dufour S, Kahn M, Zheng J, LaMoia T, Guerra M, Taki Y, Kawashima Y, Yimlamai D, Perelis M, Vatner D, Petersen K, Huttasch M, Knebel B, Kahl S, Roden M, Samuel V, Tanaka T, Shulman G. Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2502978122. PMID: 40310463, PMCID: PMC12067271, DOI: 10.1073/pnas.2502978122.Peer-Reviewed Original ResearchConceptsCholine-deficient l-amino acid-defined high-fat dietBempedoic acidLiver fibrosisLiver diseaseL-amino acid-defined high-fat dietAdvanced liver diseaseCholesterol contentHSD17B13 variantsHigh-fat dietTotal liver cholesterol contentTreated miceActivate signaling pathwaysVariant rs738409Liver cholesterol contentLiver lipidsFibrotic responsePromote inflammationTherapeutic approachesSteatotic liver diseaseDietary cholesterol supplementationFibrosisHuman liver samplesI148MAntisense oligonucleotidesProgressive formEndoplasmic reticulum Nogo drives AgRP neuronal activation and feeding behavior
Jin S, Yoon N, Wei M, Worgall T, Rubinelli L, Horvath T, Min W, Diano N, di Lorenzo A, Diano S. Endoplasmic reticulum Nogo drives AgRP neuronal activation and feeding behavior. Cell Metabolism 2025, 37: 1400-1412.e8. PMID: 40334659, PMCID: PMC12136989, DOI: 10.1016/j.cmet.2025.04.005.Peer-Reviewed Original ResearchConceptsAgRP neuron activityNogo-AAgRP neuronsNeuronal activityCeramide levelsNogo-A expressionCellular lipid metabolismIntracellular lipid transportSphingolipid de novo biosynthesisDownregulation of enzymesIncreased ceramide levelsLipid metabolismHigh-fat diet-induced obesityFeeding behaviorAgouti-related proteinControl of feedingControlling lipid metabolismAssociated with brain developmentWhole-body metabolismFatty acid oxidationReticulon 4Food intakeMitochondrial functionSynaptic plasticityLipid transportPancreatic β-cell apoptosis caused by apolipoprotein C3-rich low-density lipoprotein is attenuated by kansuinine A through oxidative stress inhibition
Lulji Taraqaz B, Hsu Y, Tsai P, Li Y, Chen F, Yang W, Shen M. Pancreatic β-cell apoptosis caused by apolipoprotein C3-rich low-density lipoprotein is attenuated by kansuinine A through oxidative stress inhibition. Biomedicine & Pharmacotherapy 2025, 187: 118066. PMID: 40262236, DOI: 10.1016/j.biopha.2025.118066.Peer-Reviewed Original ResearchConceptsB cell apoptosisRat pancreatic B-cellsLow-density lipoproteinPathway analysisSignaling pathwayOxidative stressApoptosisImproved cell viabilityRIN-m5FB cellsLectin-like oxidized low-density lipoprotein receptor-1Pancreatic B-cellsHigh-fat dietCell viabilityInsulin toleranceAntiapoptotic propertiesKansuinine AMitigated apoptosisMechanism of actionMolecular dockingStress inhibitionPathwayLow-density lipoprotein receptor-1Improved glucoseHigh-fatReduced Notch signaling in hypothalamic endothelial cells mediates obesity-induced alterations in glucose uptake and insulin signaling
Zhu Y, Mehlkop O, Backes H, Cremer A, Porniece M, Klemm P, Steuernagel L, Chen W, Johnen R, Wunderlich F, Jais A, Brüning J. Reduced Notch signaling in hypothalamic endothelial cells mediates obesity-induced alterations in glucose uptake and insulin signaling. Cell Reports 2025, 44: 115522. PMID: 40186867, DOI: 10.1016/j.celrep.2025.115522.Peer-Reviewed Original ResearchConceptsShort-term HFD feedingNotch signalingIntracellular domainGlucose uptakeBrain microvascular endothelial cellsNotch intracellular domainHFD feedingDownregulation of Notch signalingHigh-fat dietBlood-brain barrierReduced Notch signalingGLUT1 expressionInsulin signalingSystemic insulin sensitivityBlood-brain barrier permeabilityNotch activationInduced expressionObesity-induced alterationsCaveolae formationPleiotropic effectsEndothelial cellsMicrovascular endothelial cellsExpressionBlood-brain barrier functionCultured brain microvascular endothelial cellsNotch1 Signalling Is Downregulated by Aerobic Exercise, Leading to Improvement of Hepatic Metabolism in Obese Mice
Gaspar R, Macêdo A, Nakandakari S, Muñoz V, Abud G, Vieira R, de Sousa Neto I, Pavan I, da Silva L, Simabuco F, da Silva A, Salgado W, Marchini J, Nonino C, Cintra D, Ropelle E, Pajvani U, de Freitas E, Pauli J. Notch1 Signalling Is Downregulated by Aerobic Exercise, Leading to Improvement of Hepatic Metabolism in Obese Mice. Liver International 2025, 45: e70068. PMID: 40078075, DOI: 10.1111/liv.70068.Peer-Reviewed Original ResearchConceptsNotch1 signalingAerobic exerciseRegulation of hepatic glucoseObese miceImpact of aerobic exerciseEffects of Notch1 signalingAerobic exercise trainingMTORC1 pathway activationNotch1 pathwayObese individualsTissue of obese miceCross-sectional studyNotch1 mRNA levelsMitochondrial respirationExercise trainingLivers of obese individualsTreadmill runningGluconeogenic enzymesHepG2 cell lineLipid accumulationTraining groupHepatic glucoseHepatic metabolismNotch1 proteinPathway activationSuppression of endothelial ceramide de novo biosynthesis by Nogo-B contributes to cardiometabolic diseases
Rubinelli L, Manzo O, Sungho J, Del Gaudio I, Bareja R, Marino A, Palikhe S, Di Mauro V, Bucci M, Falcone D, Elemento O, Ersoy B, Diano S, Sasset L, Di Lorenzo A. Suppression of endothelial ceramide de novo biosynthesis by Nogo-B contributes to cardiometabolic diseases. Nature Communications 2025, 16: 1968. PMID: 40000621, PMCID: PMC11862206, DOI: 10.1038/s41467-025-56869-9.Peer-Reviewed Original ResearchConceptsNogo-BEndothelial dysfunctionHFD miceCardiometabolic diseasesSphingolipid signalingDevelopment of therapeutic strategiesBioactive sphingolipidsCeramide degradationSphingosine-1-phosphateHepatic glucose productionIn vivo evidenceEndothelial cellsEndothelial specific deletionCeramideBiosynthesisHigh-fat dietPathological implicationsSphingolipidsGlucose productionHFDIn vivoMale miceMetabolic dysfunctionTherapeutic strategiesMetabolic disordersDeletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH
Parthasarathy G, Venkatesan N, Sidhu G, Song M, Liao C, Barrow F, Mauer A, Sehrawat T, Nakao Y, Daniel P, Dasgupta D, Pavelko K, Revelo X, Malhi H. Deletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH. Hepatology Communications 2025, 9: e0613. PMID: 39899672, DOI: 10.1097/hc9.0000000000000613.Peer-Reviewed Original ResearchConceptsMyeloid cellsMonocyte-derived macrophagesHigh-fatLiver injuryProinflammatory monocyte-derived macrophagesReceptor 1Cell-specific knockout miceMass cytometryT cell subsetsSphingosine 1-phosphate receptor 1Cardiometabolic risk factorsS1P receptor 1Accumulation of monocyte-derived macrophagesImmune cell typesWild-typeLiver inflammatory infiltrationGene ontology pathway analysisWild-type controlsDevelopment of steatohepatitisSphingosine 1-phosphateMitogen-activated protein kinase pathwayT cellsIntrahepatic macrophagesInflammatory infiltrateKnockout mice
2024
Shear stress is uncoupled from atheroprotective KLK10 in atherosclerotic plaques
Zhou Z, Korteland S, Tardajos-Ayllon B, Wu J, Chambers E, Weninck J, Simons M, Dunning M, Schenkel T, Diagbouga M, Wentzel J, Fragiadaki M, Evans P. Shear stress is uncoupled from atheroprotective KLK10 in atherosclerotic plaques. Atherosclerosis 2024, 398: 118622. PMID: 39413592, DOI: 10.1016/j.atherosclerosis.2024.118622.Peer-Reviewed Original ResearchConceptsShear stressPhysiological shear stressComputational fluid dynamicsDiseased arteriesHealthy arteriesGene Ontology termsFluid dynamicsSingle-cell RNA sequencingApoptotic gene expressionEffect of physiological shear stressPromote vascular homeostasisOntology termsRNA sequencingFunctional enrichmentEndothelial cellsGene expressionRisk of cardiovascular complicationsKeep It Moving: Physical Activity in the Prevention of Obesity-Driven Pancreatic Cancer.
Sogunro A, Muzumdar M. Keep It Moving: Physical Activity in the Prevention of Obesity-Driven Pancreatic Cancer. Cancer Research 2024, 84: 2935-2937. PMID: 39279380, DOI: 10.1158/0008-5472.can-24-1474.Peer-Reviewed Original ResearchConceptsPancreatic ductal adenocarcinomaTumor microenvironmentAntitumor effectPancreatic cancerObese micePhysical activityAdvanced tumor growthSystemic cytokine productionMyeloid cell infiltrationPancreatic ductal adenocarcinoma developmentEffect of obesityHigh-fat diet-induced obesityDiet-induced obesitySyngeneic allograftsAdvanced tumorsProtumorigenic effectsLean miceWhite adipose tissueCell infiltrationDuctal adenocarcinomaObesity-associatedTumor growthCytokine productionImpact of physical activityInflammatory cytokinesTlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis
Wang P, Yang X, Zhang L, Sha S, Huang J, Peng J, Gu J, Pearson J, Hu Y, Zhao H, Wong F, Wang Q, Wen L. Tlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis. Nature Communications 2024, 15: 4232. PMID: 38762479, PMCID: PMC11102548, DOI: 10.1038/s41467-024-48611-8.Peer-Reviewed Original ResearchConceptsToll-like receptor 9Gut microbiotaGut microbial communityTransferred to germ-free miceB cellsGerm-free miceTLR9 deficiencyKO miceGene sequencesGerminal center B cellsMicrobial communitiesMarginal zone B cellsGut dysbiosisFollicular helper cellsSelf-DNAMetabolic homeostasisAssociated with increased frequencyPro-inflammatory stateFat tissue inflammationGutHigh-fat dietMicrobiotaHelper cellsT cellsControl miceHigh-fat diet, microbiome-gut-brain axis signaling, and anxiety-like behavior in male rats
de Noronha S, de Moraes L, Hassell J, Stamper C, Arnold M, Heinze J, Foxx C, Lieb M, Cler K, Karns B, Jaekel S, Loupy K, Silva F, Chianca-Jr. D, Lowry C, de Menezes R. High-fat diet, microbiome-gut-brain axis signaling, and anxiety-like behavior in male rats. Biological Research 2024, 57: 23. PMID: 38705984, PMCID: PMC11071217, DOI: 10.1186/s40659-024-00505-1.Peer-Reviewed Original ResearchConceptsDefensive behavioral responsesSerotonergic gene expressionDorsal raphe nucleusSlc6a4 mRNA expressionBehavioral responsesMicrobiome-gut-brainRaphe nucleusAnxiety-related behavioral responsesBrain serotonergic systemSerotonergic brain systemAnxiety-like behaviorMale ratsAxis signalingHigh-fat dietBrain systemsSerotonergic systemAssociated with stressCommunity compositionGut microbiomeGene expressionAbundance of BlautiaHTR1AGut microbiome diversityTPH2SLC6A4Single cell tracing of Pomc neurons reveals recruitment of ‘Ghost’ subtypes with atypical identity in a mouse model of obesity
Leon S, Simon V, Lee T, Steuernagel L, Clark S, Biglari N, Lesté-Lasserre T, Dupuy N, Cannich A, Bellocchio L, Zizzari P, Allard C, Gonzales D, Le Feuvre Y, Lhuillier E, Brochard A, Nicolas J, Teillon J, Nikolski M, Marsicano G, Fioramonti X, Brüning J, Cota D, Quarta C. Single cell tracing of Pomc neurons reveals recruitment of ‘Ghost’ subtypes with atypical identity in a mouse model of obesity. Nature Communications 2024, 15: 3443. PMID: 38658557, PMCID: PMC11043070, DOI: 10.1038/s41467-024-47877-2.Peer-Reviewed Original ResearchConceptsPOMC neuronsMouse models of obesityHypothalamic pro-opiomelanocortinAdult male miceDiet-induced obese miceModels of obesityReporter micePOMC expressionHypothalamic functionMale miceMature hypothalamusMouse modelDiversity of neuronsNeuronal diversityNeuronal identityObese micePro-opiomelanocortinSingle cell tracingNeuron numberPOMCMiceLineage tracingNeuronsWeight lossMetabolic output
2023
CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice
Hammerschmidt P, Steculorum S, Bandet C, Del Río-Martín A, Steuernagel L, Kohlhaas V, Feldmann M, Varela L, Majcher A, Quatorze Correia M, Klar R, Bauder C, Kaya E, Porniece M, Biglari N, Sieben A, Horvath T, Hornemann T, Brodesser S, Brüning J. CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice. Nature Communications 2023, 14: 7824. PMID: 38016943, PMCID: PMC10684560, DOI: 10.1038/s41467-023-42595-7.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCeramidesDiet, High-FatGlucoseHomeostasisHypothalamusMiceMice, ObeseNeuronsObesityPro-OpiomelanocortinConceptsMitochondrial stressSpecific ceramide speciesSteroidogenic factor 1Hypothalamic neuronsMitochondrial dynamicsMitochondrial morphologyCeramide synthaseObese miceGlucose homeostasisCeramide speciesCeramide synthesisConditional deletionHypothalamic lipotoxicityCultured hypothalamic neuronsAdverse metabolic effectsFactor 1High-fat dietImpairs glucose homeostasisDiet-induced alterationsCerS6DeletionHomeostasisGlucose toleranceCeramideInsulin sensitivityShort-term consumption of highly processed diets varying in macronutrient content impair the sense of smell and brain metabolism in mice
Makhlouf M, Souza D, Kurian S, Bellaver B, Ellis H, Kuboki A, Al-Naama A, Hasnah R, Venturin G, da Costa J, Venugopal N, Manoel D, Mennella J, Reisert J, Tordoff M, Zimmer E, Saraiva L. Short-term consumption of highly processed diets varying in macronutrient content impair the sense of smell and brain metabolism in mice. Molecular Metabolism 2023, 79: 101837. PMID: 37977411, PMCID: PMC10724696, DOI: 10.1016/j.molmet.2023.101837.Peer-Reviewed Original ResearchConceptsMacronutrient contentIncrease food safetyGrain-based dietShort-term consumptionElectro-olfactogramFood safetyProcessed dietsFood processingBrain regionsBrain metabolismOdor-guided behaviorStandard chow dietShort-term intakeDietGlucose metabolism imagingHigh-fat dietFoodResponses to odorantsBrain glucose metabolismOlfactory mucosaModern dietFood consumptionChow dietChronic consumptionMetabolic phenotypeGlucocorticoid signaling and the impact of high-fat diet on adipogenesis in vivo
Babel N, Feldman B. Glucocorticoid signaling and the impact of high-fat diet on adipogenesis in vivo. Steroids 2023, 201: 109336. PMID: 37944652, PMCID: PMC11005958, DOI: 10.1016/j.steroids.2023.109336.Peer-Reviewed Original ResearchFXR agonists INT‐787 and OCA increase RECK and inhibit liver steatosis and inflammation in diet‐induced ob/ob mouse model of NASH
Di Pasqua L, Cagna M, Palladini G, Croce A, Cadamuro M, Fabris L, Perlini S, Adorini L, Ferrigno A, Vairetti M. FXR agonists INT‐787 and OCA increase RECK and inhibit liver steatosis and inflammation in diet‐induced ob/ob mouse model of NASH. Liver International 2023, 44: 214-227. PMID: 37904642, DOI: 10.1111/liv.15767.Peer-Reviewed Original ResearchConceptsNon-alcoholic steatohepatitisHigh-fat dietOb/ob mouse modelObeticholic acidAgonist obeticholic acidSerum alanine transaminaseAlanine transaminaseMMP-2MMP-9Mouse modelCollagen depositionHepatic ischaemia/reperfusion injuryFarnesoid X receptor agonist obeticholic acidControl dietFXR agonist obeticholic acidIschaemia/reperfusion injuryHepatic stellate cell activationMMP-9 activityStellate cell activationMMP-2 expressionΑ-SMA levelsOCA administrationHFD groupReperfusion injuryLiver steatosisTime-restricted feeding combined with resistance exercise prevents obesity and improves lipid metabolism in the liver of mice fed a high-fat diet
Damasceno de Lima R, Fudoli Lins Vieira R, Rosetto Muñoz V, Chaix A, Azevedo Macedo A, Calheiros Antunes G, Felonato M, Rosseto Braga R, Castelo Branco Ramos Nakandakari S, Calais Gaspar R, Ramos da Silva A, Esper Cintra D, Pereira de Moura L, Mekary R, Rochete Ropelle E, Pauli J. Time-restricted feeding combined with resistance exercise prevents obesity and improves lipid metabolism in the liver of mice fed a high-fat diet. AJP Endocrinology And Metabolism 2023, 325: e513-e528. PMID: 37755454, DOI: 10.1152/ajpendo.00129.2023.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseResistance exercise trainingTime-restricted feedingFatty liver diseaseHigh-fat dietLiver diseaseExercise trainingWeight gainGlycemic homeostasisMetabolic disordersEffects of TRFCommon liver diseaseDiet-induced obesityMajor risk factorEnergy expenditureFatty acid oxidation genesLiver of miceAccumulation of fatBody weight gainRespiratory exchange rateAccumulation of lipidsLower mRNA expressionRT groupPrevents obesityRisk factorsDifferential outcomes of high‐fat diet on age‐related rescaling of cochlear frequency place coding
Zhang Y, Lin G, Xue N, Wang Y, Du T, Liu H, Xiong W, Shang W, Wu H, Song L. Differential outcomes of high‐fat diet on age‐related rescaling of cochlear frequency place coding. The FASEB Journal 2023, 37: e23167. PMID: 37651093, DOI: 10.1096/fj.202300457rr.Peer-Reviewed Original ResearchConceptsAge-related hearing lossHigh-fat dietHearing lossEffects of HFDLoss of OHCsActivation of TRPV1Sensorineural hearing lossCBA/CaJPlace codingCochlear frequency selectivityTRPV1 expressionOHC functionInflammatory responseCommon causeHFD cohortGenetic backgroundYounger ageArachidonic acidCochlear lengthHair cellsPrestin levelsLipid homeostasisRescuing effectCochlear amplificationAgeExploring the Plasticity of Diet on Gut Microbiota and Its Correlation with Gut Health
Yao S, Zhao Y, Chen H, Sun R, Chen L, Huang J, Yu Z, Chen S. Exploring the Plasticity of Diet on Gut Microbiota and Its Correlation with Gut Health. Nutrients 2023, 15: 3460. PMID: 37571397, PMCID: PMC10420685, DOI: 10.3390/nu15153460.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBacteriaDietDiet, High-FatDiet, High-ProteinGastrointestinal MicrobiomeMiceMice, Inbred C57BLRNA, Ribosomal, 16SConceptsGut microbiotaGut healthComposition of gut microbiotaGut microbiota of miceProtecting gut healthRRNA gene sequencesMicrobiota of miceGut microbiota changesGene sequencesAlpha diversityHigh fiber dietMicrobiota changesPathogenic bacteriaMicrobiotaGutGenusHigh-protein dietSwitching dietsDietary impactExperimental timeframeBacteriaProbioticsHigh-protein diet groupSequenceAIN-93G dietAbsence of either Ripk3 or Mlkl reduces incidence of hepatocellular carcinoma independent of liver fibrosis
Mohammed S, Thadathil N, Ohene-Marfo P, Tran A, Van Der Veldt M, Georgescu C, Oh S, Nicklas E, Wang D, Haritha N, Luo W, Janknecht R, Miller B, Wren J, Freeman W, Deepa S. Absence of either Ripk3 or Mlkl reduces incidence of hepatocellular carcinoma independent of liver fibrosis. Molecular Cancer Research 2023, 21: 933-946. PMID: 37204757, PMCID: PMC10472095, DOI: 10.1158/1541-7786.mcr-22-0820.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseProgression of NAFLDHepatocellular carcinomaChronic inflammationLiver fibrosisMale miceMouse modelCholine-deficient high-fat dietFemale wild-type miceOncogenic pathwaysFatty liver diseaseMarkers of inflammationHigh-fat dietLow-fat dietDevelopment of inflammationValid therapeutic targetWild-type miceHepatic inflammationInflammation contributesLiver diseaseWT miceFemale miceSex-specific differencesInflammationTherapeutic target
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