2025
83-OR: GLP-1RA Efficacy Doubled with Small Molecule Modulators of Pyruvate Kinase for Obesity Treatment
KIBBEY R, CARDONE R, RUZ-MALDONADO I, ZHAO X, BROWN S, FOSTER H, MERRINS M. 83-OR: GLP-1RA Efficacy Doubled with Small Molecule Modulators of Pyruvate Kinase for Obesity Treatment. Diabetes 2025, 74 DOI: 10.2337/db25-83-or.Peer-Reviewed Original ResearchGLP-1 RAsLean massCombo groupInsulin secretionOptimal treatment of obesityPreservation of lean massObesity treatmentTreatment groupsIslet healthCa2+ oscillationsCa2+ imagingFasting glucose levelsC57BL/6J male miceTreatment of obesityImproved insulin sensitivityGLP-1RAAUC glucoseOptimal treatmentDIO miceMale miceStudy endPlaceboGLP-1Body compositionInsulin sensitivityChemPerturb-seq screen identifies a small molecule cocktail enhancing human beta cell survival after subcutaneous transplantation
Vandana J, Zhu J, Giani A, Zhang T, Lacko L, Leng D, Taylor D, Lee B, Han Z, Jiao T, Huang Y, Zhao M, Liu X, Chong A, Xue D, Meng Z, Xiang J, Pan C, Wang W, Naji A, Evans T, Liu J, Collins F, Liu C, Chen S. ChemPerturb-seq screen identifies a small molecule cocktail enhancing human beta cell survival after subcutaneous transplantation. Cell Stem Cell 2025 PMID: 40562034, DOI: 10.1016/j.stem.2025.06.002.Peer-Reviewed Original ResearchGly-βMCA modulates bile acid metabolism to reduce hepatobiliary injury in Mdr2 KO mice
Hasan M, Wang H, Luo W, Du Y, Li T. Gly-βMCA modulates bile acid metabolism to reduce hepatobiliary injury in Mdr2 KO mice. AJP Gastrointestinal And Liver Physiology 2025, 329: g45-g57. PMID: 40418643, PMCID: PMC12178242, DOI: 10.1152/ajpgi.00044.2025.Peer-Reviewed Original ResearchConceptsKO miceBile acid compositionBile acid pool sizeBile acid poolBile acid hydrophobicityHepatic bile acidsHepatobiliary toxicityBile acid metabolismMale miceTherapeutic benefitCholestasis modelMdr2-KO miceDecreased liver injuryBile acidsSerum alkaline phosphataseBile acid absorptionAlkaline phosphataseFecal bile acid excretionAcid compositionDiminished therapeutic efficacyImpaired bile flowAcid metabolismHepatobiliary injuryUnique pharmacokineticsBiliary injuryGDF8 and activin A blockade protects against GLP-1–induced muscle loss while enhancing fat loss in obese male mice and non-human primates
Mastaitis J, Gomez D, Raya J, Li D, Min S, Stec M, Kleiner S, McWilliams T, Altarejos J, Murphy A, Yancopoulos G, Sleeman M. GDF8 and activin A blockade protects against GLP-1–induced muscle loss while enhancing fat loss in obese male mice and non-human primates. Nature Communications 2025, 16: 4377. PMID: 40360507, PMCID: PMC12075787, DOI: 10.1038/s41467-025-59485-9.Peer-Reviewed Original ResearchConceptsGlucagon-like peptide-1 receptor agonistsPeptide-1 receptor agonistsReceptor agonistsA blockadeGlucagon-like peptide-1 receptor agonist treatmentMuscle lossMuscle massFat lossObese male miceNon-human primatesType II activin receptorTreatment of obesityQuality of weight lossSignificant muscle lossIncrease muscle massEnhanced fat lossAgonist treatmentMale miceMuscle preservationAppetite suppressionActivin AActivin receptorsObese miceCaloric restrictionWeight lossSex Differences in Histamine Regulation of Striatal Dopamine
Van Zandt M, Pittenger C. Sex Differences in Histamine Regulation of Striatal Dopamine. Journal Of Neuroscience 2025, 45: e2182242025. PMID: 40355265, PMCID: PMC12160404, DOI: 10.1523/jneurosci.2182-24.2025.Peer-Reviewed Original ResearchConceptsSubstantia nigra pars compactaAttention deficit hyperactivity disorderStriatal dopamineTourette syndromeSex differencesNeuropsychiatric conditionsModulation of striatal dopamineDysregulation of dopamineRegulation of dopamineReplicating previous workDeficit hyperactivity disorderInfusion of agonistsStriatal circuitryDopamine modulationHyperactivity disorderDopamineHistamine regulationBasal gangliaH3R agonistTargeted infusionGABAergic neuronsIntracerebroventricularMale miceEffect of histamineHistamine receptorsSex-specific effects of exogenous asparagine on colorectal tumor growth, 17β-estradiol levels, and aromatase
Aladelokun O, Benitez K, Wang Y, Jain A, Berardi D, Maroun G, Shen X, Roper J, Gibson J, Sumigray K, Khan S, Johnson C. Sex-specific effects of exogenous asparagine on colorectal tumor growth, 17β-estradiol levels, and aromatase. Pharmacological Research 2025, 215: 107736. PMID: 40228761, PMCID: PMC12100670, DOI: 10.1016/j.phrs.2025.107736.Peer-Reviewed Original ResearchTumor-specific survivalColorectal cancerTumor growthR2G2 miceIncreased serum estradiol levelsSerum estradiol levelsSub-populations of macrophagesAssociated with cancer prognosisSuppressed tumor growthColorectal tumor growthExogenous asparagineColorectal cancer developmentColorectal cancer cellsNegative feed-back effectEstradiol levelsGlutamate levelsSex-related differencesSex-specific effectsMale miceCancer prognosisAsparagine supplementationCancer progressionMiceDecreased numberTumorProjectome-based characterization of hypothalamic peptidergic neurons in male mice
Jiao Z, Gao T, Wang X, Wang A, Ma Y, Feng L, Gao L, Gou L, Zhang W, Biglari N, Boxer E, Steuernagel L, Ding X, Yu Z, Li M, Gao M, Hao M, Zhou H, Cao X, Li S, Jiang T, Qi J, Jia X, Feng Z, Ren B, Chen Y, Shi X, Wang D, Wang X, Han L, Liang Y, Qian L, Jin C, Huang J, Deng W, Wang C, Li E, Hu Y, Tao Z, Li H, Yu X, Xu M, Chang H, Zhang Y, Xu H, Yan J, Li A, Luo Q, Stoop R, Sternson S, Brüning J, Anderson D, Poo M, Sun Y, Xu S, Gong H, Sun Y, Xu X. Projectome-based characterization of hypothalamic peptidergic neurons in male mice. Nature Neuroscience 2025, 28: 1073-1088. PMID: 40140607, DOI: 10.1038/s41593-025-01919-0.Peer-Reviewed Original ResearchConceptsHypothalamic peptidergic neuronsMale micePeptidergic neuronsStructural basisInnate behaviorsHypothalamic functionBrain regionsPhysiological homeostasisAxonal projectionsCircuit mechanismsPeptidergic axonsHypothalamic axonsSoma distributionsHypothalamusMiceAxonsNeuropeptideTopographic organizationNeuronsMaleSuppression 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 disordersTransient Upregulation of Procaspase-3 during Oligodendrocyte Fate Decisions
Kamen Y, Chapman T, Piedra E, Ciolkowski M, Hill R. Transient Upregulation of Procaspase-3 during Oligodendrocyte Fate Decisions. Journal Of Neuroscience 2025, 45: e2066242025. PMID: 39837665, PMCID: PMC11924999, DOI: 10.1523/jneurosci.2066-24.2025.Peer-Reviewed Original ResearchProcaspase-3Fate decisionsOligodendrocyte precursor cellsCell death mechanismsNeurodegenerative conditionsOligodendrocyte differentiationSurvival decisionsCellular checkpointsDeath mechanismsMolecular markersPrecursor cellsOligodendrocyte markersPromote oligodendrocyte differentiationPharmacological inhibitionDifferentiation stageTransient upregulationDifferentiationZymogenCellsOligodendrocyte densityMorphological stateMale miceOligodendrocyte deathMyelin dysfunctionMarkers
2024
Cxcl10 is protective during mouse-adapted SARS-CoV-2 infection
Majumdar S, Weaver J, Pontejo S, Minai M, Lu X, Gao J, Holmes G, Johnson R, Zhang H, Kelsall B, Farber J, Alves D, Murphy P. Cxcl10 is protective during mouse-adapted SARS-CoV-2 infection. Journal Of Leukocyte Biology 2024, 117: qiae252. PMID: 39607906, PMCID: PMC11953068, DOI: 10.1093/jleuko/qiae252.Peer-Reviewed Original ResearchSARS-CoV-2 infectionSARS-CoV-2Mouse-adapted strain of SARS-CoV-2Absence of CXCL10Associated with poor outcomesCXCL10-/- miceLungs of male miceInflammatory gene inductionAcute SARS-CoV-2 infectionMouse-adapted strainSevere COVID-19Wild type controlsCXCL10-deficientChemokine CXCL10Lymphocytic infiltrationSevere acute respiratory syndrome coronavirus 2Poor outcomeAcute respiratory syndrome coronavirus 2Circulating levelsMale miceRespiratory syndrome coronavirus 2Infected miceSARS-CoV-2 pathogenesisVirus loadCXCL10Vγ6/Vδ1+ γδ T cells protect from angiotensin II effects on blood pressure and endothelial function in mice
Mahmoud A, Caillon A, Shokoples B, Ferreira N, Comeau K, Hatano S, Yoshikai Y, Lewis J, Tigelaar R, Paradis P, Schiffrin E. Vγ6/Vδ1+ γδ T cells protect from angiotensin II effects on blood pressure and endothelial function in mice. Journal Of Hypertension 2024, 43: 109-119. PMID: 39248136, DOI: 10.1097/hjh.0000000000003871.Peer-Reviewed Original ResearchGd T cellsT cellsBlood pressureAngII infusionEndothelial dysfunctionBP elevationPerivascular tissueAngiotensin II (AngII)-induced hypertensionSpecific T cell receptorMesenteric arterial functionArtery endothelial dysfunctionAngiotensin II effectsDescending thoracic aortaT cell receptorAngII-infused micePerivascular adipose tissuePressure myographyHypertensive effectEndothelial functionThoracic aortaII effectsMale miceVascular injuryArterial functionFlow cytometryAT1b receptors contribute to regional disparities in angiotensin II mediated aortic remodelling in mice
Cavinato C, Spronck B, Caulk A, Murtada S, Humphrey J. AT1b receptors contribute to regional disparities in angiotensin II mediated aortic remodelling in mice. Journal Of The Royal Society Interface 2024, 21: 20240110. PMID: 39192727, PMCID: PMC11350382, DOI: 10.1098/rsif.2024.0110.Peer-Reviewed Original ResearchConceptsAngiotensin II infusionAT1B receptorsII infusionAngiotensin IIChronic angiotensin II infusionDays of angiotensin II infusionWild-typeAortas of WTSmooth muscle contractilityDescending thoracic aortaAngiotensin II signalingInflammatory cell responseRenin-angiotensin systemRegulating blood pressureAngII infusionAortic remodelingCell biological changesImmunohistological changesIndependent of sexMuscle contractilityMale miceMouse modelAbdominal aortaArterial remodelingBlood pressureSmall molecule inhibition of glycogen synthase I reduces muscle glycogen content and improves biomarkers in a mouse model of Pompe disease
Gaspar R, Sakuma I, Nasiri A, Hubbard B, LaMoia T, Leitner B, Tep S, Xi Y, Green E, Ullman J, Petersen K, Shulman G. Small molecule inhibition of glycogen synthase I reduces muscle glycogen content and improves biomarkers in a mouse model of Pompe disease. AJP Endocrinology And Metabolism 2024, 327: e524-e532. PMID: 39171753, PMCID: PMC11482269, DOI: 10.1152/ajpendo.00175.2024.Peer-Reviewed Original ResearchGAA-KO miceMouse model of Pompe diseaseModel of Pompe diseasePompe diseaseMetabolic dysregulationRegular chowMouse modelSmall molecule inhibitionInsulin sensitivityReduced spontaneous activityGroups of male miceEnzyme acid alpha-glucosidaseProgressive muscle weaknessImprove metabolic dysregulationSynthase IWhole-body insulin sensitivityAcid alpha-glucosidaseImproved glucose toleranceIncreased AMPK phosphorylationWT miceAbnormal accumulation of glycogenGlycogen storage disorderMale miceSpontaneous activityImproved biomarkersHydrogen sulfide produced by the gut microbiota impairs host metabolism via reducing GLP-1 levels in male mice
Qi Q, Zhang H, Jin Z, Wang C, Xia M, Chen B, Lv B, Peres Diaz L, Li X, Feng R, Qiu M, Li Y, Meseguer D, Zheng X, Wang W, Song W, Huang H, Wu H, Chen L, Schneeberger M, Yu X. Hydrogen sulfide produced by the gut microbiota impairs host metabolism via reducing GLP-1 levels in male mice. Nature Metabolism 2024, 6: 1601-1615. PMID: 39030389, DOI: 10.1038/s42255-024-01068-x.Peer-Reviewed Original ResearchConceptsHost metabolismGLP-1 productionGut microbiotaUnfolded protein responseMicrobiota-derived metabolitesIntestinal L cellsInhibit mitochondrial respirationDiet-induced metabolic disordersGut hormone glucagon-like peptide 1Hormone glucagon-like peptide 1Intestinal symbiontsProtein responseGLP-1Male miceGLP-1 secretionMitochondrial respirationGene expressionL cellsGutGlucagon-like peptide 1Production of hydrogen sulfideMicrobiotaPathogenesis of metabolic syndromeGLP-1 levelsDesulfovibrioRenalase peptides reduce pancreatitis severity in mice
Kolodecik T, Guo X, Shugrue C, Guo X, Desir G, Wen L, Gorelick F. Renalase peptides reduce pancreatitis severity in mice. AJP Gastrointestinal And Liver Physiology 2024, 327: g466-g480. PMID: 39010833, PMCID: PMC11427088, DOI: 10.1152/ajpgi.00143.2024.Peer-Reviewed Original ResearchAcute pancreatitisRecombinant renalaseProsurvival propertiesSeverity of acute pancreatitisModel of acute pancreatitisAcute inflammatory injuryClinically relevant modelAnti-inflammatoryHistological tissue injuryPost-ERCPCerulein modelCerulein-inducedInitial dosePancreatitis severityPreclinical modelsImmunohistochemical markersQuantify inflammationInflammatory changesMale micePancreatitisMacrophage populationsTissue injuryCerulein pancreatitisTherapeutic effectRenalaseSex differences in the distribution and density of regulatory interneurons in the striatum
Van Zandt M, Flanagan D, Pittenger C. Sex differences in the distribution and density of regulatory interneurons in the striatum. Frontiers In Cellular Neuroscience 2024, 18: 1415015. PMID: 39045533, PMCID: PMC11264243, DOI: 10.3389/fncel.2024.1415015.Peer-Reviewed Original ResearchFast spiking interneuronsCholinergic interneuronsDorsal striatumSex differencesTourette syndromeVentral striatumNeuropsychiatric disordersSomatostatin expressionContext of psychopathologyHuman neuropsychiatric disordersBasal ganglia functionInvestigate sex differencesNucleus accumbensCaudate-putamenBehavioral pathologyStriatumSomatostatin-expressing interneuronsStriatal interneuronsGABAergic interneuronsMale miceStereological quantificationFemale miceInterneuronsDisordersAccumbensCaloric restriction reduces trabecular bone loss during aging and improves bone marrow adipocyte endocrine function in male mice
Rinne C, Soultoukis G, Oveisi M, Leer M, Schmidt-Bleek O, Burkhardt L, Bucher C, Moussa E, Makhlouf M, Duda G, Saraiva L, Schmidt-Bleek K, Schulz T. Caloric restriction reduces trabecular bone loss during aging and improves bone marrow adipocyte endocrine function in male mice. Frontiers In Endocrinology 2024, 15: 1394263. PMID: 38904042, PMCID: PMC11188307, DOI: 10.3389/fendo.2024.1394263.Peer-Reviewed Original ResearchConceptsBone marrow adipose tissueTrabecular bone lossAged miceCaloric restrictionBone lossEndocrine profileMale C57BL6J miceCardio-metabolic diseasesTime of CRAge-matched littermatesBiochemical lipid profilesAssess bone microstructureFree food accessC57BL6J miceBone healthYoung miceContext of agingMale miceDietary interventionNutritional interventionAnatomical localizationLipid profileAdipogenic gene expressionBone dysfunctionTrabecular bone structureVolume microscopic analysis of membrane contact sites in mouse kidney renal proximal tubule epithelial cells
Pandya R, Pang S, Lackner E, Reyna-Neyra A, Li W, Sy K, Burdyniuk M, Weisz O, Xu C, Caplan M. Volume microscopic analysis of membrane contact sites in mouse kidney renal proximal tubule epithelial cells. Physiology 2024, 39: 1086. DOI: 10.1152/physiol.2024.39.s1.1086.Peer-Reviewed Original ResearchMembrane contact sitesProximal tubule epithelial cellsTubule epithelial cellsEndoplasmic reticulumEpithelial cellsContact sitesPlasma membraneER volumeRenal proximal tubule epithelial cellsFunction of membrane contact sitesVolume of endoplasmic reticulumProximal tubule cellsInter-organelle communicationBasal-lateral surfacesRenal epithelial cellsAdvanced imaging techniquesMedian volumeTubule cellsMale miceCell plasma membraneRenal cortexScanning electron microscopyFIB-SEMMouse kidneySmooth ERFatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring
Sun J, Esplugues E, Bort A, Cardelo M, Ruz-Maldonado I, Fernández-Tussy P, Wong C, Wang H, Ojima I, Kaczocha M, Perry R, Suárez Y, Fernández-Hernando C. Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring. Nature Metabolism 2024, 6: 741-763. PMID: 38664583, DOI: 10.1038/s42255-024-01019-6.Peer-Reviewed Original ResearchConceptsFatty acid binding protein 5Tumor-associated macrophagesHepatocellular carcinomaImmunosuppressive phenotype of tumor-associated macrophagesIncreased CD8+ T cell activationCD8+ T cell activationPhenotype of tumor-associated macrophagesPro-inflammatory tumor microenvironmentCo-stimulatory molecules CD80T cell activationHepatocellular carcinoma burdenTransformation of hepatocytesBinding protein 5Potential therapeutic approachImmunosuppressive phenotypeTumor microenvironmentFerroptosis-induced cell deathMale miceEnhanced ferroptosisTherapeutic approachesPharmacological inhibitionGenetic ablationIncreased expressionSingle-cell atlasAnalysis of transformed cellsSingle 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
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