2024
Divergent role of Mitochondrial Amidoxime Reducing Component 1 (MARC1) in human and mouse
Smagris E, Shihanian L, Mintah I, Bigdelou P, Livson Y, Brown H, Verweij N, Hunt C, Johnson R, Greer T, Hartford S, Hindy G, Sun L, Nielsen J, Halasz G, Lotta L, Murphy A, Sleeman M, Gusarova V. Divergent role of Mitochondrial Amidoxime Reducing Component 1 (MARC1) in human and mouse. PLOS Genetics 2024, 20: e1011179. PMID: 38437227, PMCID: PMC10939284, DOI: 10.1371/journal.pgen.1011179.Peer-Reviewed Original ResearchConceptsAssociation studiesExome-wide association studyHuman genome-wide association studiesGenome-wide association studiesLoss of function variantsFamily enzymesMissense variantsObserved phenotypesFunctional variantsAberrant localizationProtein instabilityAncestry groupsHepatic triglyceride accumulationDivergent rolesLiver phenotypePhysiological functionsTriglyceride accumulationPhenotypeDeletionMouse liverIn vitro studiesHepatic cellsProteinEnzymeKnockout mice
2023
Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency
Altarejos J, Pangilinan J, Podgrabinska S, Akinci B, Foss-Freitas M, Neidert A, Ray Y, Zheng W, Kim S, Kamat V, Huang M, Min S, Mastaitis J, Dominguez-Gutierrez G, Kim J, Stevis P, Huang T, Zambrowicz B, Olson W, Godin S, Bradley E, Gewitz A, Baker M, Hench R, Davenport M, Chenevert T, DiPaola F, Yancopoulos G, Murphy A, Herman G, Musser B, Dansky H, Harp J, Gromada J, Sleeman M, Oral E, Olenchock B. Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency. Science Translational Medicine 2023, 15: eadd4897. PMID: 37992152, DOI: 10.1126/scitranslmed.add4897.Peer-Reviewed Original ResearchConceptsLeptin concentrationsBody weightHepatic steatosisAdipose-derived hormone leptinClass 3 obesityCompassionate use treatmentHigher baseline leptinLeptin knockout miceAcceptable safety profileLower leptin concentrationsPresence of leptinHuman monoclonal antibodyLeptin receptor signalingTreatment of individualsPhase 1Baseline leptinLepr signalingLeptin deficiencyMetabolic sequelaeLiver diseaseClinical benefitSafety profileInsulin resistanceBlood glucoseInsulin sensitivity
2008
Increased fear‐ and stress‐related anxiety‐like behavior in mice lacking tuberoinfundibular peptide of 39 residues
Fegley DB, Holmes A, Riordan T, Faber CA, Weiss JR, Ma S, Batkai S, Pacher P, Dobolyi A, Murphy A, Sleeman MW, Usdin TB. Increased fear‐ and stress‐related anxiety‐like behavior in mice lacking tuberoinfundibular peptide of 39 residues. Genes Brain & Behavior 2008, 7: 933-942. PMID: 18700839, PMCID: PMC2605196, DOI: 10.1111/j.1601-183x.2008.00432.x.Peer-Reviewed Original ResearchConceptsAnxiety-like behaviorAnxiety-related behaviorTuberoinfundibular peptideElevated plus-maze assayParathyroid hormone 2 receptorMedial paralemniscal nucleusGreater anxiety-like behaviorPavlovian fear conditioning paradigmShock-probe testGroups of neuronsMedial prefrontal cortexSubparafascicular areaNeurons projectAnxiety-related phenotypesLateral brainstemParalemniscal nucleusLateral septumBed nucleusStria terminalisFear conditioning paradigmEnvironmental provocationTargeted null mutationBrain regionsFear extinctionPrefrontal cortexHypothalamic Fatty Acid Metabolism Mediates the Orexigenic Action of Ghrelin
López M, Lage R, Saha AK, Pérez-Tilve D, Vázquez MJ, Varela L, Sangiao-Alvarellos S, Tovar S, Raghay K, Rodríguez-Cuenca S, Deoliveira RM, Castañeda T, Datta R, Dong JZ, Culler M, Sleeman MW, Álvarez C, Gallego R, Lelliott CJ, Carling D, Tschöp MH, Diéguez C, Vidal-Puig A. Hypothalamic Fatty Acid Metabolism Mediates the Orexigenic Action of Ghrelin. Cell Metabolism 2008, 7: 389-399. PMID: 18460330, DOI: 10.1016/j.cmet.2008.03.006.Peer-Reviewed Original ResearchMeSH KeywordsAMP-Activated Protein Kinase KinasesAnimalsBlotting, WesternCarnitine O-PalmitoyltransferaseFas ReceptorFastingFatty Acid SynthasesFatty AcidsFeeding BehaviorGhrelinHypothalamusIn Situ HybridizationLeptinMaleMalonyl Coenzyme AMiceMice, Inbred C57BLMice, KnockoutMice, ObesePhosphorylationProtein KinasesRatsRats, Sprague-DawleyConceptsHypothalamic fatty acid metabolismFatty acid metabolismFatty acid synthaseAcid metabolismCarnitine palmitoyltransferase 1 activityFatty acid biosynthesisRegion-specific mannerGhrelin's effectsOrexigenic responseHypothalamic levelOrexigenic actionVentromedial nucleusFood intakeCurrent evidenceFAS expressionGhrelinAcid biosynthesisRelevant regulatory systemGenetic approachesProtein kinaseAMPK activityAcid synthaseSpecific inhibitionRegulatory systemPhysiological mechanismsThe mutation ROR2W749X, linked to human BDB, is a recessive mutation in the mouse, causing brachydactyly, mediating patterning of joints and modeling recessive Robinow syndrome
Raz R, Stricker S, Gazzerro E, Clor JL, Witte F, Nistala H, Zabski S, Pereira RC, Stadmeyer L, Wang X, Gowen L, Sleeman MW, Yancopoulos GD, Canalis E, Mundlos S, Valenzuela DM, Economides AN. The mutation ROR2W749X, linked to human BDB, is a recessive mutation in the mouse, causing brachydactyly, mediating patterning of joints and modeling recessive Robinow syndrome. Development 2008, 135: 1713-1723. PMID: 18353862, DOI: 10.1242/dev.015149.Peer-Reviewed Original ResearchAbnormalities, MultipleAnimalsBody Mass IndexBone Morphogenetic ProteinsFertilityGenes, RecessiveGrowth Differentiation Factor 5HumansJointsLimb Deformities, CongenitalMaleMiceMice, Mutant StrainsMusculoskeletal AbnormalitiesMutationReceptor Protein-Tyrosine KinasesReceptor Tyrosine Kinase-like Orphan ReceptorsSyndrome
2007
Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure
Pfluger PT, Kirchner H, Günnel S, Schrott B, Perez-Tilve D, Fu S, Benoit SC, Horvath T, Joost HG, Wortley KE, Sleeman MW, Tschöp M. Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure. AJP Gastrointestinal And Liver Physiology 2007, 294: g610-g618. PMID: 18048479, DOI: 10.1152/ajpgi.00321.2007.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAnimalsAnthropometryBlood GlucoseBody CompositionBody TemperatureBody WeightEatingEnergy MetabolismGene DeletionGenotypeGhrelinGlucose Tolerance TestInsulin ResistanceLigandsLipidsMiceMice, KnockoutMotor ActivityReceptors, GhrelinReverse Transcriptase Polymerase Chain ReactionRNA, MessengerConceptsFood intakeSimultaneous deletionStandard dietHigh-fat diet-induced obesityMotor activityWild-type control miceFirst mouse mutantsMetabolic phenotypeDiet-induced obesityEnergy metabolism phenotypesEnergy expenditureGene-deficient miceKnockout mice exhibitSingle gene-deficient miceSame genetic backgroundMost speciesWT miceControl miceStandard chowMolecular controlBody adiposityBiological roleLean massMouse mutantsMeal patterns