2025
B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity
Puente-Ruiz S, Ide L, Schuller J, Ben-Kraiem A, Hoffmann A, Ghosh A, Noé F, Wolfrum C, Krause K, Gericke M, Klöting N, Brüning J, Wunderlich F, Blüher M, Jais A. B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity. IScience 2025, 28: 112819. DOI: 10.1016/j.isci.2025.112819.Peer-Reviewed Original ResearchMacrophage recruitmentMetabolic inflammationGlucose toleranceEffects of nociceptin/orphanin FQInsulin resistanceN/OFQ-NOP systemAdverse metabolic effectsImpaired glucose toleranceImmune cell migrationDiet-induced obesityNociceptin/orphanin FQB cellsEnhanced insulin sensitivityKnockout miceOpioid peptidesImmune regulationGlucose intoleranceMetabolic effectsImmunomodulatory propertiesInflammatory processN/OFQInsulin sensitivityObesityTherapeutic targetAdipose tissueFGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression
Gliniak C, Gordillo R, Youm Y, Lin Q, Crewe C, Zhang Z, Field B, Fujikawa T, Virostek M, Zhao S, Zhu Y, Rosen C, Horvath T, Dixit V, Scherer P. FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression. Cell Metabolism 2025, 37: 1547-1567.e6. PMID: 40527315, DOI: 10.1016/j.cmet.2025.05.011.Peer-Reviewed Original ResearchInflammatory immune cellsVisceral adipose tissueDiet-induced obesityAged transgenic miceHigh-fat dietAbsence of adiponectinTreat metabolic syndromeFibroblast growth factor 21Immune cellsLipotoxic ceramidesMetabolic syndromeReduced liver steatosisTransgenic miceMetabolic profileMetabolic benefitsInsulin sensitivityLiver steatosisIn adulthoodAdipose tissueMiceFat tissueImprove metabolismGrowth suppressionMetabolic issuesAge-related diseases
2024
Keep 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 cytokinesGlobal deletion of G protein‐coupled receptor 55 impairs glucose homeostasis during obesity by reducing insulin secretion and β‐cell turnover
Liu B, Ruz‐Maldonado I, Persaud S. Global deletion of G protein‐coupled receptor 55 impairs glucose homeostasis during obesity by reducing insulin secretion and β‐cell turnover. Diabetes Obesity And Metabolism 2024, 26: 4591-4601. PMID: 39113250, DOI: 10.1111/dom.15816.Peer-Reviewed Original ResearchGPR55<sup>-/-</sup> miceDiet-induced obesityIncreased islet cell apoptosisHigh-fat dietB cell proliferationWild-typeCytokine-induced apoptosisInsulin secretionCaspase-3/7 activityIslet cell apoptosisGlucose homeostasisInsulin secretion in vivoWT miceB cellsDynamic insulin secretionImpaired glucose-Standard chowSusceptibility to diet-induced obesityPerifusion of isolated isletsIslet functionG protein-coupled receptorsG protein-coupled receptor 55Weeks of dietary interventionReduced insulin secretionB cell turnoverDietary pyruvate targets cytosolic phospholipase A2 to mitigate inflammation and obesity in mice
Hasan S, Ghani N, Zhao X, Good J, Huang A, Wrona H, Liu J, Liu C. Dietary pyruvate targets cytosolic phospholipase A2 to mitigate inflammation and obesity in mice. Protein & Cell 2024, 15: 661-685. PMID: 38512816, PMCID: PMC11365557, DOI: 10.1093/procel/pwae014.Peer-Reviewed Original ResearchCytosolic phospholipase A2White adipose tissue inflammationAdipose tissue inflammationTissue inflammationState of chronic low-grade inflammationChronic low-grade inflammationHFD-induced weight gainLow-grade inflammationAttenuation of inflammationMolecular targetsPotential therapeutic optionDevelopment of metabolic disordersProtective effect of pyruvateAdipogenic differentiation in vitroDiet-induced obesityNonalcoholic fatty liver diseaseDifferentiation in vitroDrug affinity responsive target stabilityFatty liver diseasePhospholipase A2Meta-inflammationTherapeutic optionsDrug responseGlobal ablationMultifactorial etiologyTAAR1 agonists improve glycemic control, reduce body weight and modulate neurocircuits governing energy balance and feeding
Dedic N, Wang L, Hajos-Korcsok E, Hecksher-Sørensen J, Roostalu U, Vickers S, Wu S, Anacker C, Synan C, Jones P, Milanovic S, Hopkins S, Bristow L, Koblan K. TAAR1 agonists improve glycemic control, reduce body weight and modulate neurocircuits governing energy balance and feeding. Molecular Metabolism 2024, 80: 101883. PMID: 38237896, PMCID: PMC10839149, DOI: 10.1016/j.molmet.2024.101883.Peer-Reviewed Original ResearchConceptsTrace amine-associated receptor 1Trace amine-associated receptor 1 agonistAntipsychotic drugsEffects of TAAR1 agonistsOlanzapine-induced weight gainDiet-induced obesityReduced body weightFood intakeHigh-fat dietSub-chronic administrationC-Fos protein expressionDiet-induced obese miceImprove glycemic controlRegulators of metabolic controlGlycemic controlGastric emptyingSchizophrenia patientsTAAR1 agonistsHedonic feedingLimbic structuresBody weightMetabolic parametersMouse modelGlucose toleranceWeight gain
2023
Time-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 factorsA multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke
Lyden P, Diniz M, Bosetti F, Lamb J, Nagarkatti K, Rogatko A, Kim S, Cabeen R, Koenig J, Akhter K, Arbab A, Avery B, Beatty H, Bibic A, Cao S, Simoes Braga Boisserand L, Chamorro A, Chauhan A, Diaz-Perez S, Dhandapani K, Dhanesha N, Goh A, Herman A, Hyder F, Imai T, Johnson C, Khan M, Kamat P, Karuppagounder S, Kumskova M, Mihailovic J, Mandeville J, Morais A, Patel R, Sanganahalli B, Smith C, Shi Y, Sutariya B, Thedens D, Qin T, Velazquez S, Aronowski J, Ayata C, Chauhan A, Leira E, Hess D, Koehler R, McCullough L, Sansing L. A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke. Science Translational Medicine 2023, 15: eadg8656. PMID: 37729432, DOI: 10.1126/scitranslmed.adg8656.Peer-Reviewed Original ResearchConceptsPreclinical assessmentFocal cerebral ischemic insultAcute ischemic strokeCerebral ischemic insultLarge clinical trialsDiet-induced obesityNew clinical interventionsIntravascular thrombectomyIschemic strokeStroke treatmentHypertensive ratsIschemic insultBlinded assessmentClinical trialsYoung miceTreatment candidatesExclusion criteriaAnimal modelsYoung ratsFutile interventionsPreclinical trialsClinical interventionsFutility boundariesMiceDisease areasO-linked N-acetylglucosamine modification is essential for physiological adipose expansion induced by high-fat feeding
Nakamoto A, Ohashi N, Sugawara L, Morino K, Ida S, Perry R, Sakuma I, Yanagimachi T, Fujita Y, Ugi S, Kume S, Shulman G, Maegawa H. O-linked N-acetylglucosamine modification is essential for physiological adipose expansion induced by high-fat feeding. AJP Endocrinology And Metabolism 2023, 325: e46-e61. PMID: 37224467, PMCID: PMC10292976, DOI: 10.1152/ajpendo.00263.2022.Peer-Reviewed Original ResearchConceptsFKO miceAdipose tissueBody weight gainPrimary cultured adipocytesAdipose expansionFree fatty acidsInflammatory genesWeight gainFree fatty acid effluxCultured adipocytesDiet-induced obesityHigh-fat dietHigh-fat feedingLess body weightDe novo lipogenesisAdipose tissue physiologyDe novo lipogenesis genesFatty acid effluxWeeks of ageAdipose inflammationGlucose intoleranceRAW 264.7 macrophagesControl miceFatty acidsSevere fibrosisHepatic follistatin increases basal metabolic rate and attenuates diet-induced obesity during hepatic insulin resistance
Tao R, Stöhr O, Wang C, Qiu W, Copps K, White M. Hepatic follistatin increases basal metabolic rate and attenuates diet-induced obesity during hepatic insulin resistance. Molecular Metabolism 2023, 71: 101703. PMID: 36906067, PMCID: PMC10033741, DOI: 10.1016/j.molmet.2023.101703.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceInsulin resistanceAdipose massBasal metabolic rateHepatic disruptionDiet-induced obesityFat mass accumulationTotal lean massHigh-fat dietBody weight changesHFD consumptionFat massLean massFOXO1-dependent mannerHepatic overexpressionHepatic insulinObesityMetabolic rate
2022
IgM-associated gut bacteria in obesity and type 2 diabetes in C57BL/6 mice and humans
Pearson JA, Ding H, Hu C, Peng J, Galuppo B, Wong FS, Caprio S, Santoro N, Wen L. IgM-associated gut bacteria in obesity and type 2 diabetes in C57BL/6 mice and humans. Diabetologia 2022, 65: 1398-1411. PMID: 35587276, PMCID: PMC9283171, DOI: 10.1007/s00125-022-05711-8.Peer-Reviewed Original ResearchConceptsFecal microbiota transplantType 2 diabetesNormal glucose toleranceB6 miceWild-type miceGlucose toleranceIgM antibodiesObese youthGut microbiotaWeight gainGut bacteriaObese young individualsImpaired glucose toleranceDiet-induced obesityConclusions/interpretationOur resultsBody weight gainGreater weight gainMice fecal microbiotaHuman stool samplesGlucose intoleranceClinical featuresC57BL/6 miceMicrobiota transplantRecipient miceStool samplesBrown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance
Huang Y, Zhou JH, Zhang H, Canfrán-Duque A, Singh AK, Perry RJ, Shulman G, Fernandez-Hernando C, Min W. Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance. Journal Of Clinical Investigation 2022, 132 PMID: 35202005, PMCID: PMC9057632, DOI: 10.1172/jci148852.Peer-Reviewed Original ResearchConceptsBrown adipose tissueBAT inflammationInsulin resistanceMitochondrial reactive oxygen speciesReactive oxygen speciesAberrant innate immune responsesDiet-induced insulin resistanceSystematic metabolismDiet-induced obesityNLRP3 inflammasome pathwayWhole-body energy metabolismCGAS/STINGInnate immune responseFatty acid oxidationExcessive mitochondrial reactive oxygen speciesMetabolic benefitsImmune responseInflammasome pathwayAdipose tissueInflammationInhibition reversesLipid uptakeLipid metabolismThioredoxin 2Adaptive thermogenesisEffects of diet-induced obesity in the development of lymphedema in the animal model: A literature review
Khan N, Huayllani MT, Lu X, Boczar D, Cinotto G, Avila FR, Guliyeva G, Forte AJ. Effects of diet-induced obesity in the development of lymphedema in the animal model: A literature review. Obesity Research & Clinical Practice 2022, 16: 197-205. PMID: 35659463, DOI: 10.1016/j.orcp.2022.05.003.Peer-Reviewed Original ResearchConceptsAerobic exerciseT cellsAnimal modelsLymphatic dysfunctionEffect of obesityLipid metabolism disordersDiet-induced obesityHigh-fat dietDevelopment of lymphedemaAdipose tissue depositionVEGFR-3 expressionImpaired lymphatic drainageInhibition of lymphangiogenesisUnderlying cellular mechanismsInflammatory cascadeOvid EmbaseDiet/Metabolism disordersPharmacological interventionsEligibility criteriaLymphatic drainageContractile propertiesLong-term exposureObesityLymphatic endothelial cellsA hypothalamic pathway for Augmentor α–controlled body weight regulation
Ahmed M, Kaur N, Cheng Q, Shanabrough M, Tretiakov EO, Harkany T, Horvath TL, Schlessinger J. A hypothalamic pathway for Augmentor α–controlled body weight regulation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2200476119. PMID: 35412887, PMCID: PMC9169862, DOI: 10.1073/pnas.2200476119.Peer-Reviewed Original ResearchConceptsParaventricular nucleusBody weightDiet-induced obesityBody weight regulationDiscrete neuronal populationsMelanocortin receptor 4Whole-body energy homeostasisPhysiological rolePeptide neuronsHypothalamic pathwaysReceptor 4Neuronal pathwaysPhysical activityLittermate controlsWeight regulationNeuronal populationsMetabolic diseasesTherapeutic opportunitiesMutant miceEnergy homeostasisMiceALKCancerHuman cancersALK mutantsInhibition of high-fat diet–induced obesity via reduction of ER-resident protein Nogo occurs through multiple mechanisms
Wang X, Yang Y, Zhao D, Zhang S, Chen Y, Chen Y, Feng K, Li X, Han J, Iwakiri Y, Duan Y, Yang X. Inhibition of high-fat diet–induced obesity via reduction of ER-resident protein Nogo occurs through multiple mechanisms. Journal Of Biological Chemistry 2022, 298: 101561. PMID: 34998825, PMCID: PMC8814669, DOI: 10.1016/j.jbc.2022.101561.Peer-Reviewed Original ResearchConceptsHigh-fat dietMetabolic disordersHigh-fat diet-induced obesityBody mass index valuesInhibition of NogoSerum proinflammatory cytokinesDiet-induced obesityInfiltration of macrophagesType 2 diabetesWT littermate control miceLittermate control miceEffects of NogoMass index valuesBrown adipose tissueProtect miceNormal chowControl miceProinflammatory cytokinesInsulin resistanceObesity treatmentRisk factorsLipid profileCardiovascular diseaseProtein NogoObesity
2021
Astrocytic lipid metabolism determines susceptibility to diet-induced obesity
Varela L, Kim JG, Fernández-Tussy P, Aryal B, Liu ZW, Fernández-Hernando C, Horvath TL. Astrocytic lipid metabolism determines susceptibility to diet-induced obesity. Science Advances 2021, 7: eabj2814. PMID: 34890239, PMCID: PMC11323787, DOI: 10.1126/sciadv.abj2814.Peer-Reviewed Original ResearchDiet-induced obesityHypothalamic astrocytesPeroxisome proliferator-activated receptor gammaHypothalamic neuronal circuitsProliferator-activated receptor gammaControl of feedingFatty acid homeostasisSystemic glucoseMetabolic milieuGlucose homeostasisBody weightReceptor gammaSynaptic plasticityNeuronal circuitsNutrient sensingLipid metabolismCellular adaptationObesityAstrocytesAcid homeostasisUnidentified roleFA metabolismEnergy metabolismElevated susceptibilityAvailability of FAIL-27 signalling promotes adipocyte thermogenesis and energy expenditure
Wang Q, Li D, Cao G, Shi Q, Zhu J, Zhang M, Cheng H, Wen Q, Xu H, Zhu L, Zhang H, Perry RJ, Spadaro O, Yang Y, He S, Chen Y, Wang B, Li G, Liu Z, Yang C, Wu X, Zhou L, Zhou Q, Ju Z, Lu H, Xin Y, Yang X, Wang C, Liu Y, Shulman GI, Dixit VD, Lu L, Yang H, Flavell RA, Yin Z. IL-27 signalling promotes adipocyte thermogenesis and energy expenditure. Nature 2021, 600: 314-318. PMID: 34819664, DOI: 10.1038/s41586-021-04127-5.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesAnimalsBariatric SurgeryDisease Models, AnimalEnergy MetabolismFemaleHumansInsulin ResistanceInterleukin-27MaleMiceObesityp38 Mitogen-Activated Protein KinasesPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaReceptors, InterleukinSignal TransductionThermogenesisUncoupling Protein 1ConceptsIL-27Beige adipose tissueAdipose tissueSerum IL-27Diet-induced obesityBariatric surgeryMetabolic morbidityImmunological factorsInsulin resistanceObesity showTherapeutic administrationMetabolic disordersMouse modelObesityPromising targetEnergy expenditureSignaling promotesThermogenesisBody temperatureMetabolic programsImportant roleTissueCritical roleImmunotherapyMorbidityHepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice
Singh AK, Chaube B, Zhang X, Sun J, Citrin KM, Canfrán-Duque A, Aryal B, Rotllan N, Varela L, Lee RG, Horvath TL, Price N, Suárez Y, Fernandez-Hernando C. Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice. Journal Of Clinical Investigation 2021, 131 PMID: 34255741, PMCID: PMC8409581, DOI: 10.1172/jci140989.Peer-Reviewed Original ResearchDiet-induced obesityGlucose intoleranceHigh-fat fed conditionsLipoprotein lipaseExcess hepatic lipid accumulationSystemic metabolic dysfunctionRole of ANGPTL4Liver lipid metabolismHepatic lipid accumulationTargeted pharmacologic therapyANGPTL4 gene expressionMetabolic turnover studiesHepatic lipase activityObesity-associated diabetesFatty acidsNovel inhibition strategiesPharmacologic therapyLiver steatosisLiver damageLipoprotein remnantsCholesterol levelsMetabolic dysfunctionHepatic uptakeANGPTL4 deficiencyHL activityObesity Induces Elevated Oxidative Stress in Uteri of Reproductive Age Mice
Huang J, Xiao E, Tal A, Kelly K, Kim J, Whirledge S, Flannery C. Obesity Induces Elevated Oxidative Stress in Uteri of Reproductive Age Mice. Journal Of The Endocrine Society 2021, 5: a752-a752. DOI: 10.1210/jendso/bvab048.1529.Peer-Reviewed Original ResearchWeeks of dietNC miceHF miceHigher body fatProtein carbonylsOxidative stressAge miceBody fatChronic diet-induced obesityDiet-induced obese miceObesity-related disruptionIndependent risk factorInsulin tolerance testingHigh-fat chowLong-term obesitySeverity of obesityC57BL/6 female miceDiet-induced obesityHigh fat consumptionUterine oxidative stressCYP enzymatic activitiesAge-dependent increaseElevated oxidative stressDNA damageCytochrome P450 expression
2020
A MicroRNA Linking Human Positive Selection and Metabolic Disorders
Wang L, Sinnott-Armstrong N, Wagschal A, Wark AR, Camporez JP, Perry RJ, Ji F, Sohn Y, Oh J, Wu S, Chery J, Moud BN, Saadat A, Dankel SN, Mellgren G, Tallapragada DSP, Strobel SM, Lee MJ, Tewhey R, Sabeti PC, Schaefer A, Petri A, Kauppinen S, Chung RT, Soukas A, Avruch J, Fried SK, Hauner H, Sadreyev RI, Shulman GI, Claussnitzer M, Näär AM. A MicroRNA Linking Human Positive Selection and Metabolic Disorders. Cell 2020, 183: 684-701.e14. PMID: 33058756, PMCID: PMC8092355, DOI: 10.1016/j.cell.2020.09.017.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytes, BrownAdiposityAllelesAnimalsCell DifferentiationCell LineCells, CulturedDiet, High-FatEnergy MetabolismEpigenesis, GeneticGenetic LociGlucoseHomeostasisHumansHypertrophyInsulin ResistanceLeptinMaleMammalsMetabolic DiseasesMice, Inbred C57BLMice, ObeseMicroRNAsObesityOligonucleotidesSpecies SpecificityConceptsPositive selectionMiR-128Additional genetic elementsCrucial metabolic regulatorAncient adaptationEvolutionary adaptationGenetic elementsMetabolic regulatorGenetic ablationLociMetabolic maladaptationLactase geneAntisense targetingMetabolic disease modelsThrifty phenotypeDisease modelsDiet-induced obesityMetabolic diseasesAbility of adultsMammalsAdaptationGenesMicroRNAsRegulatorSelection
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