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GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice

dc.rights.licenseopenen_US
hal.structure.identifierNeurocentre Magendie : Physiopathologie de la Plasticité Neuronale [U1215 Inserm - UB]
dc.contributor.authorQUARTA, Carmelo
dc.contributor.authorSTEMMER, Kerstin
dc.contributor.authorNOVIKOFF, Aaron
dc.contributor.authorYANG, Bin
dc.contributor.authorKLINGELHUBER, Felix
dc.contributor.authorHARGER, Alex
dc.contributor.authorBAKHTI, Mostafa
dc.contributor.authorBASTIDAS-PONCE, Aimee
dc.contributor.authorBAUGE, Eric
dc.contributor.authorCAMPBELL, Jonathan E.
dc.contributor.authorCAPOZZI, Megan
dc.contributor.authorCLEMMENSEN, Christoffer
dc.contributor.authorCOLLDEN, Gustav
dc.contributor.authorCOTA, Perla
dc.contributor.authorDOUROS, Jon
dc.contributor.authorDRUCKER, Daniel J.
dc.contributor.authorDUBOIS, Barent
dc.contributor.authorFEUCHTINGER, Annette
dc.contributor.authorGARCIA-CACERES, Cristina
dc.contributor.authorGRANDL, Gerald
dc.contributor.authorHENNUYER, Nathalie
dc.contributor.authorHERZIG, Stephan
dc.contributor.authorHOFMANN, Susanna M.
dc.contributor.authorKNERR, Patrick J.
dc.contributor.authorKULAJ, Konxhe
dc.contributor.authorLALLOYER, Fanny
dc.contributor.authorLICKERT, Heiko
dc.contributor.authorLISKIEWICZ, Arek
dc.contributor.authorLISKIEWICZ, Daniela
dc.contributor.authorMAITY, Gandhari
dc.contributor.authorPEREZ-TILVE, Diego
dc.contributor.authorPRAKASH, Sneha
dc.contributor.authorSANCHEZ-GARRIDO, Miguel A.
dc.contributor.authorZHANG, Qian
dc.contributor.authorSTAELS, Bart
dc.contributor.authorKRAHMER, Nathalie
dc.contributor.authorDIMARCHI, Richard D.
dc.contributor.authorTSCHOP, Matthias H.
dc.contributor.authorFINAN, Brian
dc.contributor.authorMULLER, Timo D.
dc.date.accessioned2023-01-31T13:58:05Z
dc.date.available2023-01-31T13:58:05Z
dc.date.issued2022-08-04
dc.identifier.issn2522-5812en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/171831
dc.description.abstractEnDual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography–mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance. © 2022, The Author(s).
dc.description.sponsorshipRôle de Tbx3 dans la détermination de l'identité fonctionnelle des neurones POMC dans l'obésitéen_US
dc.description.sponsorshipEGID Diabetes Poleen_US
dc.language.isoENen_US
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.subject.enAlkanesulfonic Acid
dc.subject.enGlucagon Like Peptide 1
dc.subject.enGlucagon Like Peptide 1 Receptor
dc.subject.enGlucose
dc.subject.enPeroxisome Proliferator Activated Receptor Alpha
dc.subject.enPhenylpropionic Acid Derivative
dc.subject.enTesaglitazar
dc.subject.enBody Weight
dc.subject.enMale
dc.subject.enMetabolism
dc.subject.enMouse
dc.subject.enNon Insulin Dependent Diabetes Mellitus
dc.subject.enObesity
dc.subject.enAlkanesulfonates
dc.subject.enDiabetes Mellitus
dc.subject.enType 2
dc.subject.enMice
dc.subject.enPhenylpropionates
dc.subject.enPpar Alpha
dc.title.enGLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice
dc.title.alternativeNat Metaben_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1038/s42255-022-00617-6en_US
dc.subject.halSciences du Vivant [q-bio]/Neurosciences [q-bio.NC]en_US
dc.identifier.pubmed35995995en_US
bordeaux.journalNature Metabolismen_US
bordeaux.page1071-1083en_US
bordeaux.volume4en_US
bordeaux.hal.laboratoriesNeurocentre Magendie - U1215en_US
bordeaux.issue8en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.teamPhysiopathologie de l'équilibre énergétique et obésitéen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.identifier.funderIDNovo Nordisken_US
bordeaux.identifier.funderIDAmerican Friends of the Alexander von Humboldt Foundationen_US
bordeaux.identifier.funderIDEuropean Research Councilen_US
bordeaux.identifier.funderIDSociété Française d’Endocrinologieen_US
bordeaux.identifier.funderIDSociété Française de Nutritionen_US
bordeaux.identifier.funderIDSociété Francophone du Diabèteen_US
bordeaux.identifier.funderIDEuropean Genomic Institute for Diabetesen_US
hal.identifierhal-03965703
hal.version1
hal.date.transferred2023-01-31T13:59:12Z
hal.exporttrue
dc.rights.ccCC BYen_US
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