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dc.contributor.authorSæther, Thomas
dc.contributor.authorPaulsen, Steinar M
dc.contributor.authorTungen, Jørn Eivind
dc.contributor.authorVik, Anders
dc.contributor.authorAursnes, Marius
dc.contributor.authorHolen, Torgeir
dc.contributor.authorHansen, Trond Vidar
dc.contributor.authorNebb, Hilde Irene
dc.date.accessioned2019-05-14T13:30:22Z
dc.date.available2019-05-14T13:30:22Z
dc.date.issued2018-06-18
dc.description.abstractObesity and associated disorders such as metabolic syndrome and type 2 diabetes (T2D) have reached epidemic proportions. Several natural products have been reported as Peroxisome Proliferator-Activated Receptor (PPAR) agonists, functioning as lead compounds towards developing new anti-diabetic drugs due to adverse side effects of existing PPAR drugs. We recently isolated and identified (7E)-9-oxohexadec-7-enoic acid (1) and (10E)-9-oxohexadec-10-enoic acid (2) from the marine algae Chaetoceros karianus. Herein we report the total synthesis, pharmacological characterization, and biological evaluations of these naturally occurring oxo-fatty acids (oFAs). The syntheses of 1 and 2 afforded sufficient material for extensive biological evaluations. Both oFAs show an appreciable dose-dependent activation of PPARα and -γ, with EC50 values in the micromolar range, and an ability to regulate important PPAR target genes in hepatocytes and adipocytes. Moreover, both 1 and 2 are able to drive adipogenesis when evaluated in the Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell model, but with lowered expression of adipocyte markers and reduced lipid accumulation compared to the drug rosiglitazone. This seems to be caused by a transient upregulation of PPARγ and C/EBPα expression. Importantly, whole transcriptome analysis shows that both compounds induce anti-diabetic gene programs in adipocytes by upregulating insulin-sensitizing adipokines and repressing pro-inflammatory cytokines.en_US
dc.descriptionSource at <a href=https://doi.org/10.1016/j.ejmech.2018.06.034>https://doi.org/10.1016/j.ejmech.2018.06.034. </a>en_US
dc.identifier.citationSæther, T., Paulsen, S.M., Tungen, J.E., Vik, A., Aursnes, M., Holen, T. ... Nebb, H.I. (2018). Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects. <i>European Journal of Medicinal Chemistry, 155</i>, 736-753. https://doi.org/10.1016/j.ejmech.2018.06.034en_US
dc.identifier.cristinIDFRIDAID 1593672
dc.identifier.doi10.1016/j.ejmech.2018.06.034
dc.identifier.issn0223-5234
dc.identifier.issn1768-3254
dc.identifier.urihttps://hdl.handle.net/10037/15305
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.relation.journalEuropean Journal of Medicinal Chemistry
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/BIOTEK2021/208452/Norway/Nuclear receptor ligands from Arctic marine organisms; Bioprospecting, structure, synthesis and evaluation as drug to treat metabolic syndro//en_US
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/FRINATEK/230470/Norway/DEVELOPMENT OF AN ENANTIOSELECTIVE ORGANOCATALYZED IODOLACTONIZATION REACTION//en_US
dc.relation.urihttps://doi.org/10.1016/j.ejmech.2018.06.034
dc.rights.accessRightsopenAccessen_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710en_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710en_US
dc.titleSynthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effectsen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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