title: 2-(2-Bromophenyl)-formononetin and 2-heptyl-formononetin are PPARγ partial agonists and reduce lipid accumulation in 3T3-L1 adipocytes.
abstract: Isoflavones are bioactive compounds that have been shown to decrease lipid accumulation in vitro. However, the knowledge of the isoflavone formononetin is limited. The aim of the study was to assess the effects of formononetin and its two synthetic analogues, 2-(2-bromophenyl)-formononetin and 2-heptyl-formononetin, on lipid accumulation in 3T3-L1 adipocytes and investigate possible mechanisms. Formononetin and the two analogues were added day 0-8 or day 8-10 of the differentiation period, and lipid accumulation, glycerol release and gene expression were measured. Additionally, competitive peroxisome proliferator-activated receptor (PPAR)-γ binding assay, PPARγ transactivation assay and Western blot for phosphorylated AMP-activated protein kinase (AMPK) were performed. Chronic treatment (day 0-8) with formononetin increased lipid accumulation, whereas the two analogues decreased lipid accumulation partly due to decreased differentiation. The two analogues, but not formononetin, also decreased lipid content in mature adipocytes. 2-Heptyl-formononetin increased glycerol release and lipolytic gene expression and decreased lipogenic gene expression. Formononetin did not bind to or activate PPARγ whereas both analogues bound to the receptor and behaved as PPARγ partial agonists in the transactivation assay. Neither of the compounds affected phosphorylation of AMPK. In conclusion, the analogues of formononetin decreased lipid accumulation possibly in part by acting as PPARγ partial agonists.
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 13, 2100 Copenhagen Ø, Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Andersen
authors.affiliation: Department of Biology, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Dorota
authors.initials: D
authors.lastname: Kotowska
authors.affiliation: Department of Chemistry, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Tortzen
authors.affiliation: Department of Biology, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: John
authors.initials: J
authors.lastname: Nielsen
authors.affiliation: Department of Biology, Faculty of Science, University of Copenhagen, Denmark. Electronic address: rkp@bio.ku.dk.
authors.forename: Rasmus Koefoed
authors.initials: RK
authors.lastname: Petersen
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D007529:Isoflavones / Q000737:chemistry* / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D007529:Isoflavones; D047495:PPAR gamma; C007768:formononetin; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Adipocytes; Isoflavones; PPARγ