title: Antiadipogenic effect of carnosic acid, a natural compound present in Rosmarinus officinalis, is exerted through the C/EBPs and PPARγ pathways at the onset of the differentiation program.
abstract: BACKGROUND
  Obesity is a serious health problem all over the world, and inhibition of adipogenesis constitutes one of the therapeutic strategies for its treatment. Carnosic acid (CA), the main bioactive compound of Rosmarinus officinalis extract, inhibits 3T3-L1 preadipocytes differentiation. However, very little is known about the molecular mechanism responsible for its antiadipogenic effect.
  
  
  METHODS
  We evaluated the effect of CA on the differentiation of 3T3-L1 preadipocytes analyzing the process of mitotic clonal expansion, the level of adipogenic markers, and the subcellular distribution of C/EBPβ.
  
  
  RESULTS
  CA treatment only during the first day of 3T3-L1 differentiation process was enough to inhibit adipogenesis. This inhibition was accompanied by a blockade of mitotic clonal expansion. CA did not interfere with C/EBPβ and C/EBPδ mRNA levels but blocked PPARγ, and FABP4 expression. C/EBPβ has different forms known as LIP and LAP. CA induced an increase in the level of LIP within 24h of differentiation, leading to an increment in LIP/LAP ratio. Importantly, overexpression of LAP restored the capacity of 3T3-L1 preadipocytes to differentiate in the presence of CA. Finally, CA promoted subnuclear de-localization of C/EBPβ.
  
  
  CONCLUSIONS
  CA exerts its anti-adipogenic effect in a multifactorial manner by interfering mitotic clonal expansion, altering the ratio of the different C/EBPβ forms, inducing the loss of C/EBPβ proper subnuclear distribution, and blocking the expression of C/EBPα and PPARγ.
  
  
  CONCLUSIONS
  Understanding the molecular mechanism by which CA blocks adipogenesis is relevant because CA could be new a food additive beneficial for the prevention and/or treatment of obesity.
authors.affiliation: Laboratory of Plant Biochemistry, Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas Buenos Aires I.I.B.B.A-CONICET, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Mauro
authors.initials: M
authors.lastname: Gaya
authors.forename: Victoria
authors.initials: V
authors.lastname: Repetto
authors.forename: Judith
authors.initials: J
authors.lastname: Toneatto
authors.forename: Claudia
authors.initials: C
authors.lastname: Anesini
authors.forename: Graciela
authors.initials: G
authors.lastname: Piwien-Pilipuk
authors.forename: Silvia
authors.initials: S
authors.lastname: Moreno
mesh_terms: D041721:3T3-L1 Cells; D045784:Abietanes / Q000737:chemistry / Q000494:pharmacology*; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D050556:Fatty Acid-Binding Proteins / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D027542:Rosmarinus / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D045784:Abietanes; D000975:Antioxidants; D022762:CCAAT-Enhancer-Binding Proteins; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D047495:PPAR gamma; D010936:Plant Extracts; C018381:salvin