title: Brazilian propolis-derived components inhibit TNF-α-mediated downregulation of adiponectin expression via different mechanisms in 3T3-L1 adipocytes.
abstract: BACKGROUND
  Previous reports suggest that Brazilian propolis has multiple biological functions and may help to restore adiponectin expression and insulin sensitivity. However, little is known about the molecular mechanisms by which these compounds inhibit the downregulation of adiponectin.
  
  
  METHODS
  The effect of various Brazilian propolis-derived components on inhibition of tumor necrosis factor-α (TNF-α)-mediated downregulation of adiponectin expression in 3T3-L1 adipocytes and molecular mechanism was investigated.
  
  
  CONCLUSIONS
  Pretreatment with either artepillin C (C3) or its derivative (C4) significantly inhibited TNF-α-mediated downregulation of adiponectin expression in 3T3-L1 adipocytes. Interestingly, C3 strongly activated peroxisome proliferator-activated receptor γ (PPARγ) transcriptional activity. Treatment of adipocytes with C3 resulted in the upregulation of adiponectin and fatty acid-binding protein 4 expression, but C4 did not significantly induce PPARγ transactivation. C4 did, however, inhibit the TNF-α-induced c-Jun-NH(2)-terminal kinase (JNK) signaling that is involved in adiponectin expression. Molecular docking studies based on hPPARγ with C3 and JNK1 with C4 clearly supported our experimental results. These data demonstrate that 1) both C3 and C4 significantly inhibit the TNF-α-mediated downregulation of adiponectin in adipocytes, 2) C3 functions as a PPARγ agonist, and its inhibition of the effect of TNF-α is due to this PPARγ transactivation, and 3) C4 is an effective inhibitor of JNK activation, thus inhibiting the TNF-α-mediated downregulation of adiponectin.
  
  
  CONCLUSIONS
  Brazilian propolis-derived components (C3 and C4) can significantly inhibit TNF-α-mediated downregulation of adiponectin in adipocytes, although they do so via different mechanisms.
authors.affiliation: College of Bioscience and Biotechnology, Chubu University, Kasugai, Aichi 487-8501, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Ikeda
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Teruo
authors.initials: T
authors.lastname: Kawada
authors.forename: Shigenori
authors.initials: S
authors.lastname: Kumazawa
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yamaotsu
authors.forename: Izumi
authors.initials: I
authors.lastname: Nakagome
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
authors.forename: Takanori
authors.initials: T
authors.lastname: Tsuda
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000737:chemistry / Q000494:pharmacology; D001938:Brazil; D003373:Coumaric Acids / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D010666:Phenylpropionates / Q000737:chemistry / Q000494:pharmacology; D011429:Propolis / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D052242:Adiponectin; D000813:Anilides; D000873:Anthracenes; D003373:Coumaric Acids; D047495:PPAR gamma; D010666:Phenylpropionates; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; C102259:artepillin C; D011429:Propolis; D048031:JNK Mitogen-Activated Protein Kinases