title: A possible role for AMP-activated protein kinase activated by metformin and AICAR in human granulosa cells.
abstract: BACKGROUND
  Women with polycystic ovary syndrome (PCOS) are generally insulin- resistant and are consequently often treated with metformin. We investigated the effect of metformin and AICAR on the AMP-activated protein kinase (AMPK) pathway.
  
  
  METHODS
  We evaluated the effects of 5-amino-imidazole-4-carboxyamide-1- beta-D-ribofuranoside (AICAR) and metformin on tumor necrosis factor (TNF)-alpha- stimulated chemokine production in human granulosa cells. The phosphorylations of AMPK, I-kappaB, 4E-BP-1, p70S6K were analyzed by western immunoblotting.
  
  
  RESULTS
  AICAR and metformin markedly reduced the IL-8 and GROalpha production induced by TNF-alpha. AICAR and metformin also reduced the TNF-alpha-induced phosphorylation of I-kappaB. The phosphorylations of I-kappaB, 4EBP-1, p70S6K were inhibited via an AMPK-dependent signal transduction.
  
  
  CONCLUSIONS
  These results suggest that metformin promotes granulosa cell function by reducing a TNF-alpha- and chemokine-mediated inflammatory reaction through an AMPK-dependent pathway. These finding may have implications for metformin's actions during the treatment of PCOS with metformin.
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita, 879-5593, Japan. yufukou@oita-u.ac.jp.
authors.forename: Yufuko
authors.initials: Y
authors.lastname: Kai
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita, 879-5593, Japan. kawayas@oita-u.ac.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawano
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita, 879-5593, Japan. h-sawa@oita-u.ac.jp.
authors.forename: Hanae
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita, 879-5593, Japan. naraharh@oita-u.ac.jp.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Narahara
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D018797:Cell Cycle Proteins; D018925:Chemokines / Q000378:metabolism; D005260:Female; D006107:Granulosa Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D012265:Ribonucleotides / Q000494:pharmacology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D018925:Chemokines; C087000:EIF4EBP1 protein, human; D020672:I-kappa B Proteins; D010750:Phosphoproteins; D012265:Ribonucleotides; D014409:Tumor Necrosis Factor-alpha; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide