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Visfatin is expressed in human granulosa cells: regulation by metformin through AMPK/SIRT1 pathways and its role in steroidogenesis.
MedLine Citation:
PMID:  23315983     Owner:  NLM     Status:  Publisher    
Visfatin is a cytokine hormone and an enzyme involved in metabolic (obesity, type II diabetes) and immune disorders. Some data suggest a role of visfatin in ovarian function. Here, we identified visfatin in human follicles and investigated the molecular mechanisms involved in the regulation of its expression in response to insulin sensitizers, metformin and rosiglitazone, in primary human granulosa cells (hGCs) and in a human ovarian granulosa-like tumour cell line (KGN). We also studied the effects of human recombinant visfatin (RhVisf) on steroid production and on the activation of various signalling pathways. By RT-PCR, immunoblotting and immunohistochemistry we showed that visfatin is expressed in hGCs and KGN cells, but also in human cumulus cells and oocytes. In hGCs and KGN cells, metformin increased visfatin mRNA in a dose-dependent manner (0.1, 1 and 10 mM), and rosiglitazone increased visfatin mRNA expression (only at 10 µM) after treatments for 24 h, whereas both reduced it after 48 h of incubation. This regulation was confirmed at the protein level for the metformin treatment only. By using the compound C and Aicar, inhibitor and activator of AMP-activated protein kinase (AMPK), respectively, and Sirtinol, an inhibitor of sirtuin-1 (SIRT1), we observed that these metformin effects on visfatin expression were mediated through the AMPK/SIRT1 signalling pathways. RhVisf (10 ng/ml) significantly increased IGF-1 (10 nM)- but not FSH (10 nM)-induced secretion of progesterone and oestradiol as determined by radioimmunoassay and IGF-1-induced thymidine incorporation in hGCs and KGN cells. Finally, rhVisf rapidly activates the mitogen-activated protein kinase (MAPK) pathway via ERK1/2, P38 and Akt phosphorylation under basal conditions in primary hGC cells. In conclusion, visfatin is present in ovarian human follicles, and in hGCs and KGN cells, visfatin increases IGF-1-induced steroidogenesis and cell proliferation and metformin regulates visfatin expression through the AMPK/SIRT1 signalling pathway.
Maxime Reverchon; Marion Cornuau; Lucie Cloix; Christelle Ramé; Fabrice Guerif; Dominique Royère; Joëlle Dupont
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-11
Journal Detail:
Title:  Molecular human reproduction     Volume:  -     ISSN:  1460-2407     ISO Abbreviation:  Mol. Hum. Reprod.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9513710     Medline TA:  Mol Hum Reprod     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Unité de Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique, UMR85, F-37380 Nouzilly, France.
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