Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts.
It was shown recently that synovial fibroblast transformation into adipocytes reduced the expression of interleukin-6 (IL-6) and IL-8. However, the synovial fibroblast adipogenesis was inhibited in inflammatory conditions induced by the tumor necrosis factor-alpha (TNF-alpha). Furthermore, adipogenesis is often accompanied by leptin production, a proinflammatory adipokine in rheumatic diseases. In this study, we tested the phytohormone genistein for adipogenic and anti-inflammatory properties on human synovial fibroblasts. Results showed that genistein was able to transform synovial fibroblasts into adipocytes that expressed perilipin-A and produced adiponectin, but not leptin. Furthermore, genistein enhanced glucocorticoid-mediated synovial fibroblast adipogenesis and, in parallel, downregulated glucocorticoid-induced leptin and leptin receptor. Endogenous and TNF-alpha-induced expressions of IL-6, IL-8, p38, p65 and C/EBP-beta were also downregulated by genistein, showing its anti-inflammatory properties. Peroxisome proliferator- activated receptor-gamma (PPAR-gamma) agonist, rosiglitazone, had a synergic effect on genistein-induced adipogenesis, whereas the non-active tyrosine kinase inhibitor, daidzein, had a significantly inferior adipogenic activity than genistein. The Janus kinase-2 tyrosine kinase inhibitor, AG 490, mimicked the anti-leptin effect of genistein. These results showed that genistein-induced adipogenesis involves PPAR-gamma induction and tyrosine kinase inhibition. In conclusion, genistein, alone or coupled with glucocorticoids, have both adipogenic and anti-inflammatory effects on synovial fibroblasts.
Department of Rheumatology, GIGA-Research, University of Liège, CHU de Liège, Liège, Belgium.
Biserka
B
Relic
Mustapha
M
Zeddou
Aline
A
Desoroux
Yves
Y
Beguin
Dominique
D
de Seny
Michel G
MG
Malaise
D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D020738:Leptin / Q000096:biosynthesis*; D047495:PPAR gamma / Q000096:biosynthesis; D048789:Phytoestrogens / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; C508606:CXCL8 protein, human; D017931:DNA Primers; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D020738:Leptin; D047495:PPAR gamma; D048789:Phytoestrogens; D047428:Protein Kinase Inhibitors; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D003907:Dexamethasone; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D015230:Prostaglandin D2