Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts

Abstract

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-a (TNF-a). 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-a-induced expressions of IL-6, IL-8, p38, p65 and C/EBP-b were also downregulated by genistein, showing its anti-inflammatory properties. Peroxisome proliferatoractivated receptor-g (PPAR-g) 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-g induction and tyrosine kinase inhibition. In conclusion, genistein, alone or coupled with glucocorticoids, have both adipogenic and anti-inflammatory effects on synovial fibroblasts.

Differential Signalling Through ALK-1 and ALK-5 Regulates Leptin Expression in Mesenchymal Stem Cells

“…Thus, recently, the need for a cell model that expresses leptin and robustly responds to hormonal signals for the study of leptin expression has emerged [3]. Our earlier study showed that SVF, belonging to mesenchymal lineages, expresses leptin, which is strongly enhanced by glucocorticoids [11]. Here, we have shown that BM-MSC, another MSCs, also expressed a basal level of leptin that was markedly enhanced by glucocorticoids.…”

“…SVF, which we have recently shown to be leptin producers [11], were used as a positive control. ELISA analysis showed that BM-MSC expressed leptin, and that this expression was markedly up regulated by prednisolone (10 -6 M) treatment ( Fig.…”

“…Although described as an adipocyte-derived hormone, leptin is also secreted by several other cell types [7,10]. We have recently shown an in vitro leptin expression that was enhanced by glucocorticoids in mesenchymal synovial fibroblasts (SVF) [11]. Single or repeated injections of glucocorticoids were also shown to elevate rat plasma leptin in a dose-dependent manner [12].…”

Anti-obesity effects of gochujang products prepared using rice koji and soybean meju in rats

“…The leptin hormone produced in adipose cells regulates the energy balance and body weight (Havel 2000;Park and Ahima 2015;Sainz et al 2015). Genistein in gochujang products supposedly partly contributes to the anti-obesity effects by inhibition of synthesis and secretion of leptin (Phrakonkham et al 2008;Relic et al 2009). …”

Genistein Derivatization – From a Dietary Supplement to a Pharmaceutical Agent

“…Docking studies, supported by the functional assay, characterized genistein as a full PPAR agonist (Salam et al, 2008). Subsequent studies shown, that agonistic action of genistein on PPAR stimulates adipogenesis (Relic et al, 2009). It is worth to keep in mind that genistein concurrently activates two different transcriptional factors, ERs and PPAR , which have opposite effects on osteogenesis or adipogenesis.…”