Genistein and daidzein repress adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells via Wnt/β-catenin signalling or lipolysis.

OBJECTIVES One aspect of the effects of isoflavones against fat deposition might be at least associated with the mechanism by which Wnt/β-catenin signalling inhibits adipocyte differentiation. However, it remains completely unknown as to whether isoflavones might influence Wnt signalling during commitment of pluripotent mesenchymal stem cells (MSCs) to adipose lineages. In the present study, we have investigated the mechanisms underlying effects of genistein and daidzein, the major soy isoflavones, on anti-adipogenic Wnt/β-catenin signalling. MATERIALS AND METHODS Adipose tissue-derived (AD) MSCs were exposed continuously to genistein and daidzein (0.01-100 μm) during adipogenic differentiation (21 days). An oestrogen antagonist, ICI 182,780, was used to determine whether or not the isoflavones activated Wnt signalling via oestrogen receptors (ERs). RESULTS Genistein and daidzein suppressed adipogenic differentiation of AD-MSCs in a dose-dependent manner and inhibited expression of adipogenic markers, PPARγ, SREBP-1c and Glut 4, from mid-phase differentiation. Microarrays showed that anti-adipogenic effects of genistein were principally attributable to activation of Wnt signalling via ERs-dependent pathway, such as Erk/JNK signalling and LEF/TCF4 co-activators. These findings were supported by evidence that the effects of genistein were offset by ICI182,780. Unlike genistein, daidzein inhibited adipogenesis through stimulation of lipolysis, with for example, PKA-mediated hormone sensitive lipase. This is consistent with the increase in glycerol released from AD-MSCs. In conclusion, understanding that different sets of mechanisms of the two isoflavones on adipogenesis will help the design of novel strategies to prevent observed current epidemic levels of obesity, using isoflavones.