TM-25659 is a modulator of TAZ with anti-osteoporotic and anti-obesity effects.
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The protein transcriptional co-activator with PDZ-binding motif (TAZ), also referred to as WW domain-containing transcriptional co-regulator (WWTR1), was originally cloned as an interacting protein of the 14-3-3 protein that is involved in the control of cell cycle progression, cell differentiation and apoptosis through interaction with phosphorylated signalling molecules. TM-25659 acts as a TAZ modulator that enhances TAZ expression in the nucleus. Treatment of COS-7 cells with TM-25659 for 30 min increased GFP (green fluorescence protein)-TAZ intensities in a dose-dependent manner. The nuclear level of endogenous TAZ was increased by TM-25659 which was confirmed by immunofluorescence staining with anti-TAZ antibody. In 3T3-L1 cells, TM-25659 treatment for 2 hrs significantly suppressed the normal adipocyte differentiation and lipid droplet formation. As a result of attenuated adipogenic differentiation by TM-25659, the increased levels of PPARγ in differentiated adipocytes were decreased by TM-25659 in a concentration-dependent manner, whereas TAZ expression was substantially elevated. In addition, the adipogenic marker aP2 and adiponectin expression were further decreased by TM-25659. These results demonstrate that TM-25659 acted as a suppressor of PPARγ-dependent adipocyte differentiation. Moreover, the expression levels of osteogenic markers, such as osteocalcin, ALP and osterix were significantly increased by treatment with TM-25659, even at a concentration of 2 µM. In vivo, body weight increase caused by the HFD (high fat diet) was substantially diminished in the TM-25659-treated group compared with the vehicle-treated group[1].
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