Abstract
Adipogenesis is dependent on the sequential activation of transcription factors including the CCAAT/enhancer-binding proteins (C/EBP), peroxisome proliferator-activated receptor gamma (PPARgamma), and steroid regulatory element-binding protein (SREBP). We show that the mood stabilizing drug valproic acid (VPA; 0.5-2 mm) inhibits mouse 3T3 L1 and human preadipocyte differentiation, likely through its histone deacetylase (HDAC) inhibitory properties. The HDAC inhibitor trichostatin A (TSA) also inhibited adipogenesis, whereas the VPA analog valpromide, which does not possess HDAC inhibitory effects, did not prevent adipogenesis. Acute or chronic VPA treatment inhibited differentiation yet did not affect mitotic clonal expansion. VPA (1 mm) inhibited PPARgamma induced differentiation but does not activate a PPARgamma reporter gene, suggesting that it is not a PPARgamma ligand. VPA or TSA treatment reduced mRNA and protein levels of PPARgamma and SREBP1a. TSA reduced C/EBPalpha mRNA and protein levels, whereas VPA only produced a decrease in C/EBPalpha protein expression. Overall our results highlight a role for HDAC activity in adipogenesis that can be blocked by treatment with VPA.
Highlights
Valproic acid (VPA)1 has been used as an anticonvulsant agent for the treatment of epilepsy, as well as a mood stabilizer for the treatment of bipolar disorder, for several decades
We examined the effect of valproic acid (VPA) treatment on MDIinduced preadipocyte differentiation
Our results show that VPA treatment prevents mouse and human adipocyte differentiation in vitro
Summary
We show that the mood stabilizing drug valproic acid (VPA; 0.5–2 mM) inhibits mouse 3T3 L1 and human preadipocyte differentiation, likely through its histone deacetylase (HDAC) inhibitory properties. The HDAC inhibitor trichostatin A (TSA) inhibited adipogenesis, whereas the VPA analog valpromide, which does not possess HDAC inhibitory effects, did not prevent adipogenesis. VPA or TSA treatment reduced mRNA and protein levels of PPAR␥ and SREBP1a. Up to 70% of adult patients receiving VPA treatment gain weight (5–14 kg) [6]. We demonstrate that VPA treatment inhibits mouse 3T3-L1 and human adipocyte differentiation. Adipocytes differentiate from preadipocytes via a well defined series of transcriptional events involving several key transcription factors, including members of the CCAAT/enhancer-binding protein (C/EBP) family, peroxisome proliferator-activated receptor ␥ (PPAR␥), and steroid regulatory element-binding protein (SREBP) [14]. Experiments using either the structurally unrelated HDAC inhibitor trichostatin A (TSA) or valpromide (VPM), an amide analog of VPA that does not inhibit HDACs, support the hypothesis that HDAC activity is required for initiation of adipogenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
