Trichostatin A Modulates Thiazolidinedione-Mediated Suppression Of Tumor Necrosis Factor Alpha-Induced Lipolysis In 3t3-L1 Adipocytes

In obesity, high levels of tumor necrosis factor a (TNF alpha) stimulate lipolysis in adipocytes, leading to hyperlipidemia and insulin resistance. Thiazolidinediones (TZDs), the insulin-sensitizing drugs, antagonize TNF alpha-induced lipolysis in adipocytes, thereby increasing insulin sensitivity in diabetes patients. The cellular target of TZDs is peroxisome proliferator-activated receptor gamma (PPAR gamma), a nuclear receptor that controls many adipocyte functions. As a transcription factor, PPAR gamma is closely modulated by coregulators, which include coactivators and corepressors. Previous studies have revealed that in macrophages, the insulin-sensitizing effect of PPAR gamma may involve suppression of proinflammatory gene expression by recruiting the corepressor complex that contains corepressors and histone deacetylases (HDACs). Therefore, we investigated whether the corepressor complex is involved in TZD-mediated suppression of TNF alpha-induced lipolysis in 3T3-L1 adipocytes. Trichostatin A (TSA), a pan HDAC inhibitor (HDACI) that inhibits class I and II HDACs, was used to examine the involvement of HDACs in the actions of TZDs. TSA alone increased basal lipolysis and attenuated TZD-mediated suppression of TNF alpha-induced lipolysis. Increased basal lipolysis may in part result from class I HDAC inhibition because selective class I HDACI treatment had similar results. However, attenuation of TZD-mediated TNF alpha antagonism may be specific to TSA and related hydroxamate-based HDACI rather than to HDAC inhibition. Consistently, corepressor depletion did not affect TZD-mediated suppression. Interestingly, TSA treatment greatly reduced PPAR gamma levels in differentiated adipocytes. Finally, extracellular signal-related kinase 1/2 (ERK1/2) mediated TNF alpha-induced lipolysis, and TZDs suppressed TNF alpha-induced ERK phosphorylation. We determined that TSA increased basal ERK phosphorylation, and attenuated TZD-mediated suppression of TNF alpha-induced ERK phosphorylation, consistent with TSA's effects on lipolysis. These studies suggest that TSA, through down-regulating PPAR gamma, attenuates TZD-mediated suppression of TNF alpha-induced ERK phosphorylation and lipolysis in adipocytes.