Trichostatin A Modulates Thiazolidinedione-Mediated Suppression of Tumor Necrosis Factor α-Induced Lipolysis in 3T3-L1 Adipocytes
Journal
PLoS ONE
Journal Volume
8
Journal Issue
8
Date Issued
2013-08-09
Author(s)
Abstract
In obesity, high levels of tumor necrosis factor α (TNFα) stimulate lipolysis in adipocytes, leading to hyperlipidemia and insulin resistance. Thiazolidinediones (TZDs), the insulin-sensitizing drugs, antagonize TNFα-induced lipolysis in adipocytes, thereby increasing insulin sensitivity in diabetes patients. The cellular target of TZDs is peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor that controls many adipocyte functions. As a transcription factor, PPARγ is closely modulated by coregulators, which include coactivators and corepressors. Previous studies have revealed that in macrophages, the insulin-sensitizing effect of PPARγ 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 TNFα-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 TNFα-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 TNFα 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 PPARγ levels in differentiated adipocytes. Finally, extracellular signal-related kinase 1/2 (ERK1/2) mediated TNFα-induced lipolysis, and TZDs suppressed TNFα-induced ERK phosphorylation. We determined that TSA increased basal ERK phosphorylation, and attenuated TZD-mediated suppression of TNFα-induced ERK phosphorylation, consistent with TSA's effects on lipolysis. These studies suggest that TSA, through down-regulating PPARγ, attenuates TZD-mediated suppression of TNFα-induced ERK phosphorylation and lipolysis in adipocytes. © 2013 Lu et al.
SDGs
Other Subjects
glitazone derivative; mitogen activated protein kinase 1; mitogen activated protein kinase 3; peroxisome proliferator activated receptor gamma; peroxisome proliferator activated receptor gamma 1; peroxisome proliferator activated receptor gamma 2; retinoic acid; thyroid hormone receptor; trichostatin A; tumor necrosis factor alpha; unclassified drug; article; cell strain 3T3; controlled study; depletion; dose response; down regulation; drug antagonism; enzyme phosphorylation; gene expression; gene repression; human; human cell; lipolysis; protein blood level; protein depletion; tissue differentiation
Publisher
PUBLIC LIBRARY SCIENCE
Type
journal article
File(s)![Thumbnail Image]()
Loading...
Name
journal.pone.0071517.PDF
Size
1.57 MB
Format
Adobe PDF
Checksum
(MD5):747acef81565da264cfb45ffbaaed3f6