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.
Highlights
Obesity is characterized by increased proinflammatory cytokine secretion from hypertrophied adipocytes and infiltrated macrophages as well as elevated levels of circulating free fatty acids (FFAs), primarily resulting from lipolysis of triglycerides (TG) stored in adipocytes
Treatment with 5 or 20 mM SAHA elevated basal lipolysis and attenuated Rosi-mediated suppression of TNFainduced lipolysis. These results suggest that the effects of Trichostatin A (TSA) treatment on Rosi-mediated suppression of Tumor necrosis factor a (TNFa)-induced lipolysis may be specific to hydroxamate-based HDAC inhibitor (HDACI) rather than general histone deacetylases (HDACs) inhibition
Because TSA and SAHA, but not MS275, attenuated the Rosi-mediated suppression of TNFa-induced lipolysis (Fig. 4B,C), these results suggested that a mechanism by which TSA and SAHA attenuated Rosi-mediated suppression of TNFa-induced lipolysis may result from downregulation of both PPARc1 and 2 in differentiated adipocytes
Summary
Obesity is characterized by increased proinflammatory cytokine secretion from hypertrophied adipocytes and infiltrated macrophages as well as elevated levels of circulating free fatty acids (FFAs), primarily resulting from lipolysis of triglycerides (TG) stored in adipocytes. In addition to its role in inflammation, TNFa increases lipolysis in adipocytes, which may contribute to elevated FFA circulation [3,5,6,7]. P44/42 extracellular signal-related kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK), but not p38 mitogen-activated protein kinase (MAPK), mediate TNFa-induced lipolysis [10,11]. Elevated cyclic AMP (cAMP) levels and protein kinase A (PKA) activation mediate in TNFa-induced lipolysis in human adipocytes, [7,13], whereas the involvement of cAMP and PKA in TNFa-induced lipolysis is controversial in mouse adipocytes [12,14]. TNFa-induced down-regulation of perilipin, which is a surface protein that protects stored TG in adipocyte lipid droplets from hydrolytic lipase activity, has been observed in both human and murine adipocytes [11,12]
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