TNF-α reduces g0s2 expression and stimulates lipolysis through PPAR-γ inhibition in 3T3-L1 adipocytes

Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine that acts as a mediator of obesity-linked insulin resistance (IR). It is commonly accepted that macrophage-derived TNF-alpha acts in a paracrine manner on adjacent adipocytes, induces lipolysis, which contributes to obesity-linked hyperglycemia. Several studies suggested that G0/G1 switch gene 2 (g0s2) was up-regulated during adipogenesis, and its protein could be degraded in response to TNF-alpha stimulation. The aim of the present work was to investigate the transcriptional regulation of g0s2 by TNF-alpha stimulation. In this study, 3T3-L1 pre-adipocytes were differentiated, and treated with TNF-alpha for 24 h. The effects of TNF-alpha on lipolysis and lipase expression were then examined. Our results revealed that TNF-alpha exerted dose- and time-dependent lipolytic effects, which could be partially reversed by overexpression of g0s2 and peroxisome proliferator-activated receptor-gamma (ppar-gamma). In addition, TNF-alpha treatment significantly reduced the expression of adiponectin, ppar-gamma, hormone-sensitive Lipase (hsl), adipose triglyceride lipase (atgl) as well as ATGL co-factors. Interestingly, TNF-alpha significantly decreased adiponectin and PPAR-gamma protein levels, while treatment with the proteasomal inhibitor MG-132 maintained PPAR-gamma levels. Degradation of PPAR-gamma almost completely abolished the binding of PPAR-gamma to the g0s2 promoter in adipocytes treated with TNF-alpha. We propose that proteasomal degradation of PPAR-gamma and the reduction of g0s2 content are permissive for prolonged TNF-alpha induced lipolysis. (C) 2014 Elsevier Ltd. All rights reserved.