The Short- and Long-Term Effects of Tumor Necrosis Factor-  and BRL 49653 on Peroxisome Proliferator-Activated Receptor (PPAR) 2 Gene Expression and Other Adipocyte Genes

Abstract

Expression of tumor necrosis factor-alpha(TNFalpha) in adipocytes has been reported to correlate with insulin resistance associated with obesity. The thiazolidinediones such as BRL 49653 have been reported to improve insulin sensitivity in obese animals and humans. Although its exact mechanism of action is not known, BRL 49653 has been shown to antagonize some of the inhibitory actions of TNFalpha. BRL 49653 binds and activates the peroxisome proliferator-activated receptor (PPARgamma2), an important nuclear transcription factor in adipocyte differentiation; however, its regulation of PPARgamma2 in differentiated adipocytes is unknown. In this paper, we find that BRL 49653 blocked the ability of TNFalpha to down-regulate the expression and transcription of several adipocyte genes, but BRL 49653 did not prevent TNFalpha from down-regulating PPARgamma2. Moreover, BRL 49653 alone initially decreased the expression of PPARgamma2 mRNA and protein greatly. After 24 h of treatment in 3T3-L1 adipocytes, BRL 49653 down-regulated PPARgamma2 by greater than 90% and potentiated the decrease of PPARgamma2 mRNA by TNFalpha at this time. These unexpected results prompted us to repeat the experiments for a longer time to determine whether BRL 49653 would continue to down-regulate PPARgamma2. With prolonged BRL 49653 treatment, PPARgamma2 mRNA expression was not decreased as greatly, and the protein levels were decreased 20-30% below control at 72 h compared to 90% at 24 h. Although BRL 49653 continued to prevent the inhibitory effects of TNFgamma on perilipin and aP2 mRNA, by 72 h, BRL 49653 was not as potent an inhibitor of TNFalpha's down-regulation of perilipin protein. Since PPARgamma2 protein was more abundant at this time, these results suggest that the level of PPARgamma2 protein is not the sole factor that regulates the transcriptional control by BRL 49653.

Epidermis-Type Lipoxygenase 3 Regulates Adipocyte Differentiation and Peroxisome Proliferator-Activated Receptor γ Activity

“…Furthermore, the NAC-mediated inhibition was circumvented by the inclusion of an exogenous PPAR␥ ligand during differentiation. The decline in PPAR␥ mRNA levels by rosiglitazone was expected based on previous reports (11,47). As PPAR␥ ligand(s) is produced early and transiently during adipocyte differentiation, NAC should be required early in order to abolish adipogenesis.…”

Tissue-Selective, Bidirectional Regulation of PEX11α and Perilipin Genes through a Common Peroxisome Proliferator Response Element

“…2A). Production of perilipin is induced during adipocyte differentiation (22), and the level of perilipin mRNA is increased by BRL49,653, a PPAR␥ ligand, in the differentiated adipocytes (56). Hence, we inferred that the perilipin gene is regulated by PPAR␥2 through the same PPRE.…”

Involvement of TNF-α in abnormal adipocyte and muscle sortilin expression in obese mice and humans

“…Regarding the second hypothesis, TNF-α has been shown to regulate PPARγ both at the level of its production and of its activation [31]. In mature adipocytes, thiazolidinedione did not prevent TNF-α-induced decrease in PPARγ amount [43], but would be able to rescue the inhibition of PPARγ activity. However, we cannot exclude that this protective effect of rosiglitazone could be independent of PPARγ, as already described for some effects of thiazolidinediones [44].…”