Tumor necrosis factor-␣ (TNF␣) is involved in the physiological and biological abnormalities found in two opposite metabolic situations: cachexia and obesity. In an attempt to identify novel genes and proteins that could mediate the effects of TNF␣ on adipocyte metabolism and development, we have used a differential display technique comparing 3T3-L1 cells exposed or not to the cytokine. We have isolated a novel adipose cDNA encoding a TNF␣-inducible 470-amino acid protein termed TIARP, with six putative transmembrane regions flanked by a large amino-terminal and a short carboxyl-terminal domain, a structure reminiscent of channel and transporter proteins. Commitment into the differentiation process is required for cytokine responsiveness. The differentiation process per se is accompanied by a sharp emergence of TIARP mRNA transcripts, in parallel with the expression of the protein at the plasma membrane. Transcripts are present at high levels in white and brown adipose tissues, and are also detectable in liver, kidney, heart, and skeletal muscle. Whereas the biological function of TIARP is presently unknown, its pattern of expression during adipose conversion and in response to TNF␣ exposure as a transmembrane protein mainly located at the cell surface suggest that TIARP might participate in adipocyte development and metabolism and mediate some TNF␣ effects on the fat cell as a channel or a transporter. Tumor necrosis factor-alpha (TNF␣)1 exerts a wide range of effects on cells and tissues. In addition to its immunological functions, TNF␣ also markedly alters adipose tissue development and metabolism. Surprisingly, TNF␣ seems to be involved in the pathophysiology of two opposite metabolic disorders (1). High plasma levels of TNF␣ likely play an important role in the onset of cachectic states observed during cancer or severe infectious diseases (2). By contrast, more recent studies have indicated that the cytokine is overexpressed in adipose tissue of obese rodents or humans, and that this locally produced TNF␣ may be involved in the obesity-linked insulin resistance (3). Thus, since abnormalities in its production or action are associated with alterations in body fat mass, TNF␣ is likely an important effector of adipose tissue development and metabolism in vivo.Many in vitro studies also support the view that TNF␣ has profound effects on lipid metabolism and adipocyte differentiation. TNF␣ was reported to inhibit lipid storage by reducing synthesis and activity of several proteins essential for lipogenesis, such as lipoprotein lipase (4) and acetyl-coenzyme A carboxylase (5), or by inhibition in the expression and/or function of the insulin-sensitive glucose transporter GLUT4 pathway (6). Otherwise TNF␣ is able to stimulate lipolysis in adipocytes by different mechanisms (7,8). In addition to the above effects on lipid storage or mobilization, TNF␣ potently inhibits adipose conversion and even causes a dramatic de-differentiation of adipocytes in culture (9). Prevention of adipose conversion by TNF␣ has been es...

Retinoic acid (RA) has been shown to induce human neuroblastoma SKNBE cell differentiation into a neuronal phenotype. Whether this neuronal differentiation is associated with modulation of matrix gelatinase [matrix metalloproteinase (MMP)-2 and MMP-9] expression was investigated in SKNBE cell cultures exposed to RA for 14 days.

Tumor necrosis factor (TNF) K K-induced adipose-related protein (TIARP) is a novel TNFK K-stimulated protein in adipocytes. Besides TNFK K, interleukin (IL)-6 has recently been shown to be another adipocytokine implicated in insulin resistance. Therefore, the impact of IL-6 on TIARP gene expression in 3T3-L1 adipocytes was determined by quantitative real-time reverse transcription-polymerase chain reaction. Interestingly, TIARP mRNA expression was stimulated up to 3.8-fold by IL-6 in a dose-dependent fashion with signi¢cant stimulation detectable at e¡ector concentrations as low as 3 ng/ml and maximal e¡ects seen at 100 ng/ml IL-6. Induction of TIARP mRNA by IL-6 was time-dependent with signi¢cant upregulation occurring as early as 2 h after e¡ector addition and maximal e¡ects observed at 4 h. In parallel, TIARP protein synthesis was upregulated with maximal e¡ects seen after 8 h of IL-6 treatment. Furthermore, the Janus kinase 2 inhibitor AG490 decreased TIARP mRNA expression. The increase of TIARP mRNA could be reversed by withdrawal of IL-6 for 24 h. Furthermore, TIARP mRNA induction by IL-6 was also seen in brown adipocytes but not in muscle and liver cells. Taken together, these results show that TIARP is acutely regulated in adipose tissue not only by TNFK K but also by IL-6 which has been shown to be another important cytokine implicated in the pathogenesis of insulin resistance.