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Abstract
Tumor necrosis factor-alpha (TNF alpha) 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 TNFalpha 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 alpha-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 alpha 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 alpha effects on the fat cell as a channel or a transporter.
Highlights
Tumor necrosis factor-alpha (TNF␣)1 exerts a wide range of effects on cells and tissues
Since TNF␣ represents a major effector of adipose tissue development and metabolism, our objective was to identify novel genes and proteins that are markedly regulated by this cytokine in differentiating preadipocytes or in mature adipose cells
Our strategy led to the identification of TIARP, which was chosen for further investigation because of several original features, including its strong induction by TNF␣, its differentiation-dependent expression, its prominent cell-surface localization, and its homology with members of a new emerging protein family
Summary
Tumor necrosis factor-alpha (TNF␣) exerts a wide range of effects on cells and tissues. In addition to its immunological functions, TNF␣ markedly alters adipose tissue development and metabolism. 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 essentially related to reduction in C/EBP␣ and PPAR␥ expression, two key adipogenic transcription factors [6, 10]. These observations underline that TNF␣ controls the adipocyte phenotype by opposite regulations of lipid storage and mobilization, and through the blockade of adipocyte differentiation. Identification of novel genes and proteins that could mediate the effects of the cytokine on the adipose cell remains an important issue
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