Effect of tumor necrosis factor on acetyl-coenzyme A carboxylase gene expression and preadipocyte differentiation.

Abstract

Tumor necrosis factor (TNF) is secreted by macrophages in response to various stimuli and blocks lipid accumulation during the conversion of preadipocytes to adipocytes in culture. In the present report, we investigate the effect of recombinant TNF on the expression of acetyl-coenzyme-A (CoA) carboxylase, the rate-limiting enzyme for long-chain fatty acid biosynthesis. We used a preadipocyte cell line, 30A-5, derived from 10T1/2 mouse fibroblasts after treatment with 5-azacytidine. Treatment of the preadipocyte cell line with dexamethasone and insulin triggers the conversion of these cells to mature adipocytes as evidenced by the accumulation of lipid. The mRNA and enzyme levels of acetyl-CoA carboxylase as well as the enzyme activity increase markedly during the conversion process. TNF prevents the conversion of preadipocytes to adipocytes with a concomitant inhibition in the accumulation of acetyl-CoA carboxylase mRNA and decrease in enzyme activity. This observed reduction in acetyl-CoA carboxylase mRNA levels is reversible upon removal of TNF. Acetyl-CoA carboxylase mRNA levels and enzyme activity also decrease when fully differentiated adipocytes are exposed to TNF but to a much lesser extent. These results suggest that TNF affects de novo lipid synthesis in part by altering the mRNA levels of acetyl-CoA carboxylase.