The two tumor necrosis factor receptors mediate opposite effects on differentiation and glucose metabolism in human adipocytes in primary culture

Tumor necrosis factor-ru (TNF) inhibits fat cell differentiation and may al so mediate insulin resistance in adipocytes. Both TNF receptors are express ed in adipose tissue, but it is unknown how both receptors are involved in these biological functions. We therefore studied the effect of receptor-spe cific TNF muteins on adipose differentiation and insulin-stimulated glucose transport of in vitro differentiated human adipocytes in primary culture. Adipocyte precursor cells exposed to the 60-kDa TNF receptor (p60-TNFR)-spe cific TNFR32W-S86T showed a marked decrease in the percentage of differenti ating cells in response to adipogenic factors as well as a reduction in per oxisome proliferator-activated receptor-gamma 2 (PPAR gamma 2) messenger RN A (mRNA) and glycerophosphate dehydrogenase (GPDH) activity, but increased endogenous TNF mRNA expression. When cells were incubated with the p80-TNFR -specific TNFD143N-A145R, adipogenesis and PPAR gamma 2 mRNA expression wer e stimulated, GPDH activity was unchanged, and TNF mRNA was completely supp ressed. Insulin-stimulated a-deoxy-D-glucose transport was inhibited by bot h muteins. The p60-TNFR-mediated inhibition increased continuously during 6 h of treatment and was associated with a down-regulation of glucose transp orter-4 (GLUT4) mRNA and GLUT4 protein, whereas the p80-TNFR-specific mutei n caused a transient increase in GLUT4 mRNA, but did not alter GLUT4 protei n expression after a 24-h incubation. We conclude that p60-TNFR mediates th e antiadipogenic effect as well as the down-regulation of GLUT4 by TNF, the reby leading to long-term inhibition of insulin-stimulated glucose transpor t. In contrast, activation of the p80-TNFR induces an adipogenic effect and transiently up-regulates GLUT4 expression. Here, the acute inhibition of i nsulin-stimulated glucose transport may be induced by interference with the insulin signaling pathway.