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Diabetes Research Institute at the Heinrich Heine University, Dusseldorf, Germany
Address all correspondence and requests for reprints to: Hans Hauner, M.D., Diabetes Research Institute, Heinrich Heine University, Auf’m Hennekamp 65, D-40225 Duesseldorf, Germany. E-mail: hauner{at}dfi.uni-duesseldorf.de
Tumor necrosis factor-
(TNF) inhibits fat cell differentiation and
may also mediate insulin resistance in adipocytes. Both TNF receptors
are expressed in adipose tissue, but it is unknown how both receptors
are involved in these biological functions. We therefore studied the
effect of receptor-specific 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)-specific
TNFR32W-S86T showed a marked decrease in the percentage of
differentiating cells in response to adipogenic factors as well as a
reduction in peroxisome proliferator-activated receptor-
2 (PPAR2)
messenger RNA (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 PPAR2 mRNA expression were stimulated, GPDH
activity was unchanged, and TNF mRNA was completely suppressed.
Insulin-stimulated 2-deoxy-D-glucose transport was
inhibited by both muteins. The p60-TNFR-mediated inhibition increased
continuously during 6 h of treatment and was associated with a
down-regulation of glucose transporter-4 (GLUT4) mRNA and GLUT4
protein, whereas the p80-TNFR-specific mutein caused a transient
increase in GLUT4 mRNA, but did not alter GLUT4 protein expression
after a 24-h incubation. We conclude that p60-TNFR mediates the
antiadipogenic effect as well as the down-regulation of GLUT4 by TNF,
thereby leading to long-term inhibition of insulin-stimulated glucose
transport. In contrast, activation of the p80-TNFR induces an
adipogenic effect and transiently up-regulates GLUT4 expression. Here,
the acute inhibition of insulin-stimulated glucose transport may be
induced by interference with the insulin signaling pathway.
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