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-induced Insulin Resistance in 3T3-L1
Adipocytes Is Accompanied by a Loss of Insulin Receptor Substrate-1
and GLUT4 Expression without a Loss of Insulin Receptor-mediated
Signal Transduction
(Received for publication, June 24, 1996, and in revised form, September 19, 1996)
From the Department of Biochemistry, Boston University School of
Medicine, Boston, Massachusetts 02118
A number of studies have demonstrated
that tumor necrosis factor-
(TNF-) is associated with profound
insulin resistance in adipocytes and may also play a critical role in
the insulin resistance of obesity and non-insulin-dependent
diabetes mellitus. Reports on the mechanism of TNF- action have been
somewhat contradictory. GLUT4 down-regulation has been implicated as a
possible cause of insulin resistance as has been the reduced kinase
function of the insulin receptor. Here we examine the effects of tumor necrosis factor on the protein components thought to be involved in
insulin-stimulated glucose transport in adipocytes, namely the insulin
receptor, its major substrate IRS-1, and the insulin responsive glucose
transporter GLUT4. Prolonged exposure (72-96 h) of 3T3-L1 adipocytes
to TNF- causes a substantial reduction (>80%) in IRS-1 and GLUT4
mRNA and protein as well as a lesser reduction (>50%) in the
amount of the insulin receptor. Nevertheless, the remaining proteins
appear to be biochemically indistinguishable from those in untreated
adipocytes. Both the insulin receptor and IRS-1 are
tyrosine-phosphorylated to the same extent in response to acute insulin
stimulation following cellular TNF- exposure. Furthermore, the
ability of the insulin receptor to phosphorylate exogenous substrate in
the test tube is also normal following its isolation from
TNF--treated cells. These results are confirmed by the reduced but
obvious level of insulin-dependent glucose transport and
GLUT4 translocation observed in TNF--treated adipocytes. We conclude
that the insulin resistance of glucose transport in 3T3-L1 adipocytes
exposed to TNF- for 72-96 h results from a reduced amount in
requisite proteins involved in insulin action. These results are
consistent with earlier studies indicating that TNF- reduces the
transcriptional activity of the GLUT4 gene in murine adipocytes, and
reduced mRNA transcription of a number of relevant genes may be the
general mechanism by which TNF- causes insulin resistance in
adipocytes.
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