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VOL. 73 (4), 987-1008, 2007 CONTRIBUTION OF TNF-a TO OBESITY...

rosiglitazone decreased the activity of PTP1B (49), and improved
insulin sensitivity concomitant with an increase in thermogenic
differentiation, contributing globally to an accelerated glucose
disposal in BAT. Moreover, recent studies have demonstrated
increased levels and activities of PTP1B in skeletal muscle and liver
of diabetic rats whereas rosiglitazone treatment decreases this
enlargement in muscle but not in liver (50). On the other hand,
synthetic LXR agonists ameliorate TNF-a-induced insulin resistance
in fetal brown adipocytes restoring completely insulin-stimulated
GLUT4 translocation to plasma membrane. This effect was parallel
to the recovering of insulin signalling cascade IR/IRS-2/PI3K/AKT,
and could be due to the fact that T0901317 precludes the
enlargement in PTP1B expression produced by TNF-a (44),
supporting the hypothesis of nuclear receptors LXR are interesting
targets for drug treatment of insulin-resistant conditions.

Therefore, inhibition of ERK and p38MAPK activation with
rosiglitazone and down-regulation of PTP1B with either rosiglitazone
or LXR agonists restores insulin sensitivity in brown adipocytes in
the presence of TNF-, as summarized in Figure 4.

CONCLUSIONS

The mechanism by which TNF-a produces insulin resistance in
murine skeletal muscle and in BAT shows tissue specificity. TNF-a
impairs insulin-stimulated glucose uptake in myocytes at the level of
IRS-1 by a double machinery that involves serine phosphorylation at
the residue Ser307 (by IKK and p38MAPK) and tyrosine dephospho-
rylation (by PTP1B), weakening the tyrosine phosphorylation
induced by insulin. Consequently, pharmacological inhibition of IKK
with salicylate and ablation of PTP1B restores insulin sensitivity in
the presence of the cytokine.

In brown adipocytes, TNF-a-induced insulin resistance involves
serine/threonine phosphorylation of IRS-2 by MAPKs, and activation
of the phosphatases PP2A and PTP1B that inactivate AKT and IR/
IRS, respectively. Pharmacological inhibition of MAPKs and
phosphatases with rosiglitazone and LXR agonists, respectively,
recovers insulin sensitivity in the presence of TNF-a.

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