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

the development of insulin resistance because the majority of type 2
diabetic subjects are obese; TNF-a is highly expressed in adipose
tissues from obese subjects and obese mice lacking either TNF-a or
its receptors showed protection for developing insulin resistance (12).
Rather than systemically, TNF-a seems to acts locally at the site of
WAT through autocrine/paracrine mechanisms having effects on
insulin resistance and inducing interleukin-6 (9).

On the other hand, TNF-a has lypolitic and anti-adipogenic effects
on WAT (9). This paradox could be due to proliferative and anti-
apoptotic effects of this cytokine in the obese adipocyte, and could
be mediated by the differential expression of its soluble and
membrane-anchored receptors. Both ceramides and FFA had been
reported to induce insulin resistance in peripheral tissues and the
production of these molecules could be consequence of activation of
sphingomyelinase or lipolysis by TNF-a (9). Several other mediators
that are activated in response to TNF-a such as stress kinases and
inflammatory pathways could also contribute to insulin resi. In this
regard, an increased phosphorylation of p38MAPK in human
adipocytes and muscle from type 2 diabetic subjects has been
described (13).

Direct exposure of isolated cells to TNF-a inhibits insulin
signalling and induces a state of insulin resistance in several systems
including 3T3-L1 cells and human primary adipocytes by affecting
IRS proteins (12). The mechanism of IRSs regulation involves
proteasome-mediated degradation, phosphatase-mediated dephos-
phorylation and serine phosphorylation of IRS-1 that converts IRS-
1 in an inhibitor of the IR tyrosine kinase activity, as reviewed (1,
14). Both ERK and c-Jun N-terminal kinase (JNK) have been
proposed to mediate TNF-a serine/threonine phosphorylation of IRS-
1 in white adipocytes, being identified the residue Ser307 as a site
for TNF-a phosphorylation of IRS-1. In this regard, ablation of jnk1
decreases the development of insulin resistance associated with
dietary obesity. Furthermore, ERK and p38MAPKs could also inhibit
insulin signaling by TNF-a at the level of IRS-1 and IRS-2 in 3T3-L1
adipocytes, whereas JNK could mediate the feedback inhibitory effect
of insulin (1, 14). Others works also implicate inhibitor kB kinases
(IKK) activation by TNF-a on serine phosphorylation of IRS-1,
meanwhile IKK inhibition with salicylate or targeted disruption of

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