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

rosiglitazone, are agonists for PPAR? that display insulin-sensitizing
actions across a wide spectrum of insulin-resistant states, and have
recently been introduced as therapeutic agents for the treatment of
type 2 diabetes (45). Moreover, PPAR? plays a critical role in the
adipogenic differentiation process since its deletion in WAT resulted
in marked adipocyte hypocellularity and hypertrophy, elevated levels
of FFA and decreased levels of plasma leptin (46). These mice showed
insulin resistance and were more susceptible to high fat diet-induced
liver steatosis. Thus, TZD may exert effects on adipogenesis and
gene expression, such as formation of new, small, and insulin
sensitive fat cells, reduced production of TNF- and/or increased
expression of adiponectin in WAT (45). Moreover, TZD up-regulated
lipoprotein lipase (LPL) and hormone sensitive lipase (HSL) gene
expression and increased insulin responsiveness on lipolysis and
lipogenesis in human subcutaneous adipocytes, consistent with the
weight gain observed during the treatment (46). Nevertheless, the

FIGURE 4. Insulin resistance by TNF-a in brown adipocytes involves 1) serine/
treonine phosphorylation of the IRS-2 by ERK and p38MAPK; 2) generation of
ceramide and activation of the phosphatase PP2A, and 3) modulation of PTP1B
activity. Inhibition of ERK and p38MAPK activation with rosiglitazone, and
down-regulation of PTP1B with either rosiglitazone or T0901317? ameliorates
TNF-a-induced insulin resistance.

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