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

summarized in Figure 3. In this regard, new mono- and disalicylic
acid derivates have been very recently used as PTP1B inhibitors and
potential anti-obesity drugs (36).

INVOLVEMENT OF MAPK AND PHOSPHATASES IN THE
DEVELOPMENT OF INSULIN RESISTANCE BY TNF-a IN

BROWN ADIPOCYTES

BAT is present and active in mammal newborns and is
responsible for their successful defense of body temperature without
shivering. When BAT is not adrenergically stimulated, brown
adipocytes suffer apoptosis or transform into white adipocyte-like
cells that gradually loose many brown characteristics. This
phenomenon is particularly noticeable in adult humans, in which
BAT is thought to be rapidly lost postnatally, so that humans later
in life do not possess more than vestigial amounts of this tissue,
located within the white fat depots (37). However, the use of
fluorodeoxyglucose positron emission tomography has revealed the
presence of symmetrical areas of increased tracer uptake in the upper
parts of the human body, which correspond to brown adipose tissue.
The human depots are differently located from those in rodents,
mainly in the supraclavicular and the neck regions, but no
interscapular (38). These findings point out that BAT is present and
active in a substantial fraction of adult humans and that may thus
be considered of metabolic significance in human physiology.

Glucose transport in brown adipocytes is maintained mainly by
the activity of GLUT4, and insulin treatment stimulates glucose
transport by mediating GLUT4 translocation in a PI3K-, AKT- and
PKC?-dependent manner (39, 40). Furthermore, inhibition of
phospholipase C (PLC)? activity precludes insulin stimulation of
glucose uptake, GLUT4 translocation and actin reorganization,
indicating that PLC?, through the production of phosphatidic acid,
is a link between IR and PKC? (40). In addition, IRS-2 seems to be
crucial in mediating glucose uptake in brown adipocytes (41).

TNF-a acts as a negative regulator of adipogenic and thermogenic
differentiation and induces insulin resistance in BAT (4), in a similar
fashion as reported in 3T3-L1 cells and in primary human adipocytes.

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