18
Adipocytes
visceral fat mass seen in diabetic patients
treated long-term with TZDs. Visceral fat
is known to be more lipolytic in response
to catecholamine stimulation than sub-
cutaneous fat, and to efFciently deliver
free fatty acids and other secreted factors
to insulin-sensitive tissues such as liver
and muscle, possibly causing an increase
in insulin resistance. Although intrinsic
metabolic differences between subcuta-
neous and visceral fat are not completely
understood, current evidence suggests that
subjects with increased visceral fat are at
considerably higher risk for diabetes and
cardiovascular complications than those
with increased subcutaneous fat. These
observations, plus the demonstration that
PPAR
γ
levels are higher in subcutaneous
than in visceral fat, raise the possibility
that PPAR
γ
activation by TZDs is fat depot
speciFc, and that differential activation of
PPAR
γ
in subcutaneous fat leads to a ben-
eFcial reproportioning of key metabolically
active adipose beds.
The other possible mechanism by which
activation of PPAR
γ
in adipocytes could
have effects on metabolism throughout
the body, is by modulation of adipokine
production. Adiponectin is an excellent
candidate for a fat-derived hormone me-
diating the antidiabetic effects of PPAR
γ
ligands. As described above, adiponectin
has antidiabetic and antiobesity activity
when introduced into rodents. Impor-
tantly, it has recently been demonstrated
that levels of adiponectin are increased
in patients treated with TZDs and that
its expression in adipocytes is induced
by PPAR
γ
agonists. Another possibility
is that the adipokine, resistin is nega-
tively regulated by PPAR
γ
. It has been
reported that in some models, treatment
with TZDs results in a reduction of resistin
synthesis, which would have beneFcial ef-
fects on insulin sensitivity. ±inally, TZDs,
could suppress expression of genes, such
as TN±
α
and PAI-1, that might also
contribute to systemic insulin resistance.
Interestingly a mutual antagonism exists
between TN±
α
and PPAR
γ
;TN
±
α
in-
hibits PPAR
γ
expression in adipocytes
whereas PPAR
γ
activation by TZDs can
partially overcome the diabetogenic effects
of TN±
α
, potentially explaining at least
some of the insulin-sensitizing activity of
PPAR
γ
ligands.
While there is still obviously a great
deal to learn about which of these many
possible mechanisms actually mediate the
effects of PPAR
γ
activation in adipose tis-
sue, it is clear that an understanding of how
these drugs affect adipose physiology will
provide many clues into the complex path-
ways by which the adipocyte influences
metabolism throughout the organism.
See also
Diabetes Insipidus, Molec-
ular Biology of.
Bibliography
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ald, I.A.,
Coppack, S.W.
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