16
Adipocytes
diseases. As described above, our cur-
rent understanding of the role of adipose
in protecting other tissue from delete-
rious lipid accumulation suggests that
d
rug
sa
c
t
ingonth
i
sa
spe
c
to
fad
ipo
cy
te
function might have beneFcial effects.
Likewise, the observations (also described
above) on adipocyte derived hormones and
their metabolic activities, suggests that
therapeutic agents modulating the produc-
tion of key adipokines could also improve
certain metabolic parameters. The view
that drugs acting on adipocytes could be
useful is reinforced by the relatively recent
observation that a major class of antidia-
betic drugs, the thiazolidinediones, have
direct effects on adipocytes. Although this
is an active area of research, a generally ac-
cepted model of TZD action has emerged
in which the antidiabetic effect of these
drugs is mediated by activation of the
PPAR
γ
transcription factor in adipocytes.
The following is a review of our current un-
derstanding of how activation of PPAR
γ
in adipocytes might improve insulin sen-
sitivity and other metabolic parameters.
This model can serve as a general example
of how modiFcation of adipocyte physiol-
ogy could improve whole body metabolic
status.
5.1
Antidiabetic PPAR
γ
Ligands Act on
Adipocytes
In patients with type 2 diabetes, treatment
with TZD compounds results in a dra-
matic improvement in peripheral insulin
sensitivity and a reduction in plasma glu-
cose concentrations. The TZD compounds
were Frst identiFed in the 1980s as antidi-
abetic agents in rodents, well before the
discovery of the PPAR
γ
receptor and in
the absence of any knowledge of their
mechanism of action. In the 1990s, it
was discovered that TZDs could activate
PPAR
γ
and cause the differentiation of
preadipocytes into adipocytes and it is
now generally accepted that the antidia-
betic activities of the TZDs are mediated by
activation of PPAR
γ
. Perhaps the clearest
evidence that PPAR
γ
activation mediates
the antidiabetic effects of these drugs are
the recently discovered synthetic ligands
for PPAR
γ
that have been selected ex-
clusively for their ability to activate the
receptor. These non-TZD PPAR
γ
agonists
show very similar antidiabetic activity to
the TZDs.
Although the exact mechanism by which
these drugs improve peripheral insulin
sensitivity and reduce plasma glucose
concentration is not fully understood, sev-
eral general possibilities have emerged.
±irst, TZDs may have a beneFcial effect
on metabolism by increasing the fat cell
number and size, leading to greater lipid
storage capacity and increased protection
of nonadipose tissues from the deleterious
effects of excess lipid accumulation. An-
other scenario is that, PPAR
γ
agonists act
on the mature adipocyte to alter the pro-
duction of adipose-derived hormones or
metabolic signals that function to improve
metabolic parameters in other tissues and
organs such as muscle, liver and pancreas.
±inally, it is also possible that TZDs exert
some of their metabolic effects through
PPAR
γ
present in nonadipose tissues
such as skeletal muscle.
One feature of TZD treatment that could
be central to the therapeutic actions of
these compounds is a remodeling of adi-
pose tissue. TZD treatment induces the ap-
pearance of clusters of small multilocular
adipocytes and loss of large unilocular
adipocytes in Zucker diabetic rats. This
effect is also observed in mice treated
with TZD compounds as seen in ±ig. 4.
It has been hypothesized that the newly
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