Antidiabetic PPARγ Ligands Act on
Adipocytes
In patients with type 2 diabetes, treatment
with TZD compounds results in a dramatic
improvement in peripheral insulin
sensitivity and a reduction in plasma glucose
concentrations. The TZD compounds
were first identified in the 1980s as antidiabetic
agents in rodents, well before the
discovery of the PPARγ receptor and in
the absence of any knowledge of their
mechanism of action. In the 1990s, it
was discovered that TZDs could activate
PPARγ and cause the differentiation of
preadipocytes into adipocytes and it is
now generally accepted that the antidiabetic
activities of the TZDs aremediated by
activation of PPARγ . Perhaps the clearest
evidence that PPARγ activation mediates
the antidiabetic effects of these drugs are
the recently discovered synthetic ligands
for PPARγ that have been selected exclusively
for their ability to activate the
receptor. These non-TZD PPARγ 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, several
general possibilities have emerged.
First, TZDs may have a beneficial 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. Another
scenario is that, PPARγ agonists act
on the mature adipocyte to alter the production
of adipose-derived hormones or
metabolic signals that function to improve
metabolic parameters in other tissues and
organs such as muscle, liver and pancreas.
Finally, it is also possible that TZDs exert
some of their metabolic effects through
PPARγ 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 adipose
tissue. TZD treatment induces the appearance
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 Fig. 4.
It has been hypothesized that the newly
Adipocytes 17
(a)
(b)
Control (14 days) TZD (14 days)
Fig. 4 Thiazolidinedione treatment remodels
white adipose tissue. Mice were treated for
2 weeks with the TZD T174, and subcutaneous
white fat was processed by (a) hematoxylin and
eosin staining and (b) tissue autofluorescence.
Note the appearance of numerous clusters of
small multilocular adipocytes in TZD-treated
tissue.
appearing small adipocytes might bemore
insulin sensitive and/or secrete lower levels
of prodiabetes hormones and thereby
contribute to the insulin-sensitizing effects
of the drug. It is also possible that the
increased number of smaller adipocytes,
especially in the appropriate adipose beds,
may improve the ability of adipose tissue
to store excess lipid and reduce deleterious
accumulation of triglyceride in muscle,
liver, and pancreatic islets. In support of
this possibility is the observation thatmany
of the known target genes for PPARγ ,
whose expression would presumably be activated
upon TZD treatment, are involved
in lipogenesis. The increased rates of
lipogenesis resulting from gene activation
may increase the capacity of adipocytes to
store lipid, thereby preventing triglyceride
accumulation (and lipotoxicity) in nonadipose
tissue. Whether the small adipocytes
are derived from stem cell mitosis, recruitment
of committed preadipocytes, or
possibly by division of mature cells is not
known. The loss of large fat cells was attributed
to cellular apoptosis; however, the
impact of TZD treatment on the fate and
turnover of mature adipocytes has not been
investigated directly.
Consistent with the observations of adipose
tissue remodeling is the increased
subcutaneous fat mass, and reduced
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 subcutaneous
fat, and to efficiently 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 subcutaneous
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
PPARγ levels are higher in subcutaneous
than in visceral fat, raise the possibility
that PPARγ activation by TZDs is fat depot
specific, and that differential activation of
PPARγ in subcutaneous fat leads to a beneficial
reproportioning of key metabolically
active adipose beds.
The other possiblemechanism by which
activation of PPARγ 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 mediating
the antidiabetic effects of PPARγ
ligands. As described above, adiponectin
has antidiabetic and antiobesity activity
when introduced into rodents. Importantly,
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 PPARγ agonists. Another possibility
is that the adipokine, resistin is negatively
regulated by PPARγ . It has been
reported that in some models, treatment
with TZDs results in a reduction of resistin
synthesis, which would have beneficial effects
on insulin sensitivity. Finally, TZDs,
could suppress expression of genes, such
as TNFα and PAI-1, that might also
contribute to systemic insulin resistance.
Interestingly a mutual antagonism exists
between TNFα and PPARγ; TNFα inhibits
PPARγ expression in adipocytes
whereas PPARγ activation by TZDs can
partially overcome the diabetogenic effects
of TNFα, potentially explaining at least
some of the insulin-sensitizing activity of
PPARγ ligands.
While there is still obviously a great
deal to learn about which of these many
possible mechanisms actually mediate the
effects of PPARγ activation in adipose tissue,
it is clear that an understanding of how
these drugs affect adipose physiology will
providemany clues into the complex pathways
by which the adipocyte influences
metabolism throughout the organism