3. PPAR γ and Its Pivotal Role in
Adipose Tissue Function PPAR γ is highly expressed in adipose tissue, where
it plays a key role in adipose tissue development and function. There are two
major splice variants of PPAR γ, γ1 and γ2, which differ in their N-terminal region
(PPAR γ2 contains an additional 30 amino acids) and in
their tissue-specific expression; PPAR γ2 is found almost exclusively in white and
brown adipose tissues whereas PPAR γ1 is also relatively abundant in macrophages
and endothelial cells [ 16– 18]. The activity
of both isoforms is regulated by posttranscriptional modifications and by
ligand-dependent transactivation and recruitment of coactivators. For instance,
phosphorylation inhibits the transcriptional activity of PPAR γ [ 19] and promotes sumoylation, which further
reduces its transcriptional activity [ 20]. PPAR γ forms heterodimers with retinoid X receptors
(RXRs) to bind to specific DNA sequences in its target genes. In the absence of
ligands, corepressors such as nuclear receptor corepressor (N-CoR) or silencing
mediator of retinoid and thyroid (SMRT) receptors bind to these heterodimers
and recruit histone deacetylases to repress transcription (reviewed in [ 21]).
Binding of ligands to PPAR γ triggers conformational changes that allow the
recruitment of transcriptional coactivators, including members of the steroid
receptor coactivator (SRC) family [ 22] and PPAR γ-coactivator 1 α (PGC-1 α) [ 23] that ultimately recruit histone
acetyltransferase coactivators such as p300/CBP or PCAF [ 21]. However, the natural ligands for PPAR γ remain unknown. Recent studies have provided
functional evidence for an unidentified natural ligand that is produced
transiently during adipogenesis [ 24]. There is also evidence that small
lipophilic compounds, such as polyunsaturated fatty acids and fatty acid
derivatives (eiocosanoids) bind and activate this receptor [ 25], thus
supporting the concept that PPAR γ is a nutrient sensor that finely regulates
metabolic homoeostasis in response to different nutritional states. Regarding synthetic ligands, it is clear that members of the
thiazolidinedione (TZD) family of antidiabetic drugs are high-affinity agonists
for PPAR γ [ 26]. TZDs have been reported to enhance insulin sensitivity in
animals and humans [ 27]. Furthermore, cellular, genetic, and pharmacological
studies have provided strong evidence both that TZDs function via PPAR γ, and that adipose tissue is the main site
where the insulin-sensitizing effects of PPAR γ are produced (reviewed in [ 28]). It was reported that TZDs induce adipocyte differentiation even before
they were known to be ligands of PPAR γ [ 29]. By now, the key role of PPAR γ as a
master regulator of adipogenesis has been clearly established, and
gain-of-function experiments have demonstrated that PPAR γ is sufficient to
induce adipocyte differentiation in the presence of an appropriate ligand [ 30].
However, loss-of-function experiments to prove that PPAR γ is required for this
process have been more difficult, since PPAR γ homozygous inactivation results
in embryonic death due to placental alteration, in a developmental stage before
there is any adipose tissue development [ 31]. Later, however, studies utilizing
chimeric mice [ 32] and adipose-specific PPAR γ knockout mice [ 33] confirmed the
essential role of PPAR γ in adipose tissue differentiation. PPAR γ also plays an important role in regulation of
lipid metabolism in mature adipocytes. Activation of PPAR γ increases both fatty acid uptake and its
storage into adipocytes by promoting the transcription of genes such as those
encoding lipoprotein lipase, fatty acid binding protein-4 (aP2/FABP4),
phosphoenolpyruvate carboxykinase (PEPCK) [ 34– 37], and also glucose transporter
GLUT-4, in order to increase fatty acid synthesis [ 38]. These effects of PPAR γ may underlie its insulin-sensitizing effects.
Thus, together with the proadipogenic role of PPAR γ (glucose homeostasis requires adequate amounts
of adipose tissue), the improvement of lipid storage in this tissue will
prevent ectopic lipid accumulation in nonadipose tissues such as liver,
skeletal muscle, and β-cells. Furthermore, PPAR γ has been reported to induce transcription of
the PGC-1 α gene in adipose tissue [ 39]. The coactivator
PGC-1 α promotes mitochondrial biogenesis, thus
leading to an increase in fatty acid oxidation in adipose tissue, which may
protect against adipocyte hypertrophy [ 40]. Finally, adipose tissue has
endocrine functions, and PPAR γ regulates expression of genes encoding
adipokines such as adiponectin, leptin, resistin, or cytokines such as TNF α. Activation of PPAR γ promotes the expression of a
pro-insulin-sensitizing adipokine profile (i.e., induction of adiponectin and
reduction of TNF α gene expression) thus involving the cross-talk
between adipose tissue and other insulin-sensitive organs (liver, skeletal
muscle) in the insulin-sensitizing effects of PPAR γ [ 41]. Evidence from human mutations in PPAR γ has further underlined the importance of PPAR γ in the development of adipose tissue, in the
maintenance of glucose and lipid homeostasis and more generally in the control
of energy balance (reviewed in [ 42]). Patients harboring mutations in the
ligand-binding domain of PPAR γ have a stereotyped phenotype characterized by
partial lipodystrophy, severe insulin resistance, dyslipidemia, hepatic
steatosis, and hypertension, thus identifying PPAR γ as playing a molecular role in the
pathogenesis of the metabolic syndrome [ 43, 44]. PPAR γ is also expressed in macrophages
and endothelial cells, that is, cells that are present in adipose tissue
[ 17, 18, 45]. In endothelial cells, activation of PPAR γ has antiproliferative,
antiangiogenic, and anti-inflammatory effects [ 45]. PPAR γ is induced during
macrophage differentiation, and its activation increases the expression of
macrophage-specific markers, such as CD14 and CD11b [ 17, 46]. However,
loss-of-function approaches have demonstrated that PPAR γ is not essential for
monocyte/macrophage differentiation either in vivo or in vitro [ 47, 48] but
selective deletion of PPAR γ in macrophages results in increased insulin
resistance [ 49]. Recently, macrophage-mediated inflammation in adipose tissue
has been proposed to play a central role in the pathogenesis of insulin
resistance [ 50]. Two types of macrophages, proinflammatory M1 and
anti-inflammatory M2, are present in adipose tissue and their relative
abundance may change dynamically through recruitment of polarized monocytes
from the blood (macrophage infiltration) or through the effects of local
cytokines on macrophages in adipose tissue. Activation of PPAR γ by TZDs has now
been reported to increase the proportion of anti-inflammatory M2 macrophages in
adipose tissue [ 51]. Furthermore, TZDs also act through PPAR γ to inhibit the
expression of inflammatory mediators in macrophages, and as reported above, to
negatively regulate expression of cytokines such as IL-6, TNF- α, and monocyte
chemoattractant protein—1 (MCP-1/CCL-2)
in adipocytes [ 52]. In summary, activation of PPAR γ improves adipose tissue
function by having a beneficial effect on the adipocyte—macrophage
relationship, which may result in prevention of insulin resistance. |
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