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Welcome, everyone,
to Chapter 12 of
the short talk series on
nuclear receptors as
therapeutic targets.
In this chapter, we will
have a closer look at
the receptor NR1C3,
termed PPARγ,
which is a very important and
prominent nuclear receptor.
We will discuss the most
important biological roles
of PPARγ and PPARγ
targeting drugs.
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As we have already seen
in the last chapter,
PPARγ has a key role
in the development,
metabolic function, and survival
of functional fat tissue.
Therefore, it's
sometimes referred to as
master regulator
of adipose tissue.
Beyond adipose tissue, PPARγ has
an important role in
macrophages, where it regulates
macrophage differentiation
and phenotype,
inflammatory response,
and lipid metabolism.
In the context of cancer,
PPARγ is generally considered
as a tumor suppressor.
But there are also
some reports on
gain-of-function mutations
of the receptor,
for example, in bladder
cancer and somatic fusions,
for example, in
thyroid carcinomas.
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As a master regulator
of adipose tissue,
PPARγ is required for
the differentiation
of precursor cells
into mature adipocytes,
and thus, for the formation
of functional fat tissue.
In adipocytes, the
receptor regulates
the expression of genes involved
in lipid uptake into the cells,
such as lipoprotein
lipase and transporters,
as well as genes involved in
esterification of fatty
acids and in lipid storage.
PPARγ can induce a brown-like
adipose tissue phenotype,
so-called beige adipocytes,
in white adipose tissue,
which enhances thermogenesis
and energy expenditure.
In brown adipose tissue,
PPARγ regulates the
production of mitochondria
and adaptive thermogenesis.
Another important effect
of PPARγ activation
in adipose tissue is its
impact on glucose uptake.
It induces expression of
glucose transporters,
such as the
insulin-regulated GLUT-4,
and enhances glucose uptake.
PPARγ also improves
insulin sensitivity
of adipose tissue.
These effects are exploited by
the insulin-sensitizing
glitazones
that we will see
on a later slide.
