|
(page 2 of 2)
As the roles of PAI-1 in different physiological states
were being discovered in the 80s and 90s, Loskutoff became
interested in what seemed to be a connection between PAI-1
and obesity. High PAI-1 levels were observed in obesity.
"Nobody knew why it was there or where it came from," says
Loskutoff.
It turns out that the PAI-1 was being produced in adipose
tissue—fat itself—in response to specific changes
that occur in obesity. This is interesting, says Loskutoff,
because it has caused him and many of his colleagues to reassess
how they think of the adipose tissue.
"It was originally thought of as just a place to store fat,"
he says. "[Similarly], the endothelium, blood vessels, have
been thought of historically as pipes for carrying blood—that's
all."
Scientists have since discovered that endothelial cells
are not just static structures that carry blood, but are very
dynamic. They secrete proteins into blood, change the composition
of blood, and exert a profound influence on tissues, organs,
and disease states. Similarly, the cells of the adipose tissue
(the adipocytes) are extremely active biologically. They make
a lot of proteins and change the composition of blood, and
in obesity this can have profound consequences.
In various murine models of obesity, Loskutoff has observed
a consistent and very dramatic increase in PAI-1 levels, and
he thinks it may be related to the increased risk for cardiovascular
disease associated with this condition. As adiopose tissue
expands, the adipocytes produce increasing amounts of this
prothrombotic molecule.
Leptin and Atherosclerosis
Fat, says Loskutoff, is really another organ in the body—perhaps
the biggest organ in a person's body by far—and this
may be where some of the problems associated with obesity
arise. If fat cells make a protein like PAI-1, and the fat
cells enlarge and increase in number as a person becomes obese,
then the levels of that protein can become abnormally high.
In the last two decades, there has been a dramatic increase
in obesity, now a major public health concern in the United
States. According to the U.S. Centers for Disease Control
and Prevention, there are currently more than 44 million Americans
who are obese, which carries with it an increased risk of
type II diabetes, stroke, and other thromboembolic diseases.
Recently, Loskutoff has been looking at another molecule
related to obesity, leptin, which was heralded with much fanfare
when it was discovered about 10 years ago. Leptin is a protein
produced by fat cells that tells the brain when a person has
had enough to eat, and it is thus involved in a negative feedback
loop that controls food intake. When a person eats, leptin
levels increase, the protein binds to its receptor in the
hypothalamus, and the body gets the signal to stop eating.
In recent studies, Loskutoff found a link between leptin
and atherosclerosis, the coronary artery disease marked by
the accumulation of deposits of fat inside the walls of arteries.
Long-term obesity often leads to accelerated atherosclerosis
and work in the Loskutoff laboratory showed that leptin promoted
this process. This may be related to his observation that
platelets and endothelial cells contain leptin receptors on
their surfaces.
"It turns out that leptin promotes platelet aggregation,
and this may also contribute to the risk for atherothrombotic
disease in obesity," says Loskutoff.
Though he is still working out the details of this story,
Loskutoff says that his findings demonstrate a direct link
between leptin and vascular disease.
"We're really excited about that," he says.
1 | 2 |
|
