http://www.eurekalert.org/pub_releases/2008-01/uomh-tml012108.php

The missing link between belly fat and heart disease?
In animal study, U-M researchers find inflammation could be the key -
and might be reversed with medicine

ANN ARBOR, Mich. -- By now, everyone knows that overweight people have
a higher risk of heart attacks, strokes and other problems that arise
from clogged, hardened arteries. And people who carry their extra
weight around their waist - giving them a "beer belly" or an "apple"
shape -- have the highest risk of all.

But despite the impact on human health, the reasons behind this
connection between heart disease and belly fat - also known as
visceral fat -- have eluded scientists. Now, a new study in mice gives
the first direct evidence of why this link might exist - and a
tantalizing look at how it might be broken.

In a paper that will be published online today in the journal
Circulation before print publication in February, a team of University
of Michigan Cardiovascular Center scientists reports direct evidence
of a link between inflammation around the cells of visceral fat
deposits, and the artery-hardening process of atherosclerosis.

The researchers also show that a medication often given to people with
diabetes can be used to calm that inflammation, and protect against
further artery damage.

Although the scientists caution that it's far too early to apply their
findings to humans with belly fat, they hope that further research in
animals and people will reveal more about how this dangerous link
comes about, why it begins, how it can be reversed, and perhaps how it
can be diagnosed at an early stage through blood tests.

Until then, the best advice for overweight people who want to reduce
their chance of a heart attack or stroke remains the same: Work on
losing your belly fat, and your other excess body weight, through a
balanced, healthy diet and regular exercise.

The research team is led by Daniel Eitzman, M.D., a cardiologist,
laboratory scientist and associate professor in the Division of
Cardiovascular Medicine at the U-M Medical School and the VA Ann Arbor
Healthcare System.

The discovery came partly by chance. He and his colleagues had been
studying mice that lack the gene for leptin, a hormone generated by
fat cells that plays a role in appetite and metabolism as well as
reproduction. In an effort to get these obese mice to produce some
leptin, the team developed a technique to transplant clusters of fat
cells from normal mice of the same strain, into the leptin-deficient
mice.

The result surprised them. "In addition to producing leptin and
preventing obesity, the fat transplants became inflamed, attracting
immune cells called macrophages," Eitzman explains. "Since the mice
were genetically identical except for leptin, this shouldn't have
happened. But the inflammation was there, and it was chronic."

The inflammation occurred around individual fat cells, or adipocytes.
Further tests showed it was regulated by the same factors that
regulate the inflammation that other researchers have seen in the
naturally occurring fat deposits of obese mice - specifically a
chemokine called MCP-1.

But because the fat was transplanted, the inflammation could be
attributed directly to the fat, and not to overfeeding of the mice, or
the metabolic problems that overfeeding and obesity bring, such as
diabetes.

Armed with this discovery, the researchers set out to see what was
causing inflammation to occur, and what implications it had. The team
included postdoctoral fellow Miina Öhman, M.D., Ph.D., U-M professor
Daniel Lawrence, Ph.D., and members of the Eitzman and Lawrence
laboratory teams.

They were especially interested to see if there might be any link
between the inflammation and atherosclerosis - the formal name for the
process by which blood vessels become stiff, narrowed and lined with
plaque formations that can trigger the development of blood clots.

This process, which occurs throughout the body, sets the stage for
most heart attacks and strokes. Scientists and clinicians now realize
that it is based on inflammation - the abnormal reaction of the body's
immune system to its own tissue -- and in the damage that immune-system
cells and molecules can inflict.

Since normal mice don't develop atherosclerosis, the team had to turn
to a strain that had been developed to be especially prone to high
cholesterol and hardened arteries. These ApoE-negative mice, as they
are called, were divided into three groups: two that received fat
transplants from normal mice, and one that did not, but that had the
same operation that would be used to implant the fat in other mice.

Some of the fat-transplant ApoE-negative mice received transplants of
visceral fat, which forms in the belly around the major organs, while
others received transplants of subcutaneous fat - the type that's
found just under the skin throughout the body.

Sure enough, the mice that received the visceral fat transplants
developed atherosclerosis at a much-accelerated rate, and experienced
the same type of inflammation as the leptin-deficient mice had.
Meanwhile, those that received subcutaneous fat did not experience an
increase in atherosclerosis despite having increased inflammation. The
mice that had the "sham" operations developed neither inflammation nor
increased atherosclerosis.

"There appeared to be an interaction between the macrophages causing
the inflammation in the visceral fat, and the process of
atherosclerosis," says Eitzman, who notes that blood vessels far from
the site of the fat transplant developed increased atherosclerosis.

Finally, the team attempted to calm the inflammation and curb the
atherosclerosis by treating the mice with pioglitazone - a member of
the class of drugs called thiazolidinediones or TZDs that are often
used to treat diabetes. While TZD drugs have an impact on metabolism,
which makes them useful in diabetes, they also have been discovered to
have an anti-inflammatory effect.

And in fact, the drug reduced both the concentration of macrophages
and MCP-1, and atherosclerosis, in those mice that received
transplants of visceral fat. But the drug had no effect in the other
mice.

Now that they have demonstrated the linkage between belly fat,
inflammation and hardened arteries, and a potential mechanism for
reversing the phenomenon, the team is working on new pieces of the
puzzle. Specifically, they're looking for the factors that might
trigger macrophages to invade the area and bring on inflammation, and
for blood-borne molecules called biomarkers that might be used as a
way to identify early warning signs of atherosclerosis. They'll also
look at other classes of drugs to see if they might have a protective
effect, because TZD drugs act on many systems and cause some side
effects.

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Thanks Vince