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Gene Initially Implicated in Obesity Appears to Play Role in Immune Responses and Production of Reactive Oxygen species

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Duke Health News 919-660-1306

DURHAM, N.C. - The group of researchers from Duke University
Medical Center and France who found a gene in 1997 that
appeared to keep mice from getting obese on a high-fat diet
have now identified a new, and possibly more important, role
for the gene - regulating potent immune responses.

The gene they discovered, called uncoupling protein 2
(UCP2), contains the blueprint for a heat-generating protein
that appeared to play a role in regulating body temperature and
burn excess calories as body heat before they can be stored as
fat. For their new experiments, the researchers created a
strain of mice in which the UCP2 gene was deleted, or knocked
out.

"Sometimes, one of the best ways to find out what a gene
does is it eliminate it and see what effect its absence
causes," said Sheila Collins, a Duke researcher and member of
the international team.

To the researchers' surprise, they found that the knockout
mice did not gain weight when fed a high-fat diet, and they
reacted normally when challenged by cold temperature. To all
outward appearances, the knockout mice seemed to be the same as
normal mice. However, further study revealed that the knockout
mice demonstrated a heightened activity of macrophages, potent
immune system cells responsible for defeating foreign invaders
such as parasites and viruses.

In collaboration with a team from Laval University in Quebec
City, Canada, the researchers infected normal and knockout mice
with Toxoplasma gondii, a parasite known to cause lethal brain
infections in mice. While all the normal mice wasted away and
died within weeks, all the knockout mice survived,
demonstrating that the lack of UCP2 conferred protection
against a deadly infection.

Co-senior authors Collins and Daniel Ricquier, Sc.D., of the
French Centre National de la Recherche Scientifique (CNRS),
published the results of their study in the December issue of
the journal Nature Genetics. Both are researchers whose primary
research focus was on UCP2 as a possible genetic basis for
obesity and diabetes.

"This finding opens a whole new conceptual door - we have
found a type of molecule not known to exist a few years ago
that now appears to have a major impact on the immune system,"
Collins said. "The results of this study provide additional
insights into how macrophages work, which could have important
implications for our immunology colleagues."

Ricquier, who has been investigating uncoupling proteins and
obesity for more than 25 years, believes that the series of
experiments conducted by the team should lead other researchers
to reconsider the role of UCP2 in certain immune diseases in
humans.

"We observed that the knockout mice were resistant to
infection by parasites because of a more efficient immune
system," Ricquier said. "By simply disrupting the UCP2 gene, we
were able to make the immune systems of these mice more
potent."

While the exact mechanisms behind this are not clear, the
researchers found that when compared to normal mice, the
macrophages in the knockout mice produced more reactive oxygen
species (ROS), highly reactive ions that can wreak havoc within
cells.

In the living mouse models, the knockouts produced 80
percent more ROS compared to normal mice, and in an in vitro
mouse model, the killing ability of macrophages was five times
greater in knockout mice against Toxoplasma gondii. It is well
established in immunology, Collins said, that one of the
mechanisms immune system cells use to kill invaders are
ROS.

For Ricquier, the key question is the relationship between
the increased production of ROS and the absence of the UCP2
gene. It appears that a key to understanding this phenomenon
lies in the mitochondria, organelles that are located within
cells and are considered the "power generator" of all cells,
converting food into energy through the process of
oxidation.

"It is known that mitochondria can produce ROS, and this
production is based on the level of its activation," Ricquier
said. "The more energized the mitochondria, the more ROS it
produces. We believe that UCP2 somehow plays a role in
controlling the energy status of the mitochondria - this is one
of our current avenues of investigation."

In more general terms, the researchers believe these
findings can provide insights into a host of human diseases and
disorders, as well as the process of aging. Reactive oxygen
ions are the normal byproducts of cellular metabolism, and if
left unchecked, can cause damage to surrounding cells. The body
has systems to "mop up" these reactive oxygen ions and
neutralize their damaging properties.

"Since cells need a system to control the tendency of
mitochondria to over-produce ROS, it could be that the major
role of UCP2 is to respond to changing levels of these damaging
oxidants and control them," Ricquier said.

The class of UCP genes is an ancient one that has not only
been found in mammals, but in plants and fish, according to
Ricquier.

"When any cell uses oxygen, it produces a lot of energy,
which is a very efficient process for plants and animals,"
Ricquier explained. "However, the price to pay is the creation
of these highly reactive oxidant by-products. So it would make
sense to have a system to limit ROS, and these uncoupling genes
may play a more important role than we first thought."

"This is another case of finding somewhat unexpected
connections between two different areas of research, with
potentially important implications for medicine," Collins
said.

The research was supported by the National Institutes of
Health, CNRS, Association de Recherches sur le Cancer, Institut
de Recherches Servier, Association Francaise contr less
Myopathies, and the Human Frontier Science Program.

The series of experiments involved toxoplasma gondii were
conducted by Drs. Denis Arsenijevic and Denis Richard at the
Institut Universitaire de Cardiologie et de Pneumologie,
Hopital Laval, in Sainte-Foy, Canada.

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