Bone marrow cells that produce brain-derived
eurotrophic factor (BDNF), known to affect
regulation of food intake, travel to part of the
hypothalamus in the brain where they "fine-tune"
appetite, said researchers from Baylor College of
Medicine and Shiga University of Medical Science in
Otsu, Shiga, Japan, in a report that appears online
in the journal Nature Communications.
"We knew that blood cells produced BDNF," said Dr.
Lawrence Chan, professor of molecular and cellular
biology and professor and chief of the division of
diabetes, endocrinology & metabolism in the
department of medicine and director of the federally
funded Diabetes Research Center, all at BCM. The
factor is produced in the brain and in nerve cells
as well. "We didn’t know why it was produced in
blood cells."
Dr. Hiroshi Urabe and Dr. Hideto Kojima, current and
former postdoctoral fellows in Chan’s laboratory
respectively, looked for BDNF in the brains of mice
who had not been fed for about 24 hours. The bone
marrow-derived cells had been marked with a
fluorescent protein that showed up on microscopy. To
their surprise, they found cells producing BDNF in a
part of the brain’s hypothalamus called the
paraventricular nucleus.
"We knew that in embryonic development, some blood
cells do go to the brain and become microglial cells,"
said Chan. (Microglial cells form part of the
supporting structure of the central nervous system.
They are characterized by a nucleus from which "branches"
expand in all directions.) "This is the first time
we have shown that this happens in adulthood. Blood
cells can go to one part of the brain and become
physically changed to become microglial-like cells."
However, these bone marrow cells produce a bone
marrow-specific variant of BDNF, one that is
different from that produced by the regular
microglial cells already in the hypothalamus.
Only a few of these blood-derived cells actually
reach the hypothalamus, said Chan.
"It’s not very impressive if you look casually under
the microscope," he said. However, a careful
scrutiny showed that the branching nature of these
cells allow them to come into contact with a whole
host of brain cells.
"Their effects are amplified," said Chan.
Mice that are born lacking the ability to produce
blood cells that make BDNF overeat, become obese and
develop insulin resistance (a lack of response to
insulin that affects the ability to metabolize
glucose). A bone marrow transplant that restores the
gene for making the cells that produce BDNF can
normalize appetite, said Chan. However, a transplant
of bone marrow that does not contain this gene does
not reverse overeating, obesity or insulin
resistance.
When normal bone marrow cells that produce BDNF are
injected into the third ventricle (a fluid-filled
cavity in the brain) of mice that lack BDNF, they no
longer have the urge to overeat, said Chan.
All in all, the studies represent a new mechanism by
which these bone-marrow derived cells control
feeding through BDNF and could provide a new avenue
to attack obesity, said Chan.
He and his colleagues hypothesize that the bone
marrow cells that produce BDNF fine tune the
appetite response, although a host of different
appetite-controlling hormones produced by the
regular nerve cells in the hypothalamus do the
lion’s share of the work.
"Bone marrow cells are so accessible," said Chan.
“If these cells play a regulatory role, we could
draw some blood, modify something in it or add
something that binds to blood cells and give it
back. We may even be able to deliver medication that
goes to the brain," crossing the blood-brain barrier.
Even a few of these cells can have an effect because
their geometry means that they have contact with
many different neurons or nerve cells.
He credits Urabe and Kojima (now with Shiga
University of Medical Science in Japan) with doing
most of the experiments involved in the research.
Others who took part include: Tomoya Terashima,
Nobuhiro Ogawa, Miwako Katagi, Kazuori Fujino, Asako
Kumagai, Hiromichi Kawai, Akhiro Asakawa, Akio Inui,
Hitoshi Yasuda, Yutaka Eguchi, Kazuhiro Oka, Hiroshi
Maegawa, Atsunori Kashiwagi and Hiroshi Kimura, all
of Shiga University of Medical Science.
Funding for this work came from the Ministry of
Education, Culture, Sports, Science and Technology,
Japan, the President's Discretionary Fund from Shiga
University of Medical Science and the U.S. National
Institutes of Health grant HL-51586 and the Diabetes
Research Center (P30 DK79638).
Chan holds the Betty Rutherford Chair for Diabetes
Research.
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