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may clamp down on brain cholesterol
November 30, 2010 – The brain contains more
cholesterol than any other organ in the
body, has to produce its own cholesterol and
won't function normally if it doesn't churn
Defects in cholesterol metabolism have been
linked with Alzheimer's disease and other
neurodegenerative conditions. Now
researchers at Joslin Diabetes Center have
discovered that diabetes can affect how much
cholesterol the brain can make.
Scientists in the laboratory of C. Ronald Kahn,
M.D., head of Joslin's Integrative
Physiology and Metabolism research section,
found that brain cholesterol synthesis, the
only source of cholesterol for the brain,
drops in several mouse models of diabetes.
Their work was reported online in the
"Since cholesterol is required by neurons to
form synapses (connections) with other
cells, this decrease in cholesterol could
affect how nerves function for appetite
regulation, behavior, memory and even pain
and motor activity," says Dr. Kahn, who is
also Mary K. Iacocca Professor of Medicine
at Harvard Medical School. "Thus, this has
broad implications for people with
Other investigations have gathered strong
evidence that people with diabetes may
display varying types of alterations in
brain function or ways of responding to
stress, he points out.
"It is well known that insulin and diabetes
play an important role in regulating
cholesterol synthesis in the liver, where
most of the cholesterol circulating in blood
comes from," Dr. Kahn adds. "But nobody had
ever suspected that insulin and diabetes
would play an important role in cholesterol
synthesis in the brain."
In addition to its potential role in
Alzheimer's disease and other forms of
neurological dysfunction, the newly
discovered mechanism may play a role in
diabetic neuropathy, which remains a large
challenge for therapy.
People with diabetes are also known to be more
prone to depression, memory loss and eating
disorders than people without diabetes, and
imaging studies have shown that people with
diabetes have altered brain function
compared to those without.
Additionally, the finding raises a question
about potential interactions between
anti-cholesterol drugs and diabetes.
In the Joslin study, scientists first examined
gene expression in the hypothalamus of a
mouse model of insulin-deficient (type 1)
They found decreased expression for almost all
of the genes of cholesterol synthesis,
including a gene called SREBP-2, which acts
as a master regulator for cholesterol
Similar findings were present in the cerebral
cortex and other regions of the brain in
these animals and also found in several
other mouse models of diabetes.
In the insulin-deficient animals, this
phenomenon was associated with decreased
cholesterol synthesis. Treatment of the mice
with insulin, either by normal injection or
injection into the fluid surrounding the
brain, reversed the process.
"Our studies showed that these effects occurred
in both the neurons and supporting 'glial'
cells that help provide some nutrients to
the neurons," says Kahn.
"Ultimately this affects the amount of
cholesterol that can get into the membranes
of the neuron, which form the synapses and
the synaptic vesicles—the small structures
that contain neurotransmitters."
Additionally, the Joslin work showed a
connection between the decrease in brain
cholesterol synthesis and appetite.
When the scientists took normal mice and
temporarily reduced cholesterol creation in
the hypothalamus with a technique known as
RNA interference, the animals started eating
more and gained significant weight. Previous
studies by other labs have demonstrated that
diabetes may affect brain hormones involved
in appetite regulation.