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The
way to a man’s heart may be through his stomach, if the old
adage is true, but the way to everyone’s stomach may be through
a particular protein concentrated in the brain. Emory geneticist
Xiao-Jiang Li has discovered that the protein Hap1 is a critical
cog in the brain machinery that regulates eating behavior and appetite.
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Li
first discovered Hap1 (huntingtin-associated protein) in 1995 while
studying Huntington’s disease as a postdoctoral fellow at
Johns Hopkins. Huntington’s is a progressive neurologic disease
caused by a mutation in the huntingtin gene. Under normal conditions,
the huntingtin protein interacts congenially with the Hap1 protein,
but in Huntington’s disease, this interaction turns toxic
and helps fuel the degenerative effects of Huntington’s. Li’s
discovery was published in the journal Nature, and today
he and his Emory colleagues are leading the field in new findings
about the roles of this important protein.
In addition to the protein’s
part in Huntington’s disease, Li has found that Hap1 is critically
important during embryonic development and also has important links
to eating behavior and appetite control. Li and other scientists
have discovered that Hap1 conducts its business by transporting
and trafficking with other molecules and proteins within cells.
After first identifying Hap1, Li wanted
to find out more about its specific role in the brain apart from
Huntington’s as well as what would happen to animals lacking
the protein. He used a transgenic mouse model to knock out the Hap1
gene and discovered a striking phenotype: the mice without Hap1
did not eat after birth. They survived only two or three days and
died of starvation. |
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Hap1’s
connection to this eating phenomenon in newborn mice made sense
when Li discovered that Hap1 was concentrated in the hypothalamus—the
area of the brain that serves as the central switching control for
neural signals that regulate food intake, feeding behavior, and
energy balance. Without Hap1, important neurons in the hypothalamus
degenerate and die of apoptosis, a cell self-destruction program
that activates when cells fail to receive proper growth signals.
When Li examined the mouse model of
Huntington’s disease, he found that neurons in the hypothalamus
were dying of apoptosis. The mutated huntingtin protein was having
a toxic effect on Hap1. This finding fit with the physical manifestations
of Huntington’s, which in its late stages often causes patients
to lose their appetites and experience extreme weight loss.
To find out more about Hap1 and the
neural pathways involved in appetite and eating, Li needed to study
adult mice. However, the knockout mice lacking the Hap1 protein
died almost immediately and fell far short of adulthood. Along with
scientists from other universities, Li began a series of experiments
using a technique that allowed the reduction of gene expression
in adult animals by selectively interfering with RNA. RNA is the
molecule that translates genetic instructions from DNA into proteins,
and this technique is known as sRNA interference (selective RNA
interference).
With the reduced Hap1 expression,
the mice grew to adults, enabling the scientists to expand their
research. Li was now able to manipulate the level of Hap1 and explore
its interaction with other elements of the eating pathway. What
he found was that adult mice with reduced Hap1 expression ate less
food and lost body weight—just as the newborn mice had done
when they were born without Hap1. When the adult mice were forced
to fast, however, the level of Hap1 increased in the hypothalamus. |
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Next,
Li wanted to know how Hap1 interacts with the neural circuitry
already known to be involved with eating behavior, but not well
understood. Hormones such as insulin and leptin, for instance,
circulate in the blood plasma and regulate the brain’s feeding
signals to reduce appetite. Neurotransmitters in the hypothalamus
such as GABA (gamma aminubutyric acid) are an important part of
the pathway that regulates feeding behavior.
Using their selective interference
with Hap1 expression, Li and his colleagues discovered that by
reducing Hap1, they could decrease the level and activity of GABA
receptors. They also found that by administering insulin, they
could reduce the level of Hap1. In the process, they discovered
that Hap1 is important for transporting growth factor receptors
to the cell surface—a necessary step for brain cells to
differentiate and become mature neurons.
“All this work led us to several
conclusions,” says Li. “First, it told us that increasing
Hap1 leads to increased feeding behavior. Also, it helped explain
how Hap1 is linked to feeding-related molecules such as insulin
and to the function of neurons in the hypothalamus. GABA is known
to have a stimulating effect on feeding behavior. Because insulin
decreases Hap1 levels and reducing Hap1 decreases GABA receptor
activity, we think Hap1 is the link between circulating insulin
and the GABA receptors in the hypothalamus that regulate eating
behavior.”
Scientists already know that diabetes
and obesity are related to abnormalities of hypothalamic function,
Li says. However, this complicated pathway is not fully understood.
That’s where Hap1 can help. Recently, Li developed a “conditional”
knockout mouse, in which Hap1 gene expression can be turned off
in adult mice and specifically in the hypothalamus. He will be
able to isolate neurons, culture them in the laboratory, and manipulate
them to find out how they respond to growth factors or drugs.
By changing Hap1, either through deletions or over-expressions
of the protein’s genes, he can regulate eating behavior
in the mice. This work, he hopes, eventually will lead to treatments
for eating disorders and obesity.
“We now know that Hap1 has
multiple functions,” says Li. One is in the development
of the brain itself. Another is for regulating neuronal function
in the hypothalamus, which is involved in eating behavior. We
hope that our model can help us provide a good target to find
drugs to regulate Hap1.”
Holly
Korschun is director of Research Communications. Illustration
by Penny Carter. |
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