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.
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
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.
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
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
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.”
Korschun is director of Research Communications. Illustration by Penny