http://www.nytimes.com/2005/11/11/health/11hunger.html


In Study, Hormone Reduced Appetite in Mice
By DENISE GRADY

Hungry or full, fat or thin: it is mostly a matter of hormones,
dozens of them, carrying messages between the digestive tract,
the fat cells and the brain. Eat. Don't eat. Burn calories.
Store fat.

Today, researchers at Stanford University are reporting that
they have found a previously unknown member of this chemical
cascade, a hormone with a much coveted power: it sharply reduces
the desire to eat.

The new substance, which the scientists named obestatin
(OHB-statin), is made in the stomach and small intestine, and
it seems to prompt the brain to send out a signal that says
"eat less."

Mice given the hormone for eight days ate half as much as usual
and lost weight, the researchers are reporting today in the
journal Science. The hormone seems to reduce hunger in part by
slowing the passage of food through the stomach and small
intestine.

The study's director, Dr. Aaron Hsueh, said obestatin had not
been studied in people and had been tested only in mice.

But Stanford issued a statement saying Johnson & Johnson,
which sponsored the research, has rights to the discovery. With
obesity rates shooting up worldwide, drug companies are
scrambling to develop weight-loss drugs, especially appetite
suppressants.

Dr. David E. Cummings, an obesity researcher at the University
of Washington, Seattle, who was not involved in the obestatin
study, said, "The chances that this is going to hold up in
humans are very high."

But it is not clear how strong a role the molecule plays in
weight control, or whether it could lead to a new drug. To be
used as a drug, obestatin would have to be injected or perhaps
made into a nose spray. It could not be taken in pill form
because it would be broken down in the stomach.

People dislike injections, so drug companies are more likely to
try to develop a molecule that mimics obestatin but can be taken
by mouth, said Dr. Rudolph Leibel, an obesity researcher at
Columbia University.

In an essay accompanying the report in Science, another obesity
expert, Dr. Matthias Tschöp, from the University of Cincinnati,
wrote that obestatin's "effect on body weight appears to be
subtle."

Although mice given the hormone eat less, they do not lose as
much weight as would be expected. Tests also suggest that the
weight they do lose might not be fat. If the drug makes muscles
shrink, that would be undesirable, Dr. Tschöp said in an
interview.

But the molecule has been studied only in normal mice, not fat
ones. Also unknown is what a mouse feels like on obestatin. Does
the hormone simply diminish appetite - or make the animal feel
sick? The answer is not obvious, because rodents do not vomit.
A drug that produced weight loss by making people throw up might
not be a good idea.

Dr. Tschöp wrote, "The search for a magic bullet against obesity
is likely to continue."

Other researchers are eager to study the molecule. Dr. Cummings
said that as soon as he heard about it he began trying to reach
Dr. Hsueh to propose that they work together to measure its levels
in humans.

One thing that especially fascinates scientists about obestatin
is its link to another hormone, ghrelin, which makes people
hungry - the opposite of obestatin.

The scientists were surprised to find that the two hormones were
products of the same gene. The gene directs cells to make one
protein molecule, which breaks into two smaller ones, called
peptides. One is ghrelin, and the other is obestatin.

The same gene is found in at least 11 species of mammals, Dr.
Hsueh and his colleagues reported, indicating that its role in
controlling food intake must be important for survival.

But Dr. Leibel said having two hormones with opposite effects
embedded in the same molecule was like driving with one foot on
the brake and one on the gas.

"One might wonder, why would you do this?" he said. "Why design
a system like this?"

Finding the answer will require more research.

The hormone's existence helps explain something that has been
puzzling scientists about ghrelin, Dr. Cummings said. When
scientists created a mouse lacking the ghrelin gene they expected
it to be extremely skinny and lack interest in food. Instead, the
mice were nearly normal.

Today's discovery may explain why: although deleting the gene
took away ghrelin, the hunger signal, it also took away obestatin,
the fullness signal. The deletion wound up having no net effect.