Dallas,
TX (2/20/98)- Hormones that stir hunger pangs have been identified
by researchers at the University of Texas. The discovery could lead to
a better understanding of appetite, obesity and diabetes, and possibly
to the development of new diet drugs.
The researchers identified two new neuropeptides which stimulated the
appetites of laboratory animals. The neuropeptides, or ligands, are called
orexin-A and orexin-B. Their names, along with those for their associated
receptors, OX1R and OX2R, derive from the Greek word orexis, for appetite.
The same word forms the root for anorexia (i.e. without appetite).
Graphic: Shows hypothalamic
localization of neurons containing the novel neuropeptide orexin that regulate
food intake behavior.
"These receptors and ligands regulate feeding behavior, which is a very
important area of medical research," said Dr. Masashi Yanagisawa, professor
of molecular genetics and Howard Hughes Medical Institute (HHMI)investigator.
"This is an excellent area for further drug research to determine whether
orexins and their G protein-coupled cell-surface receptors can be targeted
to suppress eating habits."
The scientists first found the receptors, which are closely related
proteins. When bound to ligands, the receptors trigger a G protein, which
in turn sets off a series of messages to turn on or turn off genes. Next,
they found the two ligands, members of a previously unidentified family
of neuropeptides, which bind with OX1R and OX2R to begin the signaling
cascade. These proteins are located in a portion of the brain called the
lateral hypothalamus, the region that controls appetite.
After determining that they had the locks (receptors) and keys (ligands)
that fit together to begin the intercellular communication process, the
investigators tested it on rats. They used catheters to administer some
of the neuropeptides to the animals' brains and found that the proteins
stimulated food consumption.
"When we limited the food intake of the animal, even more of the neuropeptide
was produced, which is what we expected of a hormone that physiologically
regulates appetite," Yanagisawa said. "The neuron tells the animal it is
hungry by producing more orexin peptides. Increased peptides increased
the animal's appetite. In other words, it is part of a feedback loop in
the biochemical process."
Next, the researchers will use genetic engineering to produce rodents
missing three genes -- one ligand and the two receptor genes -- to see
if the rats' appetites can be decreased by inhibiting any of them.
"These neuropeptides are a very plausible molecular basis for some classical
experiments on eating habits," Yanagisawa said. "The question is what happens
in the brain to control the highly complex feeding behavior, as well as
body weight."
The brain translates information it receives from different organs into
metabolic-rate changes, which affect how much food people consume and how
fast their bodies burn it off.
"The brain is doing a lot of things like a black box in dealing with
all this information," Yanagisawa said. Part of this biochemical process
involves maintaining equilibrium between food consumption and energy expenditure.
This helps determine whether someone becomes obese and/or develops adult-onset
diabetes mellitus.
"Now is the time when we start to understand the neural network and
the molecular players that form the very complex regulation of this entire
biochemical process of appetite," he said. "We believe that neuropeptides,
including orexins, are very important components."
The new research is expected to complement current knowledge of leptin
and other proteins involved in appetite and obesity.
The research appears in the February 20, 1998 issue of Cell
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