1/8/98
MEDIA CONTACT:
Rosanne Spector, (650) 723-6911, e-mail [email protected]; or
Janet Basu, (650) 723-7582, e-mail [email protected]
FOR COMMENT:
To contact Thomas Kilduff directly, call (650) 723-9380 or e-mail [email protected]
FOR IMMEDIATE RELEASE
SCIENTISTS IDENTIFY TANTALIZING NEW BRAIN MESSENGERS
STANFORD -- Researchers have discovered two chemical messengers in the brain that may lead to new insights into weight control.
The messengers, or neurotransmitters, are described by scientists from Stanford University and four other institutions in the Jan. 6 Proceedings of the National Academy of Sciences.
"The discovery of a new neurotransmitter is always significant, but the location of these neurotransmitters in the brain makes this work particularly exciting," said senior research scientist Thomas Kilduff, a co-author on the research paper and director of molecular neurobiology at Stanford's Center for Sleep and Circadian Neurobiology.
The two newly identified neurotransmitters, dubbed hypocretins, are made only in a brain region called the hypothalamus. This pea-sized structure, located deep in the brain, controls such basic functions as temperature regulation, fluid balance, hunger and feeding behavior.
The hypocretins are made by only a few groups of cells in the hypothalamus. In other studies, researchers have linked cells in this area to the control of food consumption. "If you show the pictures of where the hypocretins are to anyone in the field, they will think of energy balance and food intake," said Kilduff, who holds dual appointments in the departments of biological sciences and psychiatry at Stanford.
The discovery of the hypocretins began with work by J. Gregor Sutcliffe, Luis de Lecea and their colleagues at the Scripps Research Institute in La Jolla, Calif. Sutcliffe's group isolated a large number of genes whose products are made only in the hypothalamus. Intrigued that the product of the hypocretin gene is made in only a tiny portion of the hypothalamus, the Scripps researchers teamed up with Kilduff and others to study that gene further.
Nerve cells chemically chop the gene's protein product into two short segments, called peptides. The researchers focused one of these peptides, known as hypocretin 2.
Hypocretin 1 and 2 are similar to each other, Kilduff said. They are also somewhat similar to the hormone secretin, which controls the secretion of gastric acids in the stomach. Other peptides have been found to have roles in both the stomach and the brain, he noted.
Kilduff and his colleagues found that hypocretin 2 meets three criteria necessary to be considered a neurotransmitter: It is made in nerve cells (neurons), it ends up in special compartments called vesicles that the neuron uses to store neurotransmitters, and, when added to neurons in culture, it triggers them to send an electrical message.
Hypocretins join a growing list of neurotransmitters, including a handful of small molecules and more than 50 peptides. Neurons release neurotransmitters in response to various signals. The neurotransmitters then latch on to a nearby neuron, causing it to fire an electrical signal from one end of the cell to the other. Once the electrical signal reaches its destination, it can cause another round of neurotransmitter release and signal generation.
The hypocretins may have functions other than weight control, noted Kilduff, so their proposed role in obesity must be confirmed by further experiments. The scientists now plan to test the effects of supplying excess hypocretins or preventing hypocretin production in experiments with mice or rats.
If it turns out that the hypocretins are involved in weight control, researchers will also want to know how the peptides fit in with the other proteins, such as leptin, that have demonstrated roles in weight control.
With all the corporate and public interest in obesity-related pharmaceuticals, Kilduff believes there will be plenty of others vying to do this follow-up work. He and his colleagues first presented the newly published work in the form of adjacent posters at the Society for Neuroscience meeting in New Orleans last October. "I've never had so many people come by a poster," he said. "One guy from a major pharmaceutical company was there for over an hour, memorizing everything."
Kilduff and Sutcliffe's collaborators in this work were Christelle Peyron and Chiaki Fukuhara, Stanford postdoctoral fellows; Anthony van den Pol, a Stanford visiting scholar and professor of neurosurgery at Yale; Xiao- Bing Gao of Yale; Luis de Lecea, Pamela Foye, Patria Danielson, Elena Battenberg and Dr. Floyd Bloom of Scripps; Vigdis Gautvik and Dr. Kaare Gautvik of the University of Oslo; and Frederick Bartlett II and Wayne Frankel of the Jackson Laboratory in Bar Harbor, Maine.
Kilduff's work was supported by grants from the National Institute on Aging and the Army Research Office. Additional funding for the study came from the Air Force Office of Scientific Research, the Norwegian Research Council, the Fyssen Foundation, and Digital Gene Technologies of La Jolla, Calif.
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