10/3/97
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Rosanne Spector, (415) 723-6911; e-mail [email protected]
RESEARCHERS DISCOVER NEW TARGET FOR OBESITY DRUGS
STANFORD -- Using clues from a fat, yellow mouse, researchers at Stanford University School of Medicine and the University of Michigan have identified a new cog in the body's main weight-regulating system. The protein they discovered may join leptin, a protein identified in 1994, as a prime target for the development of drugs to fight obesity, said Dr. Gregory Barsh, an associate professor of pediatrics and genetics at Stanford and the senior author of the study.
The researchers describe their finding in the Oct. 3 issue of the journal Science.
Leptin is produced by fat cells as a signal that the body has sufficient energy stores. When laboratory mice are injected with high levels of leptin, they initially decrease their food intake, increase their metabolic rate and become much thinner. But eventually the body adapts to the high levels of leptin and becomes resistant to its effects. "To overcome leptin resistance," said Barsh, "you need to move in further down the body's weight-regulating pathway."
The newly identified protein, agouti-related protein (AGRP), may be an ideal target for such an approach, he said.
The color of mouse hairs provided the clue leading to AGRP's discovery. Barsh was searching for proteins similar to agouti, a protein normally produced only in the skin. When a pulse of agouti alters pigment production in hair cells, the black hairs of a mouse get a tiny yellow stripe, and from a distance the mouse looks brown.
In 1992, Barsh's laboratory (and that of Rick Woychick at the Oak Ridge National Laboratory in Tennessee) isolated the mouse and human genes coding for agouti and found that some mice with a mutation in this gene produced agouti continuously and throughout the body. This made the mutant mice both yellow and obese.
While the coloring made sense, the obesity was unexpected. It suggested, said Barsh, that a protein similar to agouti was being produced elsewhere in the body and regulating weight. Only when agouti was made throughout the body could it disrupt the normally fine-tuned operations of this related protein.
A search of a DNA-sequence database turned up AGRP, and the researchers confirmed that AGRP was produced in the adrenal gland and the hypothalamus -- two areas known to be involved in weight regulation.
When the researchers made transgenic mice that produce large amounts of AGRP, the mice were noticeably weightier than their normal littermates as early as four weeks of age. By maturity, the transgenic mice were 70 to 100 percent heavier than normal mice. Their body length and food consumption were also greater than normal.
In the past, several other proteins have been shown to affect weight regulation. One of these is the melanocortin 4 receptor (MC4-R), which Barsh believes is switched off by AGRP. The stumbling block for scientists, he said, has been tying any of these proteins to the leptin pathway. "It's a reasonable hypothesis that proteins like the MC4-R direct weight regulation based on instructions from leptin, but they could just as well be involved in some other pathway," Barsh said.
In this case, however, the researchers found that mice deficient in leptin produced eight times more AGRP than normal. This suggests that leptin normally controls AGRP by keeping its levels in check. "These data are the strongest yet for identifying a component of the leptin pathway," said Barsh.
The experiments place AGRP further down than leptin in the obesity chain of command, so a drug that modifies the action of AGRP might bypass the adaptation response that eventually negates the effects of leptin administration.
"There are now two avenues to pursue," said Barsh. Drug companies could look for small molecules that either block the production or action of AGRP or stimulate the MC4-R (or its relative the MC3-R, which may also be involved in the response).
Drugs targeting the leptin/AGRP pathway would be unlikely to run into the same problems encountered with Redux and Pondimin, two diet drugs removed from the market in September at the request of the FDA because of an association with heart valve damage. These two drugs do not regulate the leptin pathway, but rather boost the levels of a brain messenger called serotonin to make patients feel more full.
Barsh's co-workers on the AGRP studies at Stanford were graduate students Michael Ollmann, Brent Wilson and Julie Kerns; and postdoctoral fellow Yanru Chen. Collaborators at the University of Michigan School of Medicine were postdoctoral fellow Ying-Kui Yang and Dr. Ira Gantz, associate professor of surgery.
Barsh is a Howard Hughes Medical Institute associate investigator and received additional funding from the National Institute of Diabetes and Digestive and Kidney Diseases.
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