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University of Florida scientists have successfully used gene therapy to control appetite and weight in obese animal models, they announced this week.

While testing in humans is years away, the research holds promise that a single injection may someday be a viable option for treating obesity, a widespread health problem that continues to defy most control efforts. The researchers are scheduled to present their findings Thursday (6/10/99) at the annual meeting of the American Society of Gene Therapy in Washington, D.C.

"This would be the couch potato's dream: You can eat what you want but stay lean," said Sergei Zolotukhin, a research associate professor of molecular genetics and microbiology in UF's College of Medicine.

An estimated 54 percent of adults in the United States are overweight, according to the National Institutes of Health. Treating obesity and its related conditions, including high blood pressure, heart disease and diabetes, is estimated to cost more than $45 billion annually, according to an August 1996 Scientific American article.

"With the incidence of obesity on the rise in the United States, we need to develop therapies that will alleviate the symptoms associated with obesity," said Harveen Dhillon, a third-year College of Medicine graduate student in UF's interdisciplinary biomedical sciences program. Dhillon is the research team's lead presenter at this week's meeting.

The UF scientists injected mice and rats with genes that increased the production of two appetite-controlling compounds already existing in the body-leptin and ciliary neurotrophic factor, or CNTF.

Leptin is a naturally occurring protein produced by fat cells that inhibits appetite and increases energy expenditure. It signals the brain, affecting the brain's secretion of appetite-regulating signals. Such signals include neuropeptide Y, a chemical that UF researchers found stimulates appetite, said Satya Kalra, a professor of neuroscience in UF's College of Medicine. This process is thought to be faulty in most obese people so that even high levels of leptin fail to turn off the hunger signal.

"The concept is that if you can turn off the production of neuropeptide Y and other appetite-stimulating signals by increasing leptin levels, it is possible to control body weight," said Kalra, who also is affiliated with UF's Gene Therapy Center and UF's Brain Institute.

Researchers injected leptin-producing genes into obese mice that did not produce the protein. To deliver the genes, researchers used a molecular vehicle known as the adeno-associated virus, a harmless virus that already exists in the majority of the adult human population. The genes were engineered to be passengers inside the vehicle virus.

Once inside the mice, the genes integrated into their cells and acted like small factories, producing increased levels of leptin. The result was weight loss in less than three weeks. Normal, lean rats given the leptin genes maintained their body weight for three months, the duration of the experiment.

Because some obese people have a resistance to leptin, the research team also experimented with an alternative appetite-suppressing protein, CNTF.

"CNTF doesn't naturally secrete from a cell, but we wanted it to be secreted and get into the brain and signal to the cells that the person should stop eating," Zolotukhin said. "So we had to redesign CNTF and put a secretion signal that now drives it out of the cell and into circulation."

The enhanced CNTF gene was inserted into the adeno-associated virus and administered to rats. After six weeks, researchers observed a decrease in body weight and food intake in the rats similar to that in the mice treated with the leptin gene. The CNTF rats have been under observation for six months and had no side effects.

UF researchers now are looking to evaluate other proteins that affect appetite control. Kalra said human application of these drugs still is in the distant future. Clinical study of CNTF and leptin gene therapy in humans will not be approved until researchers can prove that these gene treatments are safe and without side effects.

Recent UF Health Science Center news releases are available at www.health.ufl.edu/hscc/index.html. Thursday, May 20, 1999 University of Florida Health Science Center and Shands HealthCare. For more information, please call 352/392-2755 or e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

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