Stimulation or drugs that target the pro-opiomelanocortin system will be effective in treating diabetes or obesity

Jun 17 2004

There’s more than one way to slim a cat - at least that’s the hope of University of Florida obesity researchers, who believe pets and even people may someday benefit from gene therapy research aimed at breaking through the biochemical bottleneck that makes many middle-aged mammals gain weight.

A study of obese, diabetic adult rats, presented today at ENDO 2004, the 86th Annual Meeting of the Endocrine Society in New Orleans, showed that gene therapy helped the animals shed extra weight and eat less by stimulating production of a brain protein called pro-opiomelanocortin, or POMC, said Philip Scarpace, a professor of pharmacology and therapeutics with UF’s College of Medicine. The rats also showed improvement in several biochemical measurements related to diabetes.

“This study demonstrates ... that stimulation or drugs that target the POMC system will be very effective in treating diabetes or obesity,” said Scarpace, who also is affiliated with UF’s McKnight Brain Institute.

Obesity in the United States has reached epidemic proportions, with about 24 percent of U.S. adults 20 years and older considered obese, according to estimates from a National Center for Health Statistics survey conducted in 2003. The survey found the prevalence of obesity in both men and women was highest among those 40 to 59 years old, considered middle-aged.

The UF study apparently side-stepped a problem that has long vexed obesity researchers: the body’s resistance to leptin, a hormone produced in fat tissue, which helps initiate a biochemical chain reaction that controls appetite and energy expenditure. Ironically, overweight mammals produce so much of the hormone that the brain resists its effects for reasons scientists do not yet understand.

“Our idea was that maybe we could get around leptin resistance by stimulating downstream in the leptin pathway,” Scarpace said. “And one of the substances that leptin activates is POMC.”

Although the study is a preliminary step, and the researchers say a healthy diet and exercise are still the best remedies, the principle behind it might help researchers develop treatments for human patients, and also obese dogs and cats, he said. Scarpace and co-author Dr. Gang Li, a UF research associate, introduced a gene therapy solution directly into rats’ brains, but improved methods might make it possible to send the genes through less-critical parts of the body and direct them to specific sites in the brain.

Gene therapies to boost POMC production might have an advantage over some of the other weight-loss drugs that companies are working to develop, because the body’s natural regulatory mechanisms might reduce or stop POMC production as needed, Scarpace said. Levels of POMC, which is produced at multiple locations in the body, including the skin, pituitary gland and brain, frequently decline as mammals grow older.

In the study, 24 middle-aged male rats 22 months old were divided into four groups. One was a control group that received no injection, and another was a control group that received the solution without the therapeutic genes. A third group was injected with a solution containing the gene that controls POMC production, and the remaining group was given a solution containing a gene that produces a fluorescent protein with no therapeutic effect. The genes were delivered through the solution using a form of the apparently harmless adeno-associated virus.

In the three injected groups the solution was delivered into a specific region of the hypothalamus, a primitive part of the brain that controls many basic body functions. The rats that received the solution without any genes and the rats that received the fluorescent protein showed similar, temporary decreases in food intake and weight compared with the group that received no injection. These results suggested the procedure used to deliver the solution had a temporary effect on body weight regulation, Scarpace said.

The six rats that received the POMC gene steadily lost weight and 42 days after the injection were 19 percent lighter overall than those in the group that received the fluorescent protein. Those that received the POMC gene showed a substantial - though temporary - decrease in food consumption, and two measurements related to diabetes, glucose metabolism and insulin sensitivity, improved 19 percent compared with rats in the fluorescent protein group.

UF researchers plan to investigate over the next one to two years the long-term effects of the gene therapy on rats with diet-induced obesity as well as other animals with age-related obesity, Scarpace said.

Scarpace’s research suggests that age-related obesity actually may be caused by POMC deficiency rather than leptin resistance, said obesity researcher Charles V. Mobbs, an associate professor with the Mount Sinai School of Medicine in New York City.

“The fact that he’s been able to show that POMC replacement in fact can reduce obesity in older animals strongly supports the hypothesis that POMC itself may be the problem, rather than leptin,” Mobbs said.